Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[I:19]CI.N(OCCC(C)C)=O>C(#N)C>[I:19][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cnn(-c2cccc(F)c2)c1N
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(F)c2)c1I
Temperature: 50 °C
Yield: 78.8 %

Procedure:
Ethyl 5-amino-1-(3-fluorophenyl)-1H-pyrazole-4-carboxylate (518 mg, 2.08 mmol) was suspended in acetonitrile (5 mL) at ambient temperature. Diiodomethane (675 μL, 8.38 mmol) was added followed by isopentyl nitrite (565 μL, 4.21 mmol). The reaction was heated at 50° C. for one hour and was then partitioned between water and ethyl acetate. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After removal of solvents under reduced pressure, the crude material was purified using silica gel column chromatography (10-25% ethyl acetate in hexanes) to afford ethyl 5-iodo-1-(3-fluorophenyl)-1H-pyrazole-4-carboxylate (589 mg, 1.64 mmol, 79% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[C:12]([CH3:24])=[N:13][N:14](COCC[Si](C)(C)C)[CH:15]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][C:32]([F:35])([F:34])[F:33].NC1N=C(NC(C2C(C)N(COCC[Si](C)(C)C)NC=2)=O)C=CC=1C1C=CC=CC=1OC(F)(F)F.Cl>CO.O.O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[C:12]([CH3:24])=[N:13][NH:14][CH:15]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][C:32]([F:33])([F:35])[F:34]
Reactant: Cc1nn(COCC[Si](C)(C)C)cc1C(=O)Nc1ccc(-c2ccccc2OC(F)(F)F)c(N)n1
Agent: CC1C(C(=O)Nc2ccc(-c3ccccc3OC(F)(F)F)c(N)n2)=CNN1COCC[Si](C)(C)C
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Cc1n[nH]cc1C(=O)Nc1ccc(-c2ccccc2OC(F)(F)F)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
A mixture of N-{6-amino-5-[2-(trifluoromethoxy)phenyl]pyridin-2-yl}-3-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide and N-{6-amino-5-[2-(trifluoromethoxy)phenyl]pyridin-2-yl}-3-methyl-2-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (Preparation 18 as a mixture of regioisomers, 0.050 g, 0.1 mmol) was stirred in methanol (1 ml) and water (0.5 ml). To this was added HCl in 1,4-dioxane (1 ml). The reaction was stirred at room temperature for 18 hours. A further 1 ml of HCl in 1,4-dioxane was added and the reaction stirred for a further 72 hours at room temperature before concentrating in vacuo. The residue was partitioned between ethyl acetate and water. The organic extract was dried over MgSO4 and concentrated in vacuo to yield a gum. The gum was purified by trituration with diethyl ether to afford the title compound as a white solid (0.012 g, 32% yield).
Reaction SMILES: O.[OH-].[Li+].C(OC([N:11]([C:33]1[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=1)[S:12]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])=O)C(C)C.CO>O>[C:29]([CH:28]=[CH:27][C:24]1[CH:25]=[CH:26][C:21]([C:16]2[C:15]([S:12]([NH:11][C:33]3[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=3)(=[O:13])=[O:14])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:22][CH:23]=1)([OH:31])=[O:30]
Reactant: COC(=O)C=Cc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
Lithium hydroxide monohydrate (87 mg) was added to a solution of N-isobutoxycarbonyl-2-[4-(2-[methoxycarbonyl]vinyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (250 mg) in tetrahydrefuran (6.2 ml) followed by methanol (2.5 ml) and water (2.5 ml). The reaction mixture was stirred at ambient temperature for 18 hours then evaporated to dryness. The residue was dissolved in water (50 ml), washed with ethyl acetate (50 ml), acidified with 8% aqueous citric acid to pH 3-4 and extracted with ethyl acetate (100 ml). The organic layer was extracted with saturated sodium bicarbonate solution (50 ml) and the aqueous phase separated, acidified with 8% aqueous citric acid and extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried (MgSO4) and evaporated to give 2-[4-(2-carboxyvinyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (108 mg) as a solid, m.p. 233-235° C.: 1H NMR (d6 -DMSO): 2.2 (s, 3H), 3.8 (s, 3H), 6.55 (d, 1H), 7.35 (br s, 1H), 7.45 (d, 2H), 7.55-7.75 (m, 4H), 8.45 (dd, 1H), 8.8 (dd, 1H), 10.1 (br s, 1H); mass spectrum (+ve ESP) 427 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:11])([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:13][C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:15]=[C:14]([CH2:13][NH:2][C:3]([CH3:11])([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[O:18][N:17]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)CC(C)(C)N
