Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][CH2:13][CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1>>[F:1][C:2]1[CH:9]=[C:8]([CH:10]2[C:16]3[NH:17][CH:18]=[N:19][C:15]=3[CH2:14][CH2:13][NH:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(C=O)cc1F
Reactant: NCCc1c[nH]cn1
Product: N#Cc1ccc(C2NCCc3nc[nH]c32)cc1F

Procedure:
2-Fluoro-4-formyl-benzonitrile (as described in Example 29, Step A) (0.268 g, 1.79 mmol) and histamine (0.200 g, 1.79 mmol) were heated neat at 120° C. for 1.5 h. The molten liquid was cooled to give the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6].[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37](Cl)=[O:38]>>[N:21]1([C:19]([CH:2]([NH:1][C:37]([C:28]2[CH:29]=[CH:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)=[O:38])[CH2:3][NH:4][C:5]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:11][CH2:12]2)=[O:6])=[O:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Product: O=C(NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1)c1ccc2ccccc2c1
Yield: 85 %

Procedure:
Using an analogous procedure to that described in Example 2, N-[2-amino-2-(piperidinocarbonyl)ethyl]-1-(4-pyridyl)piperidine-4-carboxamide was reacted with naphthalene-2-carbonyl chloride to give N-{1-(piperidinocarbonyl)-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]-ethyl}naphthalene-2-carboxamide in 85% yield;
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][S:12][C:13]1[S:14][C:15]2[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:16]=2[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][S:12][C:13]1[S:14][C:15]2[CH:21]([OH:22])[CH2:20][CH2:19][CH2:18][C:16]=2[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCc2nc(SCc3cccc(Oc4ccccc4)c3)sc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OC1CCCc2nc(SCc3cccc(Oc4ccccc4)c3)sc21
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of 2-[(3-phenoxybenzyl)thio]-5,6-dihydro-1,3-benzothiazol-7(4H)-one (2.50 g, 6.80 mmol) in tetrahydrofuran (50 mL) was added by portions lithium aluminum hydride (280 mg) under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. Sodium sulfate decahydrate (1.5 g) was added to reaction mixture, and the mixture was stirred at room temperature for 1 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (2.20 g, yield 87%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4]([Cl:10])=[N:5][C:6](Cl)=[N:7][CH:8]=1.CCOCC.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2.C(N(CC)CC)C>[Cl-].[Zn+2].[Cl-].ClCCCl.CC(O)(C)C>[Cl:10][C:4]1[C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=[C:6]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22]3)[N:5]=1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(Nc3ncc(C(F)(F)F)c(Cl)n3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-trifluoromethyl-2,4-dichloropyrimidine (214.8 g; 0.921 mol) in 1:1 DCE/tBuOH (1.240 L) was added Zinc chloride 1M solution in ether (1 eq; 0.921 L). After 0.5 hour, 5-amino-oxindole (124 g; 0.837 mol) was added followed by triethylamine (129.4 ml; 0.921 mol) keeping temperature at 25° C. The reaction was allowed to stir at room temperature overnight, then was concentrated and the product triturated from methanol as a yellow solid (224.3 g; 82%). 1H NMR (DMSO-d6, 400 MHz) □ 3.29 (s, 2H), 6.76 (d, J=7.9 Hz, 2H), 7.39 (d, J=8.3 Hz), 7.51 (br s, 1H), 8.71 (s, 1H), 10.33 (s, 1H), 10.49 (s, 1H). 13C NMR (DMSO-d6, 100 MHz) □ 177.0, 161.3, 158.7 (br), 140.7, 132.8, 126.9, 123.7 (q, J=268 Hz), 121.0, 118.7, 111.2 (q, J=32 Hz), 109.6, 36.7; HPLC ret. time: 5.759 min. LRMS (M+) 329.1, 331.1.
Reaction SMILES: [N:1]([C:4]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=O)=[N+]=[N-].O=S(Cl)[Cl:26]>>[Br:23][C:21]1[CH:20]=[CH:19][C:5]2[C:4]([CH:22]=1)=[N:1][N:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[C:6]=2[Cl:26]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=Nc1cc(Br)ccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-n2nc3cc(Br)ccc3c2Cl)cc1
Yield: 85 %

