Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:11]2=[O:23])=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][C:11]2=[O:23])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)C(=O)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)C(=O)C1
Reaction time: 4 h
Yield: 94.9 %

Procedure:
A 250-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 100 mg dry weight) and a solution of 121a (500 mg, 1.55 mmol) in ethanol (20 mL). The bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 45 psi and shaken for 4 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (1.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×30 mL), and the filtrate was concentrated under reduced pressure to afford a 95% yield of 121b (430 mg) as an amber film: 1H NMR (500 MHz, CDCl3) δ 7.98 (d, 1H, J=2.5 Hz), 7.38 (dd, 1H, J=8.5, 2.0 Hz), 6.52 (d, 1H, J=8.5 Hz), 4.54 (s, 1H), 4.26 (s, 2H), 3.78 (t, 2H, J=5.5 Hz), 3.67 (t, 2H, J=5.0 Hz), 1.50 (s, 9H); MS (ESI+) m/z 293.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:10]([OH:12])=O)[S:8][CH:9]=1)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]([NH2:37])=[O:36])[C:30](=[O:38])[CH2:29]2.C(O)(=O)C>CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]([NH2:37])=[O:36])[C:30](=[O:38])[CH:29]2[C:10](=[O:12])[C:7]1[S:8][CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: COC(=O)c1csc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)c1
Yield: 67.9 %

Procedure:
The title compound was prepared according to the procedure of Example 55. To a solution of 1.50 g (8.06 mmoles) of 4-methoxycarbonyl-2-thiophenecarboxylic acid (prepared as described in Example 9) in 15 ml of N,N-dimethylformamide was added 1.57 g (9.67 mmoles) of 1,1'-carbonyldiimidazole. After two hours the reaction contents were slowly added to 1.54 g (7.32 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 2.66 g (21.75 mmoles) of 4-(N,N-dimethylamino)pyridine in N,N-dimethylformamide. Acidic workup of this reaction followed by filtration, drying and trituration with hot acetic acid furnished 1.88 g (4.97 mmoles, 68% yield) of title compound as a yellow solid, m.p. 244-246° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:22][O:23][CH2:24][CH:25]([NH2:28])[CH2:26][CH3:27].ClCCl>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:28][CH:25]([CH2:24][O:23][CH3:22])[CH2:26][CH3:27])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Nc2nccc(-c3ccnc(Cl)c3)n2)ccn1
Reactant: CCC(N)COC
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCC(COC)Nc1cc(-c2ccnc(Nc3ccnc(Cl)c3)n2)ccn1
Yield: 199 %

Procedure:
300 mg of N,4-bis(2-chloropyridin-4-yl)pyrimidin-2-amine (0.94 mmol), 486 mg of 1-methoxybutan-2-amine (4.71 mmol), were heated at 240° C. for 90 minutes under micro-waves irradiation in 0.6 ml of 1-Methyl-2-pyrrolidinone. After cooling, the reaction mixture was poured into 10 ml of dichloromethane, washed twice with 5 ml of water. After drying over magnesium sulfate, filtration and concentration in vacuo, the crude product was chromatographed on silica (ethyl acetate/heptane) to yield 0.72 g of N-(2-chloropyridin-4-yl)-4-(2-{[1-(methoxymethyl)propyl]amino}pyridin-4-yl)pyrimidin-2-amine (yield=19%).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[Cl:8][C:9]1[CH:14]=[CH:13]C=[CH:11][CH:10]=1.CN(C)C=[O:18]>>[Cl:8][C:9]1[CH:14]=[CH:13][C:7]([C:6]#[N+:3][O-:18])=[CH:11][CH:10]=1
Reactant: CN(C)C=O
Reactant: CCN(CC)CC
Reactant: Clc1ccccc1
Product: [O-][N+]#Cc1ccc(Cl)cc1

Procedure:
3.57 g (37 mmol) of triethylamine in 30 ml of dry dimethylformamide were added during 10 minutes while stirring and cooling at 10° C. to a solution of 6.33 g (33.3 mmol) of 4-chlorobenzene N-hydroxycarboximidoyl chloride in 60 ml of dry dimethylformamide. After 1 hour at 20° C. the solution of 4-chlorobenzonitrile oxide formed was poured into water and filtered off. The moist solid was dissolved in 150 ml of diethyl ether and dried twice with 10 g of molecular sieve (3A) each time. The ethereal solution was filtered and there were added thereto at 5° C. 6.56 g (36.6 mmol) of methyl 2-propynyloxy-2-methylpropionate in 25 ml of diethyl ether. After 24 hours the ether was removed and the product was purified by column chromatography on 220 g of silica gel using hexane/ethyl acetate (4:1) and then hexane/ethyl acetate (2:1) for the elution. There were obtained 4.67 g of methyl 2-[[3-(4-chlorophenyl)-5-isoxazolyl]methoxy]-2-methylpropionate in the form of a colourless oil having a purity of 99% according to high pressure liquid chromatography.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=O)[CH3:8])=[CH:4][CH:3]=1.BrC1C=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(=O)Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Fc1ccc(Nc2ccc(F)cc2)cc1