Reactant: Clc1ccc(-c2cc(CBr)on2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(C)NCc1cc(-c2ccc(Cl)cc2)no1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl 3-amino-3-methylbutyrate hydrochloride (333 mg) in tetrahydrofuran (4.00 mL), a solution in tetrahydrofuran (2.00 mL) of the compound (100 mg) obtained in step (2) above and potassium carbonate (406 mg) were added and the mixture was stirred at 60° C. for three days. After passing the reaction mixture through Celite (registered trademark), the filtrate was concentrated under reduced pressure and the resulting residue was roughly purified by preparative HPLC. To the resulting roughly purified product, a saturated aqueous solution of sodium hydrogencarbonate was added and extraction was conducted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-50:50) to give the titled compound as a colorless amorphous mass.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C)C=O>[C:15]([C:12]1[C:11]([O:18][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:10]([CH2:19][CH2:20][CH3:21])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:17])[CH3:16]
Reactant: CCCc1c(OCc2ccccc2)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCc2ccccc2)ccc(C(C)=O)c1OCCCC(=O)OCC
Temperature: 100 °C
Yield: 52.3 %

Procedure:
A mixture of 4'-benzyloxy-2'-hydroxy-3'-propylacetophenone (3.0 g), anhydrous potassium carbonate (2.9 g), potassium iodide (0.5 g) in N,N-dimethylformamide (40 ml) was stirred at 100° C. To this mixture was added ethyl 4-bromobutyrate (3.1 g) dropwise under stirring and the mixture was stirred for 8 hours. This mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography, eluting with benzene-ethyl acetate (20:1), to give the title compound (2.2 g, 52.3%) as brown oil.
Reaction SMILES: CO[Na].[Na].[Br:5][C:6]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:7]=1[CH2:8][NH:9][C:10]([NH:12][N:13]=[C:14]([CH3:19])[C:15](OC)=[O:16])=[S:11]>CO>[Br:5][C:6]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:7]=1[CH2:8][N:9]1[C:15](=[O:16])[C:14]([CH3:19])=[N:13][NH:12][C:10]1=[S:11]
Reactant: COC(=O)C(C)=NNC(=S)NCc1cc(F)ccc1Br
Agent: CO[Na]
Agent: [Na]
Solvent: CO
Product: Cc1n[nH]c(=S)n(Cc2cc(F)ccc2Br)c1=O

Procedure:
To a solution of MeONa (0.4 M) in methanol (30 mL), freshly prepared from sodium (273 mg, 11.88 mmol) and dry methanol (30 mL), was added methyl 2-(2-(2-bromo-5-fluorobenzylcarbamothioyl)hydrazono)propanoate (15, 1.434 g, 3.96 mmol). The mixture was heated at reflux for 22 h. Most of the solvent was evaporated. The residue was diluted with water (100 mL), acidified with 2 N HCl to pH=1˜2, and then extracted with EtOAc (50 mL×2). The extracts were washed with brine, dried over MgSO4, and concentrated to give a mixture which was separated by silica gel column, and eluted with 20-30% ethyl acetate in petroleum ether to give 4-(2-bromo-5-fluorobenzyl)-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one (16). MS: m/z, 330 (65%, M+1), 332 (60%, M+23).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.C(O[C:47]([N:49]1[CH2:53][CH2:52][CH2:51][C@H:50]1[C:54](O)=[O:55])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C=O.C([BH3-])#N.[Na+]>CN(C=O)C.CO.C1COCC1.CC(O)=O>[Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:20][CH2:21][N:22]([C:54]([C@@H:50]5[CH2:51][CH2:52][CH2:53][N:49]5[CH3:47])=[O:55])[CH2:23][CH2:24]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Agent: C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCN(C(=O)[C@@H]3CCCN3C)CC1)C2
Reaction time: 1 h

Procedure:
To a solution of 6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)-pyrimidin-2-ylamino)-5-isopropoxy-2-(piperidin-4-yl)isoindolin-1-one (52 mg, 0.09 mmol) in DMF (1.0 mL) was added (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (19 mg, 0.09 mmol), HATU (50 mg, 0.130 mmol), and DIEA (0.174 mmol, 30 μL) sequentially. The reaction mixture was stirred for 1 h, then partitioned between EtOAc and water. The organic extracts were dried (Na2SO4), and concentrated in vacuo. The crude product was stirred in a solution of DCM (1 mL) and TFA (1 mL) for 1 h, then concentrated in vacuo. To the solution of the resulting crude product in 1 mL of MeOH and 1 mL of THF was added 3 drops of AcOH, formaldehyde (37 wt. % solution in water, 0.09 mmol, 7 mg). After stirring for 1 h, sodium cyanoborohydride (0.18 mmol, 11 mg) was added, and the reaction mixture was stirred for another 30 min. The reaction mixture was filtered and the resulting filtrate was purified by preparative RP-HPLC to afford (S)-6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)-pyrimidin-2-ylamino)-5-isopropoxy-2-(1-(1-methylpyrrolidine-2-carbonyl)piperidin-4-yl)isoindolin-1-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O.O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(F)c1