Procedure:
A solution of the product of Step 2 (3 g, 0.0078 mol) in SOCl2 (15 mL) was heated at reflux for 24 h. The mixture was then concentrated and the residue partitioned between ether (3×20 mL) and Na2CO3 solution (10 mL). The organic phase was separated, dried (MgSO4) and concentrated to give 2.5 g (85% yield) of product as a tan powder. 1H NMR (360 MHz, CDCl3): 7.25 (1H, d, J 8.9 Hz), 7.37 (1H, d, 8.9 Hz), 7.80-7.95 (5H, m).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([NH2:10])=[O:9])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
To a solution of cis-2-aminocyclohexanecarboxylic acid amide (2.0 g, 14.0 mmol), and triethylamine (3.9 mL, 28 mmol) in dichloromethane (100 mL) was added 4-chlorobenzenesulfonyl chloride (2.95 g, 14.0 mmol). The resulting solution was stirred at room temperature for 18 h. The reaction was then diluted with dichloromethane (200 mL) and washed with H2O, 1.0 M HCl, brine, and dried over Na2SO4. Further purification by flash chromatography (silica gel, 1% to 10% MeOH/CHCl3) afforded cis-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (2.0 g) as a white solid in 45% yield over three steps: 1H NMR (DMSO-d6) δ 7.82 (m, 2 H), 7.63 (m, 2 H), 7.56 (d, 1 H, J=7.0 Hz), 7.22 (s br, 1 H), 6.80 (s br, 1 H), 3.43 (m, 1 H), 2.37 (m,1 H), 1.72 (m, 2 H), 1.45 (m, 3 H), 1.15 (m, 3 H); MS m/e 317.05 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[CH2:5][N:6]([CH3:26])[C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=1)=[O:8].O1[CH2:36][CH2:35]OCC1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[CH2:5][N:6]([CH3:26])[C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11]([N:10]2[CH2:36][CH2:35][N:6]([CH3:5])[CH2:7][CH2:9]2)[N:10]=1)=[O:8]
Reactant: Cc1cc(C)cc(CN(C)C(=O)c2nc(S(C)(=O)=O)ncc2-c2ccccc2C)c1
Reactant: C1COCCO1
Product: Cc1cc(C)cc(CN(C)C(=O)c2nc(N3CCN(C)CC3)ncc2-c2ccccc2C)c1
Reaction time: 16 h
Yield: 123 %

Procedure:
To a solution of 0.28 g (0.66 mmol) 2-methanesulfonyl-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-dimethyl-benzyl)-methyl-amide in 10 ml dioxane 0.18 ml (1.65 mmol) 1-methylpiperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH2Cl2 and 50 ml H2O. The aqueous layer was extracted with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 110:10:1) to give 0.18 g (61%) 2-(4-methyl-piperazin-1-yl)-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-dimethyl-benzyl)-methyl-amide as a colorless foam, MS (ISP): 444.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]4[CH:20]=[CH:19][NH:18][C:14]4=[N:15][CH:16]=3)[N:11]([CH3:21])[N:10]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C>[Br:29][C:20]1[C:13]2[C:14](=[N:15][CH:16]=[C:17]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[N:10][N:11]([CH3:21])[C:12]3=2)[NH:18][CH:19]=1
Reactant: COc1ccc(-c2nn(C)c3c2cnc2[nH]ccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COc1ccc(-c2nn(C)c3c2cnc2[nH]cc(Br)c23)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
To a solution of 3-(4-methoxyphenyl)-1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.264 g, 0.949 mmol; Example #AU.1.1) in DMF (3 mL) was added NBS (0.169 g, 0.949 mmol). The mixture was allowed to stir at about rt for about 16 h. Additional NBS (0.085 mg, 0.478 mmol) was added and the mixture was heated to about 50° C. for about 3 h. The mixture was purified by flash chromatography (40 g silica gel column, 10 to 100% EtOAc/heptane) to give 8-bromo-3-(4-methoxyphenyl)-1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.150 g, 44%). LC/MS (Table 2, Method a) Rt=2.35 min.; MS m/z: 357 (M+H)+. Syk IC50=A.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.F[B-](F)(F)F.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1([C:48]([O:50][CH3:51])=[O:49])[CH2:47][CH2:46]1)#[CH:38].CCN(CC)CC>CN(C=O)C.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>[CH3:51][O:50][C:48]([C:45]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[C:37]#[C:38][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:3]=2)[CH2:47][CH2:46]1)=[O:49]
Reactant: C#Cc1ccccc1C1(C(=O)OC)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CC1
Temperature: 120 °C
Yield: 86.5 %

