Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37]1([N:43]=[C:44]=[S:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:22]2[CH:31]=[CH:32][C:19]([O:18][CH2:17][C:15]3[N:14]([CH3:33])[C:13]4[CH:34]=[C:9]([O:8][C:7]5[CH:35]=[CH:36][C:4]([NH:3][C:44]([NH:43][C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)=[S:45])=[CH:5][CH:6]=5)[CH:10]=[CH:11][C:12]=4[N:16]=3)=[CH:20][CH:21]=2)[S:28]1
Reactant: S=C=Nc1ccccc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=S)Nc4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.9 %

Procedure:
A mixture of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), phenyl isothiocyanate (113 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 4 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was recrystallized from a mixture of ethanol and ethyl acetate (5:1) to afford the title compound (347 mg, mp 129.6-130.9° C.).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[C:18]#[CH:19].C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:9][CH:19]=[C:18]([C:17]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1=CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
N-Benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (4.7 mL) was dissolved in dichloromethane (75 mL), and the solution was cooled to 0° C. To this solution was added dropwise a solution (10 mL) of ethyl propiolate (1.55 mL) in dichloromethane, and acetic acid (0.1 mL) was further added. The mixed solution was stirred for 4 hr while gradually warming to room temperature. The reaction solution was added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the object product as a pale-yellow oil (1.37 g). The obtained compound was used for the next reaction without purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36]>ClCCl>[CH2:13]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])[CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(NC(=O)OC(C)(C)C)CC2
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
tert-Butyl 7-(aminomethyl)-1-benzyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.600 g, 1.637 mmol) was suspended in dichloromethane (5 mL) and triethylamine (0.228 mL, 1.637 mmol) and cooled to 0° C. Ethanesulfonyl chloride (0.155 mL, 1.64 mmol) was added and the solid gradually dissolved. After 30 minutes the reaction was stopped by washing it with brine (1×50 mL). The organic phase was collected and dried on MgSO4, evaporated. The residue was purified by flash-chromatography on silica gel (100% DCM). Product was obtained as yellow solid (0.653 g, 1.42 mmol, 87%).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]2)[N:21]=1>CN(C=O)C.O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:32][CH:29]2[CH2:30][CH2:31][N:26]([C:22]3[N:21]=[N:20][CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CCN(c2cccnn2)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3cccnn3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 31.1 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.240 g, 0.80 mmol), 1-pyridazin-3-ylpiperidin-4-amine (0.257 g, 1.02 mmol) and TEA (0.324 g, 3.2 mmol), was dissolved in dry DMF (10 ml) and heated in a microwave reactor at 120° C. for 30 mins. The reaction mixture was diluted with water (300 ml) and extracted with EtOAc (2×150 ml). The combined organic phases were dried (MgSO4), filtered and evaporated and the residue was purified by silica gel column chromatography using EtOAc as eluant, to give the title compound (0.110 g, 31%). 1H NMR (500 MHz, CDCl3): δ 8.55-8.52 (m, 1H), 7.55-7.50 (m, 2H), 7.47-7.42 (m, 3H), 7.19-7.14 (m, 1H), 6.85-6.82 (m, 1H), 5.21 (d, 1H), 4.17-4.11 (m, 2H), 3.22-3.13 (m, 1H), 2.60-2.52 (m, 2H), 1.80-1.73 (m, 2H), 1.72 (s, 9H), 1.42-1.32 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.5, 143.1, 133.8, 131.6, 129.9, 128.7, 127.4, 125, 112.8, 107.2, 61.6, 50.1, 43.6, 31.7, 27.5; Mass Spectrum: M−H+ 442.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.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>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:14]2[O:13][CH:17]=[CH:16][CH:15]=2)[CH:6]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: OB(O)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Cc1cccc(-c2ccco2)c1
Temperature: 50 °C
Reaction time: 14 h
Yield: 66.3 %

