Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.[CH2:10]([O:12][C:13]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[C:14]#[CH:15])[CH3:11]>[Cu]I.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.C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:15]#[C:14][C:13]([O:16][CH2:17][CH3:18])([O:12][CH2:10][CH3:11])[O:19][CH2:20][CH3:21]
Reactant: C#CC(OCC)(OCC)OCC
Reactant: Clc1ccc(Br)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: CCOC(C#Cc1cc(Cl)ccc1Br)(OCC)OCC
Temperature: 23 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A suspension of 1-bromo-4-chloro-2-iodobenzene (2.5 g, 7.9 mmol), 3,3,3-triethoxyprop-1-yne (2.4 g, 13.9 mmol), copper(I) iodide, (455 mg, 2.3 mmol), and trans-dichlorobis(triphenylphosphine)palladium(II) (559 mg, 0.79 mmol) was treated with ACN (30 mL). The reaction was capped, evacuated under vacuum, backfilled with argon, and treated with TEA (9.9 mL, 71.6 mmol). The reaction was stirred at 23° C. After 2 hours, the reaction mixture was concentrated in vacuo to remove all solvents, diluted with EtOAc (250 mL), and washed with brine (150 mL). The organic layer was dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 4% EtOAc/hexane+1% TEA) affording 2.6 g of 1-bromo-4-chloro-2-(3,3,3-triethoxyprop-1-ynyl)benzene.
Reaction SMILES: Br.[CH:2]1([C:5]2[CH:6]=[CH:7][C:8]([CH:13]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH2:14][C@@H:15]3[NH:19][C:18](=[O:20])[CH2:17][CH2:16]3)=[N:9][C:10]=2[O:11]C)[CH2:4][CH2:3]1.O>O1CCOCC1>[CH:2]1([C:5]2[C:10](=[O:11])[NH:9][C:8]([C@H:13]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH2:14][C@H:15]3[CH2:16][CH2:17][C:18](=[O:20])[NH:19]3)=[CH:7][CH:6]=2)[CH2:4][CH2:3]1
Reactant: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc(Cl)c(Cl)c2)ccc1C1CC1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC[C@H](C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccc(C3CC3)c(=O)[nH]2)N1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
48% hydrobromic acid (2 mL) was added to a solution of (5R)-5-[2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(3,4-dichlorophenyl)ethyl]pyrrolidin-2-one (120 mg) in 1,4-dioxane (4 mL), and the mixture was stirred at 65° C. for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→90:10) to give an (R,S) mixture of the title compound as a brown amorphous (78 mg). This was preparatively isolated by a chiral HPLC column (CHIRALPAK IB, hexane:ethanol=20:80 v/v, 40° C., 10 mL/min, 210 nm) to give 3-cyclopropyl-6-{(1R)-1-(3,4-dichlorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-one as a colorless amorphous (33 mg) and 3-cyclopropyl-6-{(1S)-1-(3,4-dichlorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-one as a colorless amorphous (21 mg).
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([NH:22][C:23]2[N:24]=[CH:25][N:26]([CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[CH:27]=2)=[O:21])[CH2:16][CH2:15]1)[S:10]([CH3:13])(=[O:12])=[O:11])=[O:7])(C)(C)C.[ClH:41]>>[ClH:41].[ClH:41].[C:6]([CH2:8][N:9]([C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]([NH:22][C:23]2[N:24]=[CH:25][N:26]([CH:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)[CH:27]=2)=[O:21])[CH2:18][CH2:19]1)[S:10]([CH3:13])(=[O:11])=[O:12])([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CN([C@H]1CC[C@H](C(=O)Nc2cn(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)CC1)S(C)(=O)=O
Agent: Cl
Product: CS(=O)(=O)N(CC(=O)O)[C@H]1CC[C@H](C(=O)Nc2cn(C3CCNCC3)cn2)CC1

