Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[CH3:16][S:17]([NH:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1)(=[O:19])=[O:18]>CO>[OH:1][CH:3]([CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[CH2:2][N:30]1[CH2:31][CH2:32][N:27]([C:25](=[O:26])[C:24]2[CH:33]=[CH:34][C:21]([NH:20][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:22][CH:23]=2)[CH2:28][CH2:29]1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)N2CCNCC2)cc1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CCN(CC(O)COc3cccc4ccccc34)CC2)cc1
Temperature: 25 °C

Procedure:
Add 7.89 g (42.4 mmol) of 1,2-epoxy-3-(1-naphthalenyloxy)propane to a solution of 12.0 9 (42.4 mmol) of 1-[4-[(methylsulfonyl)amino]benzoyl]piperazine in methanol. Heat the resultant solution at reflux for about 46 h. Cool the solution to room temperature and evaporate the solvent. Triturate the residue with ether toobtain crystals of the title compound.
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH2:21](I)[CH2:22][CH3:23]>>[C:2]1([N:1]=[C:8]2[N:13]([CH2:21][CH2:22][CH3:23])[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[N:18][C:10]=3[S:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCI
Reactant: O=c1nc(Nc2ccccc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: CCCn1c(=Nc2ccccc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 255 mg of 2-anilino-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 9 mg of lithium hydride and 0.098 ml of propyl iodide were used. As a result, 212 mg of 2-phenylimino-3-propyl-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: O1CCOCCOCCOCCOCCOCC1.CC(C)([O-])C.[K+].[N+:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([C:37]([NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38])=[CH:31]2)([O-:27])=[O:26].Br[CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>ClCCl.C1COCC1>[NH:39]([C:37]([C:32]1[N:33]([CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:34]2[C:30]([CH:31]=1)=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:36][CH:35]=2)=[O:38])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C(Nc1ccccc1)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cn1c(C(=O)Nc2ccccc2)cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under argon, 328 mg (1.24 mmol) of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) are initially charged in 61 ml of dichloromethane, and 15 ml (14.93 mmol) of a 1-molar potassium tert-butoxide solution in THF and 3.50 g (12.44 mmol) of 5-nitro-N-phenyl-1H-indole-2-carboxamide from Example XLVIII are added. The mixture is stirred at RT for 15 minutes and then cooled to. 0° C. A solution of 3.64 g (18.67 mmol) of tert-butyl bromoacetate in 100 ml of THF is slowly added dropwise. The ice-bath is removed and the mixture is stirred at RT overnight. For work-up, the mixture is diluted with water and the THF is removed under reduced pressure using a rotary evaporator. The aqueous residue is extracted with ethyl acetate and the organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[N:44]([CH:47]1[CH2:51][CH2:50][S:49](=[O:53])(=[O:52])[CH2:48]1)=[C:45]=[O:46]>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:45]([NH:44][CH:47]4[CH2:51][CH2:50][S:49](=[O:53])(=[O:52])[CH2:48]4)=[O:46])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: O=C=NC1CCS(=O)(=O)C1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)NC2CCS(=O)(=O)C2)CC1

Procedure:
In a manner similar to the method described in example 160, (4-amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with 3-isocyanato-tetrahydro-thiophene 1,1-dioxide (Chembridge) to give a mixture of diasteremers. The diastereomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Whelk-O column, eluting with 40% isopropanol in carbon dioxide) to give the title compound as post-peak. HR-MS (ES, m/z) calculated for C39H49Cl2N6O5 [(M+H)+] 783.2857, observed 783.2857.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[NH:4][CH:5]1[C:9]([C:10]#[N:11])=[CH:8][S:7][CH2:6]1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[NH:4][C:5]1[C:9]([C:10]#[N:11])=[CH:8][S:7][CH:6]=1
Reactant: N#CC1=CSCC1Nc1c(Cl)cccc1Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cscc1Nc1c(Cl)cccc1Cl
Yield: 75 %