Procedure:
To a solution of bromophenylacetic acid methyl ester (0.075 g, 0.328 mmol, 1.0 eq) in tetrahydrofuran (5.0 ml) was added 2-furanboronic acid (0.048 g, 0.426 mmol, 1.3 eq) and sodium carbonate (0.328 ml of a 2M soln in H2O). The solution was degassed and sonicated three times before adding tetrakis(triphenylphosphine)palladium (0.038 g, 0.033 mmol, 0.1 eq). The mixture was degassed and sonicated a further three times before stirring at 50° C. for 14 hours. After cooling to room temperature the solution was concentrated under reduced pressure. Column chromatography (silica, 20% EtOAc/hexane) yielded 3-furanylphenylacetic acid methyl ester (0.047 g, 67%) as a white solid; 1H-NMR (CDCl3, 400 MHz): δ 7.60 (1H, d, J=1.6 Hz), 7.47 (1H, t, J=1.0 Hz), 7.34 (1H, t, J=7.5 Hz), 7.19 (2H, m), 6.65 (1H, d, J=3.6 Hz), 6.48 (1H, dd, J=3.6, 1.6 Hz), 3.71 (3H, s), 3.66 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:11]3[C:12](=[O:16])[CH:13]=[CH:14][CH:15]=[C:10]3[N:9]2[S:25]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])(=[O:27])=[O:26])=[CH:4][CH:3]=1.C1C(=O)N([I:43])C(=O)C1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:17]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:11]3[C:12](=[O:16])[C:13]([I:43])=[CH:14][CH:15]=[C:10]3[N:9]2[S:25]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])(=[O:27])=[O:26])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cccc(S(=O)(=O)N2c3cccc(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1
Product: N#Cc1cccc(S(=O)(=O)N2c3ccc(I)c(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1

Procedure:
The titled compound was prepared according to general method B by reaction of rac-3-[cis-2,3-Bis-(4-chloro-phenyl)-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-sulfonyl]-benzonitrile with NIS.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12](/[CH:22]=[C:23]2\[CH2:24][CH2:25][C@H:26]3[CH2:31][NH:30][CH2:29][C@@H:28]([C:32]4[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=4)[N:27]3[C:41]\2=[O:42])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1>N1C=CC=CC=1>[C:1]([N:30]1[CH2:29][C@@H:28]([C:32]2[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=2)[N:27]2[C:41](=[O:42])/[C:23](=[CH:22]/[C:12]3[CH:13]=[CH:14][C:15]([N:16]4[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]4)=[C:10]([O:9][CH3:8])[CH:11]=3)/[CH2:24][CH2:25][C@H:26]2[CH2:31]1)(=[O:3])[CH3:2]
Reactant: COc1cc(/C=C2\CC[C@H]3CNC[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(/C=C2\CC[C@H]3CN(C(C)=O)C[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Acetic anhydride (0.5 mL) was added to a solution of (4R*,9aS*)-7-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}-4-(3,4,5-trifluorophenyl)octahydropyrido[1,2-a]pyrazin-6-one (20 mg) in pyridine (1 mL), and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate->ethyl acetate:methanol 4:1) to obtain 10.2 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([C:13](OCC)=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>NCCN1CCCC1>[C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([C:13]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1=NN(c2ccccc2)C(=O)C1
Agent: NCCN1CCCC1
Product: O=C1CC(c2ccccc2)=NN1c1ccccc1
Temperature: 130 °C
Yield: 99.2 %

Procedure:
A mixture of 2,4-dihydro-2-phenyl-5-ethoxycarbonyl-3H-pyrazol-3-one (10 g; 43 mmol) and 1-(2-aminoethyl)pyrrolidine (10 ml) was heated at 130° C. under nitrogen for 2 hours and cooled. The mixture was triturated in hexane, filtered and the solid was washed with hexane to yield 15 gm of a crude product. A portion (8.6 g ) of the crude product was purified by column chromatography (silica gel, triethylamine:methanol:methylene chloride 1:9:90) to afford 5.04 g of 2,4-dihydro-2-phenyl-5-[C(O)NH(CH2)2 -1-pyrrolidinyl]-3H-pyrazol-3-one (Formula III: R1 =Ph; R2 =C(O)NH(CH2)2 -1-pyrrolidinyl; R3 =H) as a tan solid, which was further crystallized in toluene/methanol (2×) to yield a white solid, m.p. 210°-211° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[NH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C1COCC1>[N:20]1([CH2:19][CH2:18][NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 25 h
Yield: 96.3 %