Procedure:
4-[[trans-4-(N-tert-Butoxycarbonylmethyl-N-methanesulphonyl-amino)cyclohexyl]carbonylamino]-1-(1-tert-butoxycarbonyl-4-piperidyl)imidazole is employed. By dissolving in 1N hydrochloric acid and evaporating the solvent, the hydrochloride is prepared.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:13]([C:23]([NH:25][NH2:26])=[O:24])=[N:14][C:15]([Br:22])=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.CCOC(C)=O>[NH2:11][C:12]1[C:13]([C:23]([NH:25][NH:26][C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:24])=[N:14][C:15]([Br:22])=[C:16]([C:18]([F:20])([F:21])[F:19])[N:17]=1
Reactant: NNC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)NNC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of phenyl acetic acid (95.0 mg, 0.698 mmol) in NMP (6 ml) was added a solution 3-amino-6-bromo-5-(trifluoromethyl)pyrazine-2-carbohydrazide (step 1) (250 mg, 0.837 mmol) in NMP (6 ml) followed by DIPEA (609 ul, 3.49 mmol). The resulting mixture was treated with HATU (398 mg, 1.047 mmol) portionwise and stirred at RT for 90 min. The mixture was added to EtOAc (50 ml) and washed with 0.1M NaOH (50 ml). The aqueous layer was back extracted with EtOAc (50 ml). The combined organic portions were washed with water (50 ml), brine (50 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 1:1 EtOAc/iso-hexane to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.65 (1H, s), 10.29 (1H, s), 8.02 (2H, s), 7.30 (5H, m), 3.52 (2H, s). 19F NMR (400 MHz, DMSO-d6) δ-66 (s, CF3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[C:15]([CH2:17][NH2:18])[CH:14]=[CH:13][C:12]=2[Cl:19])=[CH:5][C:4]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)=[O:22].[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1.N1C=CC=CC=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[C:15]([CH2:17][NH:18][S:34]([CH:31]3[CH2:33][CH2:32]3)(=[O:36])=[O:35])[CH:14]=[CH:13][C:12]=2[Cl:19])=[CH:5][C:4]=1[C:21]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([Br:30])=[CH:28][CH:29]=1)=[O:22]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COc1ccc(NC(=O)c2cc(CN)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc(NC(=O)c2cc(CNS(=O)(=O)C3CC3)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
A mixture of 52.5 mg N-[4-methoxy-3-(4-bromophenyl)aminocarbonyl-phenyl]-2-chloro-5-aminomethyl-benzamide (0.10 mmol), 16.8 mg cyclopropylsulphonic acid chloride (0.12 mmol), 1.0 mL pyridine and 4.0 mL acetonitrile was stirred overnight, concentrated, dissolved in 3 mL DMF and purified by prep. HPLC.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C[N:13]1[C:21]2[C:16](=[CH:17][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>>[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: Clc1ccc2ccccc2n1
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: c1ccc2nc(-c3ccc4[nH]ccc4c3)ccc2c1