Procedure:
A solution of 0.27 part of 3-(2',6'-dichloro-anilino)-4-cyanodihydrothiophene in 15 parts by volume of dry methylene chloride is added, in the course of 30 minutes, to a solution of 0.12 part by volume of sulfuryl chloride in 15 parts by volume of dry methylene chloride at 0° C. The end product is isolated from the reaction mixture by the method described in Example 1c. 0.20 (75% of theory) of 3-(2',6'-dichloroanilino)-4-cyanothiophene of melting point 105°-108° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].O>C(Cl)Cl>[Si:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a stirred solution of 4-hydroxybenzaldehyde (20.0 g, 0.16 mol) in 200 mL of CH2Cl2 at 0° C., imidazole (24.5 g, 0.36 mol) and tBuSiMe2Cl (27.2 g, 0.18 mol) were added. The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was poured into H2O and extracted with CH2Cl2. The organic phase was dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes:ethyl acetate=50:1 (v/v)) to give colorless oil (35.1 g, 90.7%). 1H NMR (300 MHz, CDCl3, δ): 9.86 (s, 2H), 7.77 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 0.97 (s, 9H), 0.23 (s, 6H). 13C{1H} NMR (75 MHz, CDCl3, δ): 190.76, 161.49, 131.87, 130.50, 120.47, 25.55, 18.25, −4.37. HRMS-FAB (m/z): [M+H]+ calcd for C14H23O2Si, 251.1467; found, 251.1469.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]([C:13](OC)=[O:14])[C@@H:11]([C:17](O)=[O:18])[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C(O)(C)C>[CH2:20]([N:10]1[C@H:11]2[CH2:17][O:18][C:13](=[O:14])[C@H:12]2[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@H]1[C@@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
A solution of (4S,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (mp., 149°-150° C., [α]36525 =-27.6° at c=1 in DMF, 368 mg) in isopropanol (6 ml) was added dropwise to a mixture of sodium borohydride (98 mg) and isopropanol (8 ml) at 5°-10° C. The obtained mixture was allowed to warm up to room temperature for 20 hours. Then, 1N hydrochloric acid (10 ml) was added to the reaction mixture. The mixture was stirred at 55°-60° C. for 30 minutes and concentrated under reduced pressure. The residue was extracted with chloroform (30 ml) and water (30 ml). The chloroform layer was washed successively with 5% aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel column to yield (3aS,6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione (82 mg). M.P., 116°-117° C. [α]D25 =+61.2° (c=1, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: Fc1ccc(CNc2nc(-c3cnccn3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2(pyrazin-2-yl)-4-(4-fluorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:40])[NH:14][CH2:15][C:16]2[CH:20]=[CH:19][N:18]([C:21]3[CH:30]=[C:29]4[C:24]([NH:25][C:26](=[O:35])[C:27](=[O:34])[N:28]4[CH2:31][CH2:32][OH:33])=[CH:23][C:22]=3[C:36]([F:39])([F:38])[F:37])[CH:17]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Li+]>>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:40])[NH:14][CH2:15][C:16]2[CH:20]=[CH:19][N:18]([C:21]3[CH:30]=[C:29]4[C:24]([NH:25][C:26](=[O:35])[C:27](=[O:34])[N:28]4[CH2:31][CH2:32][OH:33])=[CH:23][C:22]=3[C:36]([F:39])([F:37])[F:38])[CH:17]=2)=[CH:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(NC(=O)NCc2ccn(-c3cc4c(cc3C(F)(F)F)[nH]c(=O)c(=O)n4CCO)c2)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(NCc1ccn(-c2cc3c(cc2C(F)(F)F)[nH]c(=O)c(=O)n3CCO)c1)Nc1ccc(C(=O)O)cc1
Yield: 94.1 %

Procedure:
0.66 g (1.2 mmol) of the compound from Example 7 and 0.14 g (8.6 mmol) of lithium hydroxide were reacted via the method of Example 4, resulting in 0.6 g (89%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.Br[CH2:25][CH2:26][O:27][CH3:28]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][N:19]([CH2:25][CH2:26][O:27][CH3:28])[C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1
Reactant: COCCBr
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1cc[nH]c(=O)c1
Product: COCCn1ccc(-n2c(C)nc(C#Cc3ccnc(Cl)c3)c2C)cc1=O

Procedure:
The title compound, light brown solid, MS: m/e=382.3, 384.1 (M+H+), was prepared in accordance with the general method of example 3 from 4-[4-(2-chloro-pyridin-4-ylethynyl)-2,5-dimethyl-imidazol-1-yl]-1H-pyridin-2-one and 2-bromoethyl-methylether.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8].[C:9]1([S:19](Cl)(=[O:21])=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>CC(C)=O>[OH:1][N:2]1[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8].[C:9]1([S:19]([O-:21])(=[O:1])=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: O=C1C=CC(=O)N1O
Solvent: CC(C)=O
Product: O=S(=O)([O-])c1cccc2ccccc12
Yield: 135 %