Procedure:
To a mixture of 1-fluoro-2-nitrobenzene (6 g, 43.0 mmol) and potassium carbonate (12 g, 86 mmol) in THF (80 mL) was added 4-(2-aminoethyl)morpholine (6.8 mL, 52.0 mmol) at 0° C. The mixture was stirred for 25 h at rt. Then the mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2/1) to afford 10.4 g (97%) of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([CH:51]=[CH:52][CH:53]=1)[NH:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:49][CH3:50])=[C:39]([O:42][CH:43]3[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]3)[CH:40]=2)[N:35]=[CH:34][N:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][N:65]1[CH2:72][CH2:71][CH2:70][C@H:66]1[C:67](O)=[O:68]>CN(C=O)C.C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([CH:51]=[CH:52][CH:53]=1)[NH:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:49][CH3:50])=[C:39]([O:42][CH:43]3[CH2:48][CH2:47][CH2:46][N:45]([C:67]([C@@H:66]4[CH2:70][CH2:71][CH2:72][N:65]4[CH3:64])=[O:68])[CH2:44]3)[CH:40]=2)[N:35]=[CH:34][N:33]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)[C@@H]2CCCN2C)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
HATU (0.26 g) was added to a solution of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride (250 mg; prepared as described in Example 45), diisopropylethylamine (210 μl) and N-methyl-L-proline (0.120 g) in DMF (7.5 ml) and the mixture was stirred at room temperature for 2.5 hours. The DMF was removed under reduced pressure and the residue dissolved in methylene chloride (50 ml) and washed with sodium bicarbonate (50 ml) then water (50 ml). Purification by flash column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (9614). The fractions containing the expected product were evaporated to give a foam. This foam was dissolved in methylene chloride (5 ml) and crystallised by the addition of isohexane (50 ml) to give the title product as a mixture of two diastereoisomers (0.130 g). 1H NMR Spectrum: (DMSO d6) 1.43-1.62 (m, 2H), 1.66-1.95 (m, 4H), 1.96-2.18 (m, 4H), 2.20-2.29 (m, 2H), 2.67-2.80 (m, 1H), 2.96 (m, 1H), 3.03-3.20 (m, 1H), 3.51-3.80 (m, 2H), 3.80-4.05 (m, 4H), 4.51-4.68 (m, 1H), 7.22-7.31 (2H), 7.47-7.59 (m, 2H), 7.89 (m, 1H), 8.39 (s, 1H), 9.55 (m, 1H); Mass Spectrum: (M+H)+ 514.
Reaction SMILES: [Na].[P:2]([O:6][CH2:7][C@@H:8]([OH:15])[C@@H:9]([OH:14])[C@@H:10]([OH:13])[CH:11]=[O:12])([OH:5])([OH:4])=[O:3].[BH4-].[Na+]>CO>[P:2]([O:6][CH2:7][C@@H:8]([OH:15])[C@@H:9]([OH:14])[C@@H:10]([OH:13])[CH2:11][OH:12])([OH:4])([OH:5])=[O:3]
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)COP(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=P(O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
The sodium salt of D-ribose 5-phosphate (18.5 mg, 67.5 μmol) is dissolved in methanol (600 μl, 40% (v/v)). Sodium borohydride is added. The reaction is monitored by detection of the aldehyde according to the method of Stahl (Bollinger, H. R., Brenner, M., Gänshirt, H., Mangold, H. K., Seiler, H., Stahl, E. ad Waldi, D. (1964) IN: Dünnschicht-Chromatographie; Ein Laboratoriumshandbuch (ed. Stahl, E.) Springer Verlag, Berlin, Göttingen; Heidelberg). After consumption of the aldehyde the pH of the solution is adjusted with acetic acid to 4–5. The reaction mixture is lyophillized yielding D-ribitol 5-phosphate as a dry compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14].CCN(C(C)C)C(C)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COC(=O)c1cccc(N)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(Nc2cc(Cl)ncn2)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
To a stirred solution of 4,6-dichloropyrimidine (0.5 g, 3.7 mmol) in n-butanol (10 mL) was added methyl 3-aminobenzoate (0.498 g, 3.7 mmol) and DIPEA (0.65 g, 5.0 mmol) and the reaction mixture was heated at 110° C. for 12 h. It was cooled and excess n-butanol was removed under reduced pressure. The residue was extracted with EtOAc (2×30 mL) and the combined EtOAc extract was washed with water (5 mL), brine (2.5 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was stirred with pet ether (30 mL) for 30 min, the pet ether removed by decantation and the solid obtained was dried under high vacuum to give methyl 3-(6-chloropyrimidin-4-ylamino)benzoate (0.3 g, 34%) as light brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([OH:22])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20].ClC1C=CC=CC=1.CCCCCC>CN(C)C=O.CO.C(OCC)(=O)C>[F:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[O:22][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])c(F)c2)ccn1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 27.6 %