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a solution of 3-fluorophenol (1.2 g, 11.8 mmol) in 20 mL of DMF at 0° C. is added sodium hydride (0.47 g, 10.7 mmol). After stirring for 10 minutes Ethyl bromoacetate (1.2 g, 10.7 mmol) is added dropwise. The reaction is allowed to warm to ambient temperatures and is stirred for 16 hours. To the reaction is added a saturated solution NH4Cl (aq.). The resulting mixture is diluted with EtOAc and H2O. The layers are separted. The organic layer is washed with H2O and a saturated solution NaCl (aq.). The organic layer is dried over MgSO4, filtered and concentrated to give the product (2 g, 10 mmol) as an oil. 1H NMR (CDCl3, 300 MHz) δ7.22 (m, 1H), 6.65 (m, 3H), 4.61 (s, 2H), 4.27 (q, 2H), 1.24 (t, 3H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1C=CC=CN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Br
Agent: BrCc1ccccn1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccccn3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)pyridine hydrobromide and isolated as white gum (5.0 mg, 33%). MS (m/e): 374.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Si](C)(C)C)=[C:11]([F:19])[C:10]=2[F:20])[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25].[Br:26]Br.ClCCl.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Br:26])=[C:11]([F:19])[C:10]=2[F:20])[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25]
Reactant: BrBr
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c(F)c2F)c(F)c(N)c1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Br)c(F)c2F)c(F)c(N)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.7 %

Procedure:
Methyl 4-amino-3-chloro-6-(2,3-difluoro-4-(trimethylsilyl)phenyl)-5-fluoropicolinate (2.5 g, 6.43 mmol) was dissolved in acetonitrile (32 mL) and bromine (3.31 mL, 64.3 mmol) was added. The reaction mixture was stirred at room temperature for 4 h at which time LCMS indicated the reaction was mostly complete. The reaction mixture was partitioned between dichloromethane and water and sodium thiosulfate (10.17 g, 64.3 mmol) was added. The aqueous phase was extracted with dichloromethane and the organic extracts were combined and concentrated under vacuum. The product was purified by flash chromatography (SiO2, eluting with 5-40% ethyl acetate in hexanes) to provide the title compound as a light yellow solid (1.62 g, 63.7%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17](SC)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:29][NH:30][C:31]1[N:36]=[CH:35][C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:33][N:32]=1>COCCOC.C(OCC)(=O)C.CSC.[Cu]Br.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>[CH3:29][NH:30][C:31]1[N:36]=[CH:35][C:34]([C:17]2[N:18]=[C:19]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:14]3[CH:13]=[C:12]([CH2:11][N:8]4[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]4)[S:28][C:15]=3[N:16]=2)=[CH:33][N:32]=1
Reactant: CSc1nc(N2CCOCC2)c2cc(CN3CCN(S(C)(=O)=O)CC3)sc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC)nc1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CSC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CNc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[2,3-d]pyrimidine (80 mg) in 1,2-dimethoxyethane (10 mL) was added methyl-(5-tributylstannanyl-pyrimidin-2-yl)-amine (143 mg) (prepared as above) and copper(I)bromide-dimethyl sulfide (74 mg) and the reaction mixture was stirred at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (10 mg) was then added and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic phase was dried (MgSO4), reduced in vacuo and purified by column chromatography to give 410. NMR: (CDCl3): 2.65-2.68 (4 H, m), 2.82 (3 H, s, Me), 3.12 (3 H, d, J 5.1, Me), 3.29-3.31 (4 H, m), 3.82 (2 H, s, CH2), 3.89-3.90 (4 H, m), 3.94-3.96 (4 H, m), 5.30 (1 H, q, J 5.1, NH), 7.14 (1 H, s, Ar) and 9.30 (2 H, s, Ar). MS: (ESI+): MH+=505.19
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15].O>O1CCCC1>[N+:14]([C:17]1[CH:18]=[C:19]([CH:20]=[CH:3][C:1]#[N:2])[CH:22]=[CH:23][CH:24]=1)([O-:16])=[O:15]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC=Cc1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