Procedure:
A solution of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K3) (262 mg, 0.574 mmol), PdCl2(PPh3)2 (20 mg, 0.029 mmol,) t-Bu3PH.BF4 (8 mg, 0.03 mmol), CuI (5 mg, 0.03 mmol) and methyl 1-(2-ethynylphenyl)cyclopropanecarboxylate (K2) (138 mg, 0.689 mmol) in DMF (5.0 mL) was degassed with nitrogen for 10 minutes. Et3N (1.0 mL) was added and the resulting mixture heated under microwave irradiation for 20 minutes at 120° C. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the title compound A3 as a yellow solid (308 mg, 86%); 1H NMR (400 MHz, d6-DMSO) δ 10.37 (s, 1H), 8.79 (s, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.60 (dd, J=7.6, 1.0 Hz, 1H), 7.54-7.38 (m, 3H), 7.21 (d, J=8.6 Hz, 2H), 4.07 (d, J=11.6 Hz, 2H), 3.52 (s, 3H), 2.80 (s, 2H), 2.65 (J m, 1H), 1.74 (d, J=12.4 Hz, 2H), 1.64 (q, J=4.0 Hz, 2H), 1.49 (td, J=12.6, 4.1 Hz, 2H), 1.42 (s, 9H), 1.29 (q, J=4.2 Hz, 2H). LCMS-A: rt 7.083 min; m/z 619 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:18]=[CH2:19]>>[CH:7]1([CH2:6][O:5][C:4]2[CH:3]=[C:2](/[CH:19]=[CH:18]/[CH2:17][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:15][CH:14]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C=CCNC(=O)C(F)(F)F
Reactant: Brc1cccc(OCC2CCCCCC2)c1
Product: O=C(NC/C=C/c1cccc(OCC2CCCCCC2)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
((3-Bromophenoxy)methyl)cycloheptane was coupled with N-allyl-2,2,2-trifluoroacetamide following the method used in Example 10 except that the mixture was heated for 23 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and partitioned between EtOAc and water. The combined organics were washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (10% EtOAc-hexanes) gave (E)-N-(3-(3-(cycloheptylmethoxy)phenyl)allyl)-2,2,2-trifluoroacetamide. Yield (0.7015 g, 52%): 1H NMR (400 MHz, CDCl3) δ 7.23 (t, J=7.6 Hz, 1H), 6.90-6.94 (m, 2H), 6.81 (dd, J=8.4, 1.6 Hz, 1H), 6.56 (d, J=15.6 Hz, 1H), 6.39 (br s, 1H), 6.12-6.19 (m, 1H), 4.13 (t, J=6.0 Hz, 2H), 3.73 (d, J=9.6 Hz, 2H), 1.92-2.10 (m, 1H), 1.82-1.90 (m, 2H), 1.42-1.76 (m, 8H), 1.24-1.36 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([CH3:7])=[C:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:14][C:15]1([CH3:27])[C:19]([CH3:21])([CH3:20])[O:18][B:17]([C:22]2[CH:23]=[N:24][NH:25][CH:26]=2)[O:16]1>CN(C=O)C.C(OCC)C>[CH3:7][C:3](=[C:4]([CH3:6])[CH3:5])[CH2:2][N:25]1[CH:26]=[C:22]([B:17]2[O:16][C:15]([CH3:27])([CH3:14])[C:19]([CH3:21])([CH3:20])[O:18]2)[CH:23]=[N:24]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)=C(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
1-Bromo-2,3-dimethylbut-2-ene (3.78 g, 23.19 mmol), and cesium carbonate (15.11 g, 46.4 mmol) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.0 g, 15.46 mmol) in DMF (52 mL), and the mixture was stirred at 90° C. for 18 h. The mixture was allowed to cool to room temperature, diluted with diethyl ether, washed with water (3×50 mL) and brine. The organic layers were separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-40% EtOAc/hexane) to afford 1-(2,3-dimethylbut-2-en-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 1H), 7.62 (s, 1H), 4.74 (s, 2H), 1.83 (s, 3H), 1.74 (s, 3H), 1.59 (s, 3H), 1.31 (s, 12H).
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]([C:8](=[N:14]O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:7].S(S([O-])=O)([O-])=O.[Na+].[Na+].II>CCOC(C)=O.O>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([NH2:14])[C:6]#[N:7])[CH3:13]
Reactant: CCOC(=O)C(C#N)=NO
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(N)C#N
Yield: 31 %