Procedure:
A mixture of methyl 4-chloropyridine-2-carboxylate (200 mg), 3-fluoro-4-nitrophenol (202 mg) and chlorobenzene (0.6 ml) was stirred under a nitrogen atmosphere at 120° C. for 2 hrs and 20 min. The reaction mixture was cooled down to room temperature to give a solidified reaction mixture, which was then dissolved in a small amount of N,N-dimethylformamide and subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1). Fractions containing the target compound were concentrated to provide the titled compound (94 mg, 27.5%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]([CH2:17][C@H:18]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)[CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.FC(F)(F)C(O)=O.[C:37]([OH:46])(=[O:45])[C@@H:38]([C@H:40]([C:42]([OH:44])=[O:43])[OH:41])[OH:39]>ClCCl.C(O)(C)C>[C:42]([C@@H:40]([C@H:38]([C:37]([OH:46])=[O:45])[OH:39])[OH:41])([OH:44])=[O:43].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]([CH2:17][C@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)[CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN(Cc2ccc(Cl)cc2Cl)C2CCOCC2)C1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: ClCCl
Product: Clc1ccc(CN(C[C@H]2CCNC2)C2CCOCC2)c(Cl)c1

Procedure:
A solution of (3R)-N-{[2,4-dichlorophenyl]methyl}-N-(tetrahydro-2H-pyran-4-yl)-1-tert-butyloxycarbonylpyrrolidine-3-yl-methylamine (0.36 g, 0.81 mmol) in dichloromethane (10 ml) is stirred at room temperature with trifluoroacetic acid (0.93 g, 8.10 mmol) overnight. The reaction mixture is concentrated in vacuo and the oil is dissolved in methanol, purified using a SCX-2 column (10 g), then washed with methanol. The basic product elutes with methanolic ammonia (2M). Evaporation to an oil and further purification by preparative LC-MS gives a colourless oil. Dissolve the oil in isopropyl alcohol and add L-tartaric acid (1 eq) then heat to give a clear solution. Crystallise by cooling to give the title compound as a colourless solid. 1H NMR (300 MHz, DMSO) δH: 7.57-7.56 (2H, m), 7.44-7.40 (1H, m), 3.88-3.85 (4H, m), 3.70 (2H, s), 3.24-3.03 (5H, m), 2.77-2.70 (1H, m), 2.59-2.51 (2H, m), 2.44-2.31 (1H, m), 1.94-1.88 (1H, m), 1.66-1.48 (6H, m), LCMS: Rt=4.22 (12 min method) [M+H]=343/5.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:32]=[C:33]([C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[N:39][CH:40]=1)[CH3:34]>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[N:6](/[CH:32]=[C:33](/[C:35]3[CH:40]=[N:39][C:38]([CH3:41])=[CH:37][CH:36]=3)\[CH3:34])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(=CBr)c1ccc(C)nc1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3ccccc31)CN(C)CC2)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (186 mg, 0.8 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (19 mg, 0.10 mmol), L-proline (23 mg, 0.20 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 5-(1-Bromoprop-1-en-2-yl)-2-methylpyridine (212 mg, 1 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). The product was further purified by HPLC. 1H NMR (CDCl3, TFA