Procedure:
A mixture of p-fluoroacetanilide (76.5 g, 0.5 mole), 4-bromofluorobenzene (262.5 g, 1.5 mole), K2CO3 (76 g, 0.55 mole), Cu2Br2 (157.8 g, 0.55 mole) and N-methylpyrrolidone (600 ml) were heated at 175°-180°. After allowing low boiling material to condense off, the mixture was heated at reflux for 7 days. The mixture was cooled to 60° and quenched into a mixture of 2 liters H2O, 600 ml ethylenediamine and 1.2 liters toluene, filtered and the toluene layer separated, back-washed 2×600 ml H2O, treated with activated carbon, dried over MgSO4 and concentrated to oily solids in vacuo. The latter were taken up in 1.5 liters 10% ethanolic KOH, refluxed 18 hours and concentrated in vacuo to an oil. The oil was partitioned between 750 ml H2O and 750 ml. ether. The water layer was washed 2× 200 ml ether. The organic layers were combined, back-washed 2×200 ml H2O, treated with activated carbon, dried over MgSO4, reconcentrated to an oil (60.3 g) and distilled to yield purified title product 41.6 g, b.p. 158°-160°/2 mm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])([F:6])[F:5].C(N(CC)CC)C.[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[S:22]([O:1][CH2:2][CH2:3][C:4]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])([F:6])[F:5])([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: CCOP(=O)(OCC)C(F)(F)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C(F)(F)CCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h

Procedure:
Diethyl 3-hydroxy-1,1-difluoro-propylphosphonate [1225194-19-3](4.4 g, 0.019 mol) was dissolved in CH2Cl2 (20 mL) and triethylamine (7.7 g) and treated with TsCl (5.4 g, 0.029 mol) followed by DMAP (0.23 g, 0.0019 mol) at rt for 2 h. After 2 h, an additional portion of TsCl (0.6 g) was added. After 30 m, the reaction mixture was partitioned between water and CH2Cl2. The organic layer was filtered and concentrated in vacuo. The residue was dissolved in 1:1 hexanes:CH2Cl2 (100 mL) and applied to 85 g flash silica gel (topped with Na2SO4 and equilibrated with hexanes). The column was eluted with hexanes-ethyl acetate. Intermediate 23 weighed 6.3 g (94%). 1H NMR (CDCl3) 7.2-7.8 (AB, 4H); 3.9-4.4 (m, 6H); 2.0-3.0 (m, 5H), 1.4 (t, 6H).
Reaction SMILES: C(N(CC)CC)C.N1C=CC=CC=1.[CH3:14][CH:15]([CH3:20])[CH2:16][C:17](Cl)=[O:18].[Cl:21][C:22]1[N:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28]([N:32]3[CH:40]([OH:41])[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]3=[O:42])=[N:29]2)=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:14][CH:15]([CH3:20])[CH2:16][C:17]([O:41][CH:40]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:42])[N:32]1[C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[N:31][C:22]([Cl:21])=[CH:23][CH:24]=2)[N:29]=1)=[O:18]
Reactant: CC(C)CC(=O)Cl
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
Triethylamine (12.2 g), pyridine (90 cc) and then 3-methylbutyryl chloride (9.7 g) is added to a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (12.5 g) in methylene chloride (600 cc), while the temperature is maintained in the region of 25° C. After 4 hours' stirring at a temperature in the region of 25° C., 3-methylbutyryl chloride (0.7 g) is added again and the mixture is stirred for a further 16 hours at this temperature. The reaction mixture is then concentrated to dryness under reduced pressure (3 kPa) and the residue is taken up with water (500 cc). The insoluble product formed is separated by filtration, washed, dried and then recrystallized in a mixture of isopropyl ether and ethyl acetate (50:50 by volume). 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 3-methylbutyrate (7.9 g), m.p. 154° C., is thereby obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9]O)[CH:2]=1.[N:11]1C=CC=C[CH:12]=1.CS(Cl)(=O)=O.[C-]#N.[Na+]>C(Cl)Cl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C:12]#[N:11])[CH:2]=1
Reactant: c1ccncc1
Reactant: OCCCc1cccnc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CCCCc1cccnc1
Reaction time: 4 h
Yield: 56.9 %