Procedure:
2-(1H-indol-5-yl)quinoline was prepared using general procedure A from 2-chloroquinoline (32 mg, 0.2 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (51 mg, 0.2 mmol). The product was obtained as off-white solid (22 mg, 42%). MS (ESI): 245 (M+H+).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][CH2:38][NH2:39]>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:5])[N:39]([CH2:38][CH2:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[Cl:30])[CH2:23][CH2:22]2)[CH2:7][CH2:8]1)(=[O:13])=[O:14]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: NCCc1ccccc1Cl
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(CCc2ccccc2Cl)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(2-Chloro-phenyl)-ethylamine. MS (ESI): 467.3 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]([C:5]1[CH:10]=[C:9](I)[CH:8]=[CH:7][C:6]=1[NH:12][C:13]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])=[O:4].[CH2:32](C([Sn])=C(CCCC)CCCC)[CH2:33]CC>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:31])[C:3]([C:5]1[CH:10]=[C:9]([CH:32]=[CH2:33])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])=[O:4]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CN(C)C(=O)c1cc(I)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
To a solution of 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-dimethylcarbamoyl-4-iodophenyl)amide (1.32 g) in toluene (15 mL) were added tributylvinyltin (935 mg) and tetrakistriphenylphosphine palladium(0) (142 mg), and the mixture was stirred at 140° C. for 1.5 hours under heating. The reaction solution was allowed to stand for cooling down to room temperature, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1, v/v) to give the title compound (783 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:14]=2[N:15]=[C:16]([C:18]2[O:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[O:22]1[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:14]=3[N:15]=2)=[CH:19][CH:20]=[N:21]1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccno3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-dichlorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:30]([C:32]1[C:33](=[C:48]([C:51]#[N:52])[C:49]#[N:50])[O:34][C:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:38]([F:41])([F:40])[F:39])[C:36]=1[CH3:37])#[N:31]>C(O)C.O1CCCC1>[CH2:26]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=[CH:37][C:36]3[C:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:38]([F:41])([F:39])[F:40])[O:34][C:33](=[C:48]([C:51]#[N:52])[C:49]#[N:50])[C:32]=3[C:30]#[N:31])=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=O)cc2C)c(OC)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)cc2C)c(OC)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
In 9 ml of ethanol and 3 ml of tetrahydrofuran were dissolved 400 mg (1.02 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl) vinyl]-2,5-dimethylbenzaldehyde and 360 mg (1.14 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at 70° C. for 2 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography to give 441 mg of a black powder (yield: 62.8%; mp: 177-179° C.)
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][OH:6].[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>O1CCCC1>[OH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[C:10](=[O:11])[CH2:9][C:8](=[O:12])[CH3:7]
Reactant: C=C1CC(=O)O1
Reactant: CNCCCO
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N(C)CCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 20 g (0.23 mol) of 3-methylamino-1-propanol in 50 ml tetrahydrofuran was added dropwise to a solution of 18 g of diketene (0.21 mol) in 200 ml tetrahydrofuran −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 29.2 g (0.17 mol, 79% yield) of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.Cl.[N:25]1[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:31](=[O:32])[C:28]5[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=5)[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccncc1
Yield: 78.7 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (155 mg, 0.50 mmol), N-methylpyrrolidone (3 mL) and pyridine-4-carbonylchloride hydrochloride (107 mg, 0.60 mmol), and in the same manner as in Example 162, the title compound (163 mg, yield 78%) was obtained.
Reaction SMILES: [CH2:1]([O:3][Si:4]([C:11]1[CH2:14][CH2:13][C:12]=1[Si:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2]>[Cu]Cl>[CH2:17]([O:16][Si:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])[CH:12]1[CH2:13][CH2:14][CH:11]1[Si:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])[O:8][CH2:9][CH3:10])[CH3:18]
Reactant: CCO[Si](OCC)(OCC)C1=C([Si](OCC)(OCC)OCC)CC1
Agent: Cl[Cu]
Product: CCO[Si](OCC)(OCC)C1CCC1[Si](OCC)(OCC)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1,2-Bis(tri-ethoxysilyl)acetylene represented by formula (A) was mixed with 1.2 mol equivalent of zirconocene diethyl, and the mixture was stirred at room temperature for one hr. Subsequently, 1.2 mol equivalent of iodine was mixed thereinto, and the mixture was stirred at 0° C. for 2 hr. Finally, 1.2 mol equivalent of copper(I) chloride was mixed thereinto, and the mixture was stirred at room temperature for 6 hr. Thus, the reactions were successively performed. Thereafter, the reaction solution was filtered to remove salts. The filtrate was then concentrated under the reduced pressure, and the concentrate was purified by column chromatography on alumina to give 1,2-bis(tri-ethoxysilyl)cyclobutene as a substituted position isomer mixture at a yield of 60%. In the reaction with copper(I) chloride, the yield of bis(tri-ethoxysilyl)cyclobutene when 0.1 mol equivalent of copper(I) chloride was mixed followed by stirring at room temperature for 24 hr was identical to the yield of bis(tri-ethoxysilyl)cyclobutene when 0.1 mol equivalent of copper(I) chloride was mixed followed by stirring at 50° C. for 6 hr. Subsequently, a hydrogenation reaction is performed to give 1,2-bis(tri-ethoxysilyl)cyclobutane (I-1).
Reaction SMILES: COC[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:6]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O1CCOCC1>[C:19]1([C:6]2[C:7]([C:15]([F:17])([F:18])[F:16])=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[OH:4])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COCOc1c(-c2ccccc2)c(C(F)(F)F)cc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: Oc1c(-c2ccccc2)c(C(F)(F)F)cc2ccccc12
Yield: 96.9 %