Procedure:
120 ml of acetone was added to 5.7 g of N-hydroxymaleimide and 11.3 g of 1-naphthalenesulfonyl chloride and then the same procedure as that of Preparation Example 1 was repeated to obtain 10.9 g of N-hydroxymaleimide-1-naphthalenesulfonate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]1)=[O:9].O.NN.I([O-])(=O)(=O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CS(C)=O.S([O-])([O-])(=O)=O.[Cu+2].C(O)(=O)C.O.ClCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]1)=[O:9]
Reactant: CCOC(=O)C1CCCN(C(=O)C=Cc2cccs2)C1
Agent: [Cu+2]
Agent: NN
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1CCCN(C(=O)CCc2cccs2)C1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
Ethyl 1-(3-(2-thienyl)acrylyl)-3-piperidinecarboxylate (404.1 mg; 1.38 mmol) was suspended in dimethyl sulfoxide (8 ml). The suspension was treated with hydrazine hydrate (1.7 ml; 54.7 mmol), saturated aqueous copper sulfate solution (6 drops), and glacial acetic acid (6 drops). This mixture was then stirred at ambient temperature and sodium periodate (1.47 g; 6.87 mmol) in water (20 ml) was added dropwise. After stirring an additional 1 hour, the mixture was taken up between aqueous 5% sodium thiosulfate and dichloromethane. The dichloromethane was separated, dried with anhydrous potassium carbonate, and evaporated at ambient temperature under reduced pressure. The crude product was purified by reverse phase chromatography on a C18 column, eluting with 30:70 to 40:60 acetonitrile:water as a step gradient, giving ethyl 1-(3-(2-thienyl)propionyl)-3-piperidinecarboxylate (138 mg) as a colorless oil. MS m/z (positive ion) 296 (MH+; 100).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[O:15][C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)=[N:13][N:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][CH:54]([O:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[Cl:64])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[Cl:64][C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=1[O:57][CH:54]1[CH2:53][CH2:52][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:20](=[O:22])[C:19]2[CH:18]=[CH:17][C:16]([C:14]3[O:15][C:11]([CH3:10])=[N:12][N:13]=3)=[CH:24][CH:23]=2)[CH2:56][CH2:55]1
Reactant: Cc1nnc(-c2ccc(C(=O)O)cc2)o1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C(=O)NCC(=O)N3CCC(Oc4ccccc4Cl)CC3)cc2)o1
Reaction time: 0.03 h
Yield: 22.9 %

Procedure:
DIPEA (180 mg, 1.47 mmol) was added to a stirred solution of 1 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid (100 mg, 0.48 mmol) in DMF (2 mL) followed by HOBt (79 mg, 0.58 mmol) and EDCI (113 mg, 0.587 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (179 mg, 0.587 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure The residue was purified by preparative HPLC to afford 50 mg (22.52% Yield) of N-{2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzamide. LC/MS [M+H]+: 93.97%. 1H NMR (300 MHz, DMSO-d6): δ 8.8 (s, 1H), 8.2-7.9 (m, 4H), 7.5-7.2 (m, 3H), 7.0 (bt, 1H), 4.8 (bs, 1H), 4.2 (bs, 2H), 3.7 (bs, 2H), 3.5 (m, 2H), 2.7-2.5 (m, 3H), 2.1-1.5 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:30]([O:29][C:28]([NH:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(NCCCO)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccccc2)c(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccccc2)c(OCCCNC(=O)OCc2ccccc2)c1
Reaction time: 3 h
Yield: 152.6 %

Procedure:
A solution of tert-butyl N-(2-hydroxybiphenyl-4-yl-methyl)carbamate (0.30 g), benzyl N-(3-hydroxypropyl)-carbamate (0.273 g) and triphenylphosphine (0.342 g) in tetrahydrofuran (4.0 mL) was stirred at 50° C. for 30 minutes. Then diisopropyl azodicarboxylate (40% toluene solution, 0.701 mL) was added dropwise, and the resulting mixture was stirred at50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethylacetate=3/1) to give the title compound (0.750 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:25])=[C:11]([C:14]3[C:15]([O:23][CH3:24])=[N:16][C:17]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=3)[CH:12]=2)[N:7](S(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:25])=[C:11]([C:14]3[C:15]([O:23][CH3:24])=[N:16][C:17]([N:20]([CH3:21])[CH3:22])=[CH:18][CH:19]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c2cc(Cl)c(-c3ccc(N(C)C)nc3OC)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(N(C)C)nc3OC)cc12
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To a solution of Intermediate 6-chloro-5-(6-dimethylamino-2-methoxy-pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-indole-3-carboxylic acid methyl ester (109 g, 212 mmol) in THF (1000 mL) at room temperature was added tetrabutylammonium fluoride (1.0 M in THF, 400 mL, 400 mmol). The reaction was stirred at reflux for 3 h before cooling to room temperature and diluting with ethyl acetate (2000 mL). This was washed with sat. aq. NaHCO3 (2×750 mL), sat. aq. NH4Cl (2×750 mL), water (750 mL), and brine (750 mL), and then dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with methanol (˜500 mL) and filtered. The solids were washed with methanol (300 mL) and suction dried overnight to afford desired product (71.8 g, 94%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ=11.99 (s, 1 H) 8.13 (s, 1 H) 7.82 (s, 1 H) 7.57 (s, 1 H) 7.32 (d, J=8.20 Hz, 1 H) 6.22 (d, J=8.20 Hz, 1 H) 3.78 (s, 3 H) 3.76 (s, 3 H) 3.07 (s, 6 H); MS (ES+) 360.1 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:4][N:3]1[C:14]1[C:15](=[O:28])[NH:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=2.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:4][N:3]1[C:14]1[C:15]([O:28][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
To a solution of (S)-methyl 3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (800 mg, 2.11 mmol) in dichloromethane (20 ml) under an inert atmosphere of nitrogen, was added TEA (958 mg, 9.47 mmol) followed by addition of Tf2O (1.19 g, 4.22 mmol) dropwise at −60° C. After stirring 5 min at this temperature, the reaction was quenched by the addition of water (100 ml), extracted with dichloromethane (2×30 ml), dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (2% ethyl acetate in petroleum ether) to afford (S)-methyl 3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (0.9 g, 83.4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])C#N)=[CH:4][CH:3]=1.OS(O)(=O)=O.O.[C:25]([O-:28])([O-])=[O:26].[Na+].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])[C:25]([OH:28])=[O:26])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CN1CCCC1CCC(C#N)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCCC1CCC(C(=O)O)c1ccc(Br)cc1