Procedure:
To a solution of 0.66 mL (5.11 mmol) 3-pyridine propanol in 5 mL CH2Cl2 at 0° C. was added 0.62 mL (7.67 mmol) pyridine and 0.47 mL (6.14 mmol) methanesulfonyl chloride and the reaction stirred for 4 h. The solution was concentrated under reduced pressure and the crude mesylate dissolved in 10 mL DMF. To this solution was added 902 mg (18.41 mmol) sodium cyanide and the reaction stirred at 60° C. for 3 days. Then the solution was cooled, diluted with H2O (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with H2O, dried over MgSO4, and the solvent removed under reduced pressure to give a dark red oil. The crude nitrile was purified by dissolving in EtOAc, washing with H2O, concentrating, and filtering through a silica gel plug (5% MeOH in CH2Cl2) to yield 425 mg (57%) of the nitrile.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13]CC)=[O:12])=[CH:4][CH:3]=1.Br[CH2:17][C:18]1[CH:37]=[CH:36][C:21]([O:22][CH2:23]/[C:24](/[C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)=[N:25]\[O:26][CH3:27])=[CH:20][CH:19]=1>>[C:32]([C:31]1[CH:30]=[CH:29][C:28](/[C:24](=[N:25]/[O:26][CH3:27])/[CH2:23][O:22][C:21]2[CH:36]=[CH:37][C:18]([CH2:17][O:1][C:2]3[CH:3]=[CH:4][C:5]([CH:8]4[CH2:10][CH:9]4[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=3)=[CH:19][CH:20]=2)=[CH:35][CH:34]=1)#[N:33]
Reactant: CO/N=C(\COc1ccc(CBr)cc1)c1ccc(C#N)cc1
Reactant: CCOC(=O)C1CC1c1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(C3CC3C(=O)O)cc2)cc1)c1ccc(C#N)cc1

Procedure:
Compound 45 was prepared from ethyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.1 g, 0.48 mmol), and 4-{(1Z)-2-[4-(bromomethyl) phenoxy]-N-methoxyethanimidoyl}benzonitrile (0.175 g, 0.48 mmol) by following the procedure described in scheme 17.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]3[N:22]=[C:21]([C:23](OC)=[O:24])[CH:20]=[CH:19][N:18]=3)[CH2:10][CH2:9]2)[CH:7]=1.[NH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]1[NH:35][CH:36]=[CH:37][C:38](=[O:40])[N:39]=1>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][C:17]3[N:22]=[C:21]([C:23]([NH:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]4[NH:35][CH:36]=[CH:37][C:38](=[O:40])[N:39]=4)=[O:24])[CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:13]2)[CH:7]=1
Reactant: NCCCNc1nc(=O)cc[nH]1
Reactant: COC(=O)c1ccnc(NCCN2CCN(c3cc(Cl)ccc3OC)CC2)n1
Solvent: CCCCO
Product: COc1ccc(Cl)cc1N1CCN(CCNc2nccc(C(=O)NCCCNc3nc(=O)cc[nH]3)n2)CC1

Procedure:
3.0 g (7.4 mmols) of methyl 2-[[2-[4-(5-chloro-2-methoxyphenyl)piperazin- 1-yl]ethyl]amino]-pyrimidine-4-carboxylate and 1.5 g (8.9 mmols) of 2-[(3-aminopropyl)amino]pyrimidin-4(1H)-one in 20 ml of n-butanol are introduced into a 100 ml, round bottomed flask. The mixture is heated at the reflux temperature of the solvent for 20 hours and then the solvent is evaporated under reduced pressure.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[CH:11]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1>ClCCl>[CH3:10][C:4]12[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH:3]1[CH:18]1[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: C1=CCCCCCC1
Reactant: CC1=CC(=O)CC(C)(C)C1
Solvent: ClCCl
Product: CC1(C)CC(=O)C2C3CCCCCCC3C2(C)C1
Reaction time: 7 h
Yield: 88 %