Procedure:
1-{[(Methyloxy)methyl]oxy}-2-phenyl-3-(trifluoromethyl)naphthalene (181) (0.23 g, 0.68 mmol) was treated with 4.0M HCl in dioxane at room temperature to give 0.19 g (97%) of the title compound (182) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 5.40 (s, 1H), 7.39 (d, J=7.1 Hz, 2H), 7.48-7.58 (m, 3H), 7.58-7.66 (m, 2H), 7.86 (s, 1H), 7.88-7.94 (m, 1H), 8.24-8.30 (m, 1H). LCMS (APCI): m/z 287 (M−H)−.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10](Cl)[N:9]2[N:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:8]2[N:7]=1)(=O)C.O.[SH2:21].[Na]>CO>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([SH:21])[N:9]2[N:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:8]2[N:7]=1
Reactant: S
Reactant: COC(=O)c1nc2nc(COC(C)=O)cc(Cl)n2n1
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)c1nc2nc(CO)cc(S)n2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
Methyl 5-(acetoxymethyl)-7-chloro-s-triazolo[1,5-a]pyrimidine-2-carboxylate (380 mg) (1.33 mmol) are dissolved in 20 ml of methanol. After the addition of 296 mg (4 mmol) of sodium hydrogen sulphide monohydrate the mixture is stirred at 60° C. for 5 hours. The reaction mixture is concentrated and brought to pH 3 with dilute aqueous hydrochloric acid. The product is filtered off under suction, washed with water/methanol and crystallized from methanol. There are obtained 290 mg of methyl 5-(hydroxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine-2-carboxylate as a brown powder.
Reaction SMILES: S1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+].O[O:36][S:37]([O-:39])=O.[K+]>C(#N)C.ClCCl>[S:37]1(=[O:39])(=[O:36])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCSCC1
Reactant: O=S([O-])OO
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C1CCS(=O)(=O)CC1
Reaction time: 0.83 h
Yield: 64.7 %

Procedure:
To a stirred solution of tetrahydrothiopyran-4-one (0.400 g, 3.40 mmol) in acetonitrile (4.5 mL) was added Na2EDTA (3 mL, 0.0004 M in water). Solid NaHCO3 (2.70 g, 32.0 mmol) and OXONE (trade name, 6.30 g, 10.3 mmol) were combined separately and this dry mixture was added to the reaction mixture over 30 min. Then, the reaction was allowed to stir for 50 min. The mixture was diluted with dichloromethane (80 mL) and the white inorganic material was removed by filtration. The filtrate was dried over magnesium sulfate and concentrated to give the title compound (0.326 g, 64%) as a white solid:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:39][CH2:40][CH2:41][N:42]([CH3:50])[C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH2:40][CH2:41][N:42]([CH3:50])[C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCCCl)C(=O)OC(C)(C)C
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21)C(=O)OC(C)(C)C

Procedure:
N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (280 mg, 528 μmol), tert-butyl 3-chloropropyl(methyl)carbamate (110 mg, 528 μmol) and cesium carbonate (516 mg, 1.58 mmol) in dimethylformamide (4 mL) were heated in a microwave at 100° C. for 30 min. The mixture was partitioned between ethyl acetate and water, then the organic phase washed with water 3 times, dried, filtered and concentrated. The crude residue was used in the next step without purification. MS (M+H)+=702.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1B(O)O.[F-].[Cs+]>COCCOC.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>[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: COC(=O)c1c(Cl)cccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1c(-c2ccc(C)cc2C)cccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 47.5 %

Procedure:
A mixture containing 0.5 g (2.3 mmol) of methyl 2-chloro-6-nitrobenzoate, 0.76 g (3.5 mmol) of 2,4-dimethylphenyl boronic acid, 0.7 g (4.6 mmol) of cesium fluoride, and 0.27 g (0.23 mmol) of tetrakis(triphenylphosphine)palladium(0) in 10 ml of 1,2-dimethoxyethane was heated to 100° C. under a nitrogen atmosphere overnight. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 20% ethyl acetate/hexanes gave 0.312 g (47%) of product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[C:40]#[N:41])=[CH:4][C:5](=[O:32])[N:6]([CH:8]([CH2:25][CH2:26][O:27][C:28]([F:31])([F:30])[F:29])[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:14][CH:13]=2)=[O:10])[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[C:40]#[N:41])=[CH:4][C:5](=[O:32])[N:6]([CH:8]([CH2:25][CH2:26][O:27][C:28]([F:29])([F:30])[F:31])[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:23][CH:24]=2)=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)C(CCOC(F)(F)F)n2cc(Cl)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Cl)cc1-c1cc(=O)n(C(CCOC(F)(F)F)C(=O)Nc2ccc(C(=O)O)cc2)cc1Cl

Procedure:
142 mg (purity 81%, 0.19 mmol) of tert-butyl 4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoyl}amino)benzoate (racemate) were hydrolysed with TFA according to General Method 2. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 54 mg (52% of theory)