salt) δ (ppm): 9.10 (s, 1H), 8.30 (d, 1H), 7.70 (m, 1H), 7.42 (d, 1H), 7.25 (m, 2H), 7.10 (d, 2H), 4.80 (m, 1H), 4.20 (m, 1H), 3.90 (m, 1H), 3.40 (m, 2H), 3.10 (s, 3H), 3.0 (m, 1H), 2.82 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][CH:6]([F:23])[O:7][C:8]1[C:9]([F:22])=[C:10]([C:14]([N+:19]([O-:21])=[O:20])=[C:15]([F:18])[C:16]=1[F:17])[C:11](O)=[O:12]>C1C=CC=CC=1>[F:5][CH:6]([F:23])[O:7][C:8]1[C:9]([F:22])=[C:10]([C:14]([N+:19]([O-:21])=[O:20])=[C:15]([F:18])[C:16]=1[F:17])[C:11]([Cl:3])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]
Solvent: c1ccccc1
Product: O=C(Cl)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]

Procedure:
40 ml of thionyl chloride were added to a solution of 15.97 g (0.056 moles) of 3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoic acid [(XII), R1 =--OCHF2, R3' =NO2, X=X'=F] in 50 ml of benzene, and the mixture was heated under reflux for 2 hours. At the end of this time, the benzene and the excess thionyl chloride were removed by distillation under reduced pressure to give 16.50 g of 3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl chloride [(XIII), R1 =--OCHF2, R3' =NO2, X=X'=F].
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:16][O:17][CH2:18][CH:19]=[CH2:20])[C:13]([OH:15])=O)[N:11]=1.[NH2:21][CH:22]1[C:32](=[O:33])[N:24]2[C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH2:27][S:28][C@H:23]12.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:16][O:17][CH2:18][CH:19]=[CH2:20])[C:13]([NH:21][CH:22]2[C:32](=[O:33])[N:24]3[C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH2:27][S:28][C@H:23]23)=[O:15])[N:11]=1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: C=CCON=C(C(=O)O)c1csc(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Reaction time: 0.33 h
Yield: 44.5 %

Procedure:
Phosphoryl chloride (0.84 g.) was added dropwise to a stirred suspension of 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetic acid (syn isomer, 1.0 g.), tetrahydrofuran (10 ml.) and water (0.05 ml.) at 5° C., and stirred at the same temperature for 20 minutes. Trimethylsilylacetamido (0.66 g.), phosphoryl chloride (0.84 g.) and N,N-dimethylformamide (0.45 g.) were added to a solution, and stirred at 5° C. for an hour to prepare the activated acid solution. On the other hand, trimethylsilylacetamido (4.0 g.) was added to a suspension of 7-amino-3-cephem-4-carboxylic acid (0.88 g.) in tetrahydrofuran (10 ml.) at 40° C., and stirred for 30 minutes. To the solution was added all at once the activated acid solution obtained above at -20° C., and stirred at 0° C. for an hour. After water (20 ml.) was added to the resultant solution at -20° C., the solution was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. Ethyl acetate was added to the solution, and the aqueous layer was separeted. The solution was washed with ethyl acetate and diisopropyl ether in turn, adjusted to pH 5.0 and treated with activated charcoal. After the solution was adjusted to pH 3.0, the precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.8 g.).