At 0° C., 75.5 g of diethyl cyanomethylphosphonate dissolved in tetrahydrofuran are poured into a suspension of sodium hydride in tetrahydrofuran. After 30 minutes' contact at ambient temperature, 56 g of 3-nitrobenzaldehyde dissolved in tetrahydrofuran are poured in. After 1 hour, hydrolysis is carried out with 300 ml of water and then the solvent is concentrated. Following extraction with dichloromethane, washing the organic phase with water, drying over magnesium sulphate and concentration, the precipitate is taken up in diethyl ether and filtered off.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[C:7]([C:8](Cl)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH:22]([O:26][CH3:27])[CH:23]([NH2:25])[CH3:24].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH:22]([O:26][CH3:27])[CH:23]([NH:25][C:8]([C:7]1[C:3]([CH:2]([F:13])[F:1])=[N:4][N:5]([CH3:12])[C:6]=1[F:11])=[O:9])[CH3:24]
Reactant: COC(c1ccc(Cl)cc1Cl)C(C)N
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(c1ccc(Cl)cc1Cl)C(C)NC(=O)c1c(C(F)F)nn(C)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
At ambient temperature, 233 mg (1.1 mmol) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride and 234 mg (1 mmol) of 1-(2,4-dichlorophenyl)-1-methoxypropan-2-amine are dissolved in 10 ml of dichloromethane. 121 mg (1.2 mmol) of triethylamine are added and the reaction mixture is stirred for 4 hrs at ambient temperature. The mixture is diluted by 50 ml of ethyl acetate and successively washed by a 1 N solution of HCl (twice), a saturated solution of potassium carbonate (twice) and brine and dried over magnesium sulfate. The solvents are removed and the crude amide is purified by column chromatography on silica gel (gradient heptane/ethyl acetate) to yields 400 mg (97% yield) of N-[1-(2,4-dichlorophenyl)-1-methoxypropan-2-yl]-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide as a pale yellow solid (M+H=410).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[N:24]([CH3:25])[N:23]=[N:22][N:21]=1.COC(C1C(Cl)=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O.N>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: Cn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Agent: N
Solvent: CC#N
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A 320 ml portion of acetonitrile was added to 54.5 g of 7-ACA and 25,6 g of 5-mercapto-1-methyl-1H-tetrazole, and 296.7 g of DCPA was added to the mixture with stirring and under cooling at -20° to -10° C. After the dissolution, the reaction mixture was stirred at 15° to 17° C. for 40 minutes to allow the reaction to proceed, cooled and poured into 1.8 kg of ice-water. The mixture was allowed to stand at 5° C. overnight, cooled by adding ice under stirring and adjusted to pH 4.0 with 25% aqueous ammonia. The resulting precipitate was recovered by filtration, washed with 480 ml of cold water and 500 ml of acetone successively, and dried, thereby affording 62.2 g (94.7% of yield) of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([CH3:28])[CH2:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([CH3:28])[CH2:27][CH2:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cn(C(CC2(C)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
247 mg (558 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methylcyclopropyl)propanoate (racemate) in 1 ml of dichloromethane and 859 μl (11.2 mmol) of TFA were reacted according to General Method 6A. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125×30 mm, mobile phase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 95 mg (43% of theory)
Reaction SMILES: [OH-].[Na+].C[C@:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[C:5]([O-:7])=[O:6].Cl>O1CCCC1.CO.O>[C:36]([O:35][C:33]([NH:32][C@@H:4]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
1N Sodium hydroxide solution (2.14 mL, 2.14 mmol) was added dropwise to a stirred solution of (2R)-Methyl-tert-butoxycarbonylamino-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-propionate (552 mg, 1.07 mmol) in tetrahydrofuran (15 mL) and methanol (3 mL). The clear reaction mixture was stirred at room temperature until the reaction was complete (TLC control), and then diluted with water (10 mL), and acidified to pH 3 with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5-10% methanol in methylene chloride as eluent, afforded the title compound has a white solid (486 mg, 90%), m.pt. 171-173° C. Rf: 0.35 (10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz): δ 7.86 (2H, d, J=8 Hz, Ar—H), 7.68 (6H, m, Ar—H), 7.61 (1H, d, J=8 Hz, , Ar—H), 7.43 (2H, d, J=8 Hz, Ar—H), 7.11-7.22 (2H, m, Ar—H), 6.80 (1H, br s, NH), 6.72 (1H, d, J=3.5 Hz, Ar—H), 4.06 (1H, m, CHN), 3.80 (2H, s, PhCH2), 2.86 (1H, dd, J=13, 5 Hz, CHHCHN), 2.72 (1H, dd, J=13, 8 Hz, CHHCHN), 1.40 (9H, s, CMe3), ESI-LCMS e/z calcd for C29H30N2O4S: 502.632, found 503 (M+H)+, 525 (M+Na)+.