Procedure:
To a 5-liter flask equipped with a quartz immersion well and nitrogen bubbler was added, under nitrogen, 138 g. (1.0 mol.) of isophorone and 420 g. of freshly distilled cyclooctene. The flask was filled with dichloromethane and was bubbled with nitrogen for 1 hour. The solution was irradiated for 18.5 hours with an Hanovia 450 watt medium pressure mercury arc through a Corning 9700 glass filter. After 7 hours, an additional 82 g. of cyclooctene was added. The solution was concentrated in vacuo to obtain an oil which was distilled through a 45 cm. Vigreux-column to yield 218.4 g. (0.881 mol., 88% yield) of product, b.p. 106°-110° C./0.3 mm.Hg. The product by glpc consisted of 3 isomers in the approximate ratio of 75:12.5:12.5. IR: 1692 cm-1 confirmed the production of the desired product.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:9](OS(C)(=O)=O)[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[N-:29]=[N+:30]=[N-:31].[Na+]>CCOC(C)=O.O>[N:29]([C@@H:9]([CH3:10])[C@@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[N+:30]=[N-:31]
Reactant: C[C@@H](OS(C)(=O)=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](N=[N+]=[N-])[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 55 %

Procedure:
tert-Butyl (2S,3R)-1-cyclohexyl-3-(methanesulfonyloxy)butan-2-ylcarbamate (0.46 g, 1.32 mmol) was dissolved into anhydrous DMF (10 mL), solid NaN3 (0.26 g, 4 mmol) was added and the reaction mixture was heated to 80° C. overnight. The reaction mixture was cooled to rt and diluted with EtOAc (100 mL) and water (30 mL). The organic phase was washed with water (3×30 mL), dried over Na2SO4 and evaporated. The residue was separated by chromatography on a silica gel column to give tert-butyl (2S,3S)-3-azido-1-cyclohexylbutan-2-ylcarbamate (0.215 g, 55%). 1H NMR (400 MHz, CDCl3): 4.38 (d, J=9.2 Hz, 1H), 3.72 (m, 1H), 3.60 (m, 1H), 1.82 (m, 1H), 1.67 (m, 4h), 1.44 (s, 9H), 1.40-1.00 (m, 61), 1.28 (d, J=6.4 Hz, 3H), 1.00-0.75 (m, 2H); MS (E/Z): 297 (M+H+).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:16][C:17]([CH3:22])([CH2:20][OH:21])[CH2:18]O.N1C(C)=CC=CC=1C.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([CH2:40][C@H:41]([NH2:43])[CH3:42])=[CH:32]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([CH2:40][C@H:41]([NH:43][CH2:18][C:17]([F:16])([CH3:22])[CH2:20][OH:21])[CH3:42])=[CH:32]1
Reactant: CC(F)(CO)CO
Reactant: C[C@@H](N)Cc1c[nH]c2ccccc12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(F)CO
Temperature: 25 °C
Yield: 47.7 %

Procedure:
Trifluoromethanesulfonic anhydride (1.151 ml, 6.80 mmol) was added to a solution of 2-fluoro-2-methylpropane-1,3-diol (0.70 g, 6.47 mmol) in DCM (17.85 ml) at 0° C., followed by 2,6-lutidine (0.908 ml, 7.77 mmol). The reaction was allowed to warm to room temperature over 30 min, then was washed with 2M HCl. The organic phase was passed through a phase separator cartridge and concentrated in vacuo. The residue was dissolved in dioxane (12 mL), then (R)-1-(1H-indol-3-yl)propan-2-amine (1.128 g, 6.47 mmol) and DIPEA (1.678 ml, 9.71 mmol) were added and the reaction was heated to 90° C. for 2 h. After cooling, the reaction was diluted with DCM and washed with water. The aqueous was extracted with DCM, then the organics were concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-fluoro-2-methylpropan-1-ol (0.815 g, 47.6%) as a brown gum. m/z (ES+), [M+H]+=265.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[F:25][CH2:26][CH2:27][NH2:28]>>[F:25][CH2:26][CH2:27][NH:28][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: NCCF
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCF)cn1
Yield: 95 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 2-fluoroethylamine hydrochloride instead of methylamine, to the title compound (109 mg, 95%) which was obtained as a white solid. MS: m/e=356.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[C:5]([C:12]#[N:13])=[CH:4][N:3]=1.[CH3:14][O:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CC(O)CC>[CH3:14][O:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[N:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[C:5]([C:12]#[N:13])=[CH:4][N:3]=2)=[CH:24][CH:23]=1)(=[O:21])=[O:20]
Reactant: C#CCOc1nc(Cl)ncc1C#N
Reactant: COCCNS(=O)(=O)c1ccc(N)cc1
Solvent: CCC(C)O
Product: C#CCOc1nc(Nc2ccc(S(=O)(=O)NCCOC)cc2)ncc1C#N
Yield: 66.8 %