Procedure:
Dilute aqueous saturated sodium bicarbonate (560 mL) with deionized water (700 mL). and stir the solution while adding ethyl cyanoglyoxylate-2-oxime (70.0 g, 493 mmol) in portions (note: some off-gassing and a gentle endotherm were observed). Add sodium dithionite (238 g, 1.37 mol, 2.8 eq.) in portions and stir at rt. After 2.5–3 hours, during this time the reaction was monitored by TLC (EtOAc, I2 stain), saturate the solution with sodium chloride (400 g), and extract the product CH2Cl2 (1×500 mL, 3×250 mL), making sure solid NaCl was visible (more added if necessary) during the extractions. Combine the organic layers, dry over (MgSO4), filter, and concentrate the filtrate to dryness in vacuo on a rotovapor at low bath temperature (30–35° C.) to afford 19.6 g (31%) crude amino-cyano-acetic acid ethyl ester which was used immediately in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[C:11](=[O:28])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].C(N(CC)CC)C.C(=O)(O)[O-].[K+].[I-].[Na+].[C:43]([O:49][CH2:50]Cl)(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45]>CN(C)C=O.C(OCC)(=O)C.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[C:11](=[O:28])[N:6]2[C:7]=1[C:8]([O:10][CH2:50][O:49][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45])=[O:9]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)c3c(-c4ccccc4)noc3C)[C@H]2SC1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)c3c(-c4ccccc4)noc3C)[C@H]2SC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-Methyl-7-(5-methyl-3-phenylisoxazole-4-carboxamido)ceph-3-em-4-carboxylic acid (25.9 g., 65 mmoles) was dissolved in anhydrous dimethylformamide (150 ml.). Triethylamine (19.7 g., 195 mmoles), potassium bicarbonate (19.5 g., 195 mmoles), sodium iodide (29.3 g., 195 mmoles) and chloromethyl pivalate (29.3 g., 195 mmoles) were added. An exotherm was noted, the temperature rising to approximately 35° C. After stirring for 6 hours at ambient temperature, monitoring by tlc (4:1 chloroform:ethyl acetate) indicated considerable starting material remained. Additional chloromethyl pivalate (8.4 g., 65 mmoles) was added and stirring at ambient temperature continued for 16 hours. Isolation as detailed in Preparation 1 gave pivaloyloxymethyl 3-methyl-7-(5-methyl-3-phenylisoxazole-4-carboxamido)ceph-3-em-4-carboxylate [25.3 g., 76%; Rf 0.8 (4:1 chloroform:ethyl acetate; ir (CH2Cl2) 1780, 1750, 1670 cm-1 ].
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:11][C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]2[O:12][CH:3]12.[C:14]1([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:13])[O:11][C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]([N:21]2[CH:22]=[CH:23][N:24]=[C:20]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]1[OH:12]
Reactant: CC1(C)Oc2ccncc2C2OC21
Reactant: c1ccc(-c2ncc[nH]2)cc1
Product: CC1(C)Oc2ccncc2C(n2ccnc2-c2ccccc2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclopropa[a]naphthalene and 2-phenyl-1H-imidazole as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[NH:10][N:11]=[CH:12][C:3]=12.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:11]=[CH:12][C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: CSc1nc(Cl)c2cn[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2cnn(COCC[Si](C)(C)C)c2n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.7 %