Procedure:
The oily residue of 2-(4-bromo-phenyl)-4-(1-methyl-pyrrolidin-2-yl)-butyronitrile was hydrolyzed by refluxing for 2 h with concentrated H2SO4 and water (38:28) (4 mL). The mixture was neutralized with Na2CO3, then MeOH (20 mL) was added. The solid was filtered and washed with MeOH (3×10 mL). The combined methanol solution was evaporated to give an oil product. MS: calc'd 326 (MH+), exp 326 (MH+).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[N:24]([C:30](=[O:32])[CH3:31])[N:23]=3)[C:18](Br)=[CH:17][N:16]=2)=[CH:13][CH:14]=1)=[O:9])(=[O:3])[CH3:2].CCN(CC)CC.[C:41]([Si:43]([CH3:46])([CH3:45])[CH3:44])#[CH:42]>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.[Cu]I.C1COCC1>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[N:24]([C:30](=[O:32])[CH3:31])[N:23]=3)[C:18]([C:42]#[C:41][Si:43]([CH3:46])([CH3:45])[CH3:44])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)NCCNC(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)n(C(C)=O)n3)n2)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCNC(=O)c1ccc(-c2ncc(C#C[Si](C)(C)C)c(Nc3cc(C4CC4)n(C(C)=O)n3)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
Step 5 A mixture of N-(2-acetamidoethyl)-5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-bromopyrimidin-2-yl)thiophene-2-carboxamide (294.0 mg, 0.5 mmol, 1.0 eq), Pd(PPh3)2Cl2 (40.8 mg, 0.5 mmol, 0.1 eq) and CuI (9.5 mg, 0.05 mmol, 0.1 eq) was flushed with nitrogen. Anhydrous THF (10 mL) and Et3N (154.5 mg, 1.5 mmol, 3.0 eq) were added and the reaction mixture was flushed with nitrogen. Ethynyltrimethylsilane (149.9 mg, 1.5 mmol, 3.0 equiv.) was added and the reaction mixture was stirred at room temperature for 1 h. Then, the reaction mixture was concentrated to 5 mL. The conc. liquid was extracted with EtOAc and washed with water, brine. The organic layers were concentrated to afford the residue, which was purified by silica gel chromatography (PE/EA/MeOH=2:1:0.06 as eluant) to afford N-(2-acetamidoethyl)-5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-((trimethylsilyl)ethynyl) pyrimidin-2-yl)thiophene-2-carboxamide (96.1 mg, 35.2%) as pale yellow solid. LC-MS (m/z)=549.9 [M+H]+
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]([CH3:10])[C:8](=[O:11])[N:7]([CH3:12])[C:6](=[O:13])[C:5]=1[CH:14]=O)[CH3:2].Cl.[CH3:17][O:18][NH2:19]>>[CH3:17][O:18][N:19]=[CH:14][C:5]1[C:6](=[O:13])[N:7]([CH3:12])[C:8](=[O:11])[N:9]([CH3:10])[C:4]=1[S:3][CH2:1][CH3:2]
Reactant: CON
Reactant: CCSc1c(C=O)c(=O)n(C)c(=O)n1C
Agent: Cl
Product: CCSc1c(C=NOC)c(=O)n(C)c(=O)n1C

Procedure:
The process described in Method A was followed. 6-(Ethylthio)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (Example 23, Step 1) (0.148 mg, 0.65 mmol) and methoxyamine hydrochloride (0.072 mg, 0.86 mmol) were used to obtain the title compound.