Procedure:
A solution of 2-chloro-4-(2-propyn-1-yloxy)-5-cyanopyrimidine (Method 17; 219 mg, 1.13 mmol) and 4[N-(2-methoxyethyl)sulphamoyl]aniline (Method 38; 130 mg, 0.56 mmol) in 2-butanol (8 ml) was stirred at 50° C. for 18 hours. Solvent was removed under reduced pressure and the product recrystallized from methanol to give the title compound (145 mg, 67%). NMR: 2.90 (q, 2H), 3.15 (s, 3H), 3.25 (m, 2H), 3.70 (s, 1H), 5.20 (s, 2H), 7.55 (t, 1H), 7.75 (d, 2H), 7.90 (d, 2H), 8.80 (s, 1H); m/z 387.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27](=S)[NH2:28])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:30](N)[CH2:31][NH2:32]>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]2[NH:28][CH2:30][CH2:31][N:32]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C(N)=S)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: NCCN
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C2=NCCN2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (2S,4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)-2-thiocarbamoylpyrrolidine (1.5 g) in tetrahydrofuran (20 ml) was added ethylene - diamine (1.25 ml) at 0° C. After stirring at room temperature for 24 hours, the mixture was evaporated, extracted with ethyl acetate, and washed with water and brine successively. The dried organic layer was evaporated, and the obtained oil was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane, methanol and triethylamine (90:10:1, V/V,V) to give (2S,4R)-4-t-butyldimethylsilyloxy-2-(2-imidazolin-2-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.2 g).
Reaction SMILES: C(C(CCCC)C([O-])=O)C.[Na+:11].[CH3:12][O:13][CH2:14][C:15]1[CH2:36][S:35][C@@H:18]2[C@H:19]([NH:22][C:23](/[C:25](/[C:29]3[N:33]=[C:32]([NH2:34])[S:31][CH:30]=3)=[N:26]\[O:27][CH3:28])=[O:24])[C:20](=[O:21])[N:17]2[C:16]=1[C:37]([OH:39])=[O:38]>CN(C)C(=O)C.CO>[CH3:12][O:13][CH2:14][C:15]1[CH2:36][S:35][C@@H:18]2[C@H:19]([NH:22][C:23](/[C:25](/[C:29]3[N:33]=[C:32]([NH2:34])[S:31][CH:30]=3)=[N:26]\[O:27][CH3:28])=[O:24])[C:20](=[O:21])[N:17]2[C:16]=1[C:37]([O-:39])=[O:38].[Na+:11]
Reactant: COCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
2.03 g of sodium 2-ethylhexanoate was dissolved in a mixture of 12.5 ml of N,N-dimethylacetamide and 50 ml of methanol, 5.0 g of cefpodoxime (7-[2-(2-amino-4-thiazolyl)-(Z)-2-(methoxyimino)acetamido]-3-methoxymethyl -3-cephem-4-carboxylic acid) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Then, methanol was removed under a reduced pressure and 50 ml of acetone was added thereto. The solution was stirred for 30 minutes and filtered. The filtered solid was washed with 50 ml of acetone and then with 30 ml of isopropyl ether, and vacuum-dried at room temperature to give 4.98 g of pale yellow cefpodoxime sodium salt (yield: 95%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].CN(C)C=O.S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:26])=[O:15])=[CH:12][CH:11]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=C(C)C(=O)OCCOc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCOc1ccc(C(=O)Cl)cc1

Procedure:
62.56 g of 4-methacryloyloxyethyloxybenzoic acid was charged to a flask with 0.5 g dimethyl formamide , and 54.38 ml of thionyl chloride was added dropwise under stirring. The reaction was exothermic. The reaction mixture was stirred overnight to give a clear brownish solution. The excess thionyl chloride was drawn off under vacuum. The residue was digested once with 20 ml of distilled toluene, and the toluene drawn off under vacuum. The residue was directly usable.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.O.NN>[Ni].C(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CN1CCc2cc(N)ccc21

Procedure:
Approximately 400 mg of Raney nickel is added to a mixture of 2.84 g (15.9 mmol) of 1-methyl-5-nitroindoline and 4 ml (80 mmol) of hydrazine hydrate in-60 ml of absolute ethanol. The reaction mixture is heated to reflux for 5 hours. After returning to 23° C., a little silica is added to the flask and the solvent is evaporated off under vacuum. The evaporation residue is placed directly at the top of a chromatography column. The expected product is eluted using a Heptane/AcOEt mixture (3/7). A violet powder is obtained (65%) which is used directly in the following stage.