Procedure:
4-Chloro-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (497 mg, 2.477 mmol) was dissolved in 5 mL dry DMF, and the reaction mixture was cooled to 0° C. Sodium hydride (109 mg of 60% suspension in mineral oil) was added, and the reaction mixture was stirred for five minutes. (2-Chloromethoxy-ethyl)-trimethyl-silane (0.52 mL, 2.922 mmol) was then added, and the reaction mixture was stirred for 10 minutes. The reaction mixture was quenched by addition to water, and was partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography using 5% EtOAc in hexanes to give 391 mg of 4-Chloro-6-methylsulfanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: C[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[N:11]O.[CH3:13]O>[Pd]>[CH3:13][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([NH2:11])[CH2:2]1
Reactant: CO
Reactant: CC1Cc2ccccc2C1=NO
Agent: [Pd]
Product: CC1CC(N)c2ccccc21
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of-methylindan-1-one oxime (223 mg, 1.38 mmol) and 10% palladium on carbon (14.7 mg, 50% water wet) in MeOH (5.00 mL) was stirred under an atmosphere of hydrogen overnight. The mixture was then filtered through celite, washed through with MeOH and the combined filtrates were concentrated in vacuo to afford the title compound (195 mg, 96%). 1H NMR (CDCl3, 300 MHz) δ: 7.39-7.14 (m, 4H), 4.26 (dd, J=7.2, 9.4 Hz, 1H), 3.13-2.96 (m, 1H), 2.71 (ddd, J=6.9, 6.9, 12.5 Hz, 1H), 1.75 (bs, 2H), 1.35 (d, J=6.8 Hz, 3H), 1.25 (ddd, J=9.9, 9.9, 11.7 Hz, 1H) ppm.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([Cl:16])=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19](B(O)O)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CCOC(C)=O.C(=O)(O)[O-].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:16][C:5]1[CH:4]=[CH:3][C:2]([C:19]2[C:18]([Cl:17])=[CH:23][N:22]=[C:21]([F:24])[CH:20]=2)=[N:7][C:6]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: Clc1ccc(Br)nc1NCC1CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COCCOC
Product: Fc1cc(-c2ccc(Cl)c(NCC3CCOCC3)n2)c(Cl)cn1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
A mixture of 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (F, 200 mg, 0.654 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (230 mg, 1.309 mmol), PdCl2(dppf).CH2Cl2 adduct (53.4 mg, 0.065 mmol) in DME (3 mL) and 2M aqueous sodium carbonate (3 mL, 6.00 mmol) was heated in a sealed tube at about 103° C. for 16 hr. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (˜100 mL) and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution (2×), dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [ISCO, SiO2, 25 g, EtOAc/heptane=0/100 to 30/70]. Fractions were combined and concentrated in vacuo providing 5,5′-dichloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (130 mg) as a nearly colorless liquid. LCMS (m/z): 356.1 [M+H]+; Retention time=1.10 min.
Reaction SMILES: C([O:8][C:9](=[O:21])[C:10]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][CH:12]=[CH2:13])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH3:20][C:10]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH2:11][CH2:12][CH3:13])[C:9]([OH:21])=[O:8]
Reactant: C=CCC(C)(C(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(C)(C(=O)O)c1ccccc1
Reaction time: 72 h
Yield: 99.7 %

Procedure:
A solution of 2-methyl-2-phenyl-pent-4-enoic acid benzyl ester (2.31 g, 8.24 mmol) in ethyl acetate (20 mL) was treated with 10% palladium on carbon (0.24 g, 10 weight percent) and stirred under a hydrogen balloon for 72 hours. The vessel was purged with nitrogen gas and the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound (1.58 g, 99%). 1H NMR (300 MHz, CDCl3): δ ppm 0.91 (m, 3 H) 1.23 (m, 2 H) 1.57 (m, 3 H) 1.96 (m, 2 H) 7.36 (m, 5 H). MS (DCI/NH3+) m/z 210 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C:22]1([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:24][CH2:23]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:24][CH2:23]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)C1(N)CC1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C1(Nc2nc(Cl)nc3c2SCC3)CC1
Temperature: 160 °C

Procedure:
2.7 g (II) are placed in 30 ml dioxane, then 6.8 ml diisopropyl-ethylamine and 1.8 g 2-(1-aminocyclopropyl)-propan-2-ol (cf. Liebigs Ann. Chem. 1978.1194) are added. The reaction mixture is heated to 160° C. until there is no further reaction and after cooling it is evaporated to dryness. The residue is mixed with ice water. The product is extracted with dichloromethane and purified by chromatography. 125 mg (III-8) are obtained in the form of a solid. Analytical HPLC-MS (method A): RT=1.08 min.