Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[OH:14].Br[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.O>CN(C)C=O>[NH2:13][C:9]1[C:10]([Cl:12])=[CH:11][C:6]([C:5]([OH:4])=[O:15])=[C:7]([O:14][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:8]=1
Reactant: BrCC1CCCCO1
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(OCC2CCCCO2)c(C(=O)O)cc1Cl
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
A suspension of 50% sodium hydride/oil dispersion (1.00 g, 0.025 mole) in anhydrous dimethylformamide (40 ml) under nitrogen was treated with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (4.03 g, 0.020 mole), stirred for 30 minutes, then treated with 2-(bromomethy)tetrahydro-2H-pyran (4.66 g, 0.026 mole). The mixture was heated to 95°±5° C. for 1.5 hours, then cooled and added to water (250 ml). The aqueous mixture was extracted with ether (2×200 ml), and the combined ethereal solution was dried (magnesium sulfate), concentrated in vacuo, an taken up in 95% ethanol (40 ml), water (20 ml) and 50% sodium hydroxide (20 ml) were added, and the mixture was refluxed for one hour, cooled on an ice bath, and concentrated in vacuo in order to remove most of the ethanol. Water was added to a total volume of 200 ml, and the aqueous solution was extracted with ether (2×100 ml), cooled on an ice bath, and adjusted to pH~4 with concentrated hydrochloric acid (32 ml). A solid soon precipitated, and this was filtered, washed with water, air dried, and recrystallized from ethyl acetate to afford 3.45 g (60%) of the title compound as colorless crystals; mp 146.5°-147.5° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:22])[CH:3]=1.[OH:23][C@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>>[OH:23][C@H:24]1[CH2:28][CH2:27][N:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH2:13][C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:22])[CH:3]=2)[CH2:25]1
Reactant: O[C@H]1CCNC1
Reactant: Cc1cc(Cl)c2ccc(OCc3ccc(C#N)cc3)cc2n1
Product: Cc1cc(N2CC[C@H](O)C2)c2ccc(OCc3ccc(C#N)cc3)cc2n1
Yield: 87.7 %

Procedure:
A solution of 1.42 g of (4.6 mmol) of 4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile and 1.11 g (12.5 mmol) of (S)-3-hydroxypyrrolidine in 1-methyl-2-pyrrolidine (25 ml) was heated under nitrogen at 100° C. (oil bath temperature) for 23 h. The reaction mixture was concentrated in a high vacuum, the residue taken up in methylene chloride, which was washed with water, saturated NaCl solution and then dried over magnesium sulphate. The solvent was removed in vacuo, the residue triturated with MeOH, filtered off by suction, washed subsequently with MeOH and ether and then dried in a high vaccum to give 1.45 g (83.86%) of the (S)-4-[4-(3-hydroxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile as a brown solid. ISP mass spectrum, m/e: 360.2 (M+1 calculated for C22H21N3O2: 360.2).
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].[C:10](Cl)(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:10]([NH:2][N:3]1[CH2:9][C:7](=[O:8])[NH:6][C:4]1=[O:5])(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN1CC(=O)NC1=O
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)NN1CC(=O)NC1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a pyridine solution (500 ml) of 1-aminohydantoin hydrochloride (50 g, 0.3 mole) was added cinnamoyl chloride (53 g, 0.3 mole). The stirred mixture was heated on the steam bath for 5 hours, then poured into ice water. After standing overnight, the precipitated product was removed by filtration and washed thoroughly with water. After drying, the crude white product weighed 60 g (74%). Several recrystallizations from methanol provided analytical material which melted at 276°-278°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:20]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([CH3:16])[CH2:14][NH:15][C:29](=[O:30])[C:28]3[CH:32]=[C:24]([C:21]4[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=4)[CH:25]=[N:26][CH:27]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: CC(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 28 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)propan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (75 mg, yield 28%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.47-9.46 (d, J=2.0 Hz, 1H), 9.33 (d, J=2.0 Hz, 1H), 8.88-8.87 (t, J=2.1 Hz, 1H), 8.11-8.04 (m, 3H), 7.54 (d, J=1.0 Hz, 1H), 7.18-7.14 (t, J=8.8 Hz, 2H), 4.02-3.96 (ddd, J=13.2 Hz, 6.5 Hz, 4.1 Hz, 1H), 3.53-3.46 (ddd, J=13.1 Hz, 9.0 Hz, 4.3 Hz, 1H), 3.20-3.11 (m, 1H), 1.42-1.40 (d, J=7.0 Hz, 3H). MS (ESI) m/z: Calculated for C21H15F4N5O3: 461.11. found: 462.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH:38]=[CH:37][C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:36]6[CH:37]=[CH:38][N:34]([CH3:33])[N:35]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: Cn1ccc(C2(N)CC2)n1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccn(C)n5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.15 g, 0.35 mmol, 1 eq), 1-(1-methyl-1H-pyrazol-3-yl)cyclopropanamine (0.058 g, 0.42 mmol, 1.2 eq), HOBT (0.08 g, 0.069 mmol, 1.7 eq), EDC.HCl (0.073 g, 0.014 mmol, 1.8 eq), in DCM at ambient temperature under nitrogen was added Diisopropylethylamine (0.297 g, 2.2 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer is further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and the final purification was done by preparative HPLC. Yield: 0.06 g (45%) 1H NMR (400 MHz, DMSO-d6): δ 1.18-1.20 (m, 4H), 2.29 (s, 3H), 2.81-2.82 (d, 3H, J=4.64 Hz), 3.73 (s, 3H), 3.96 (s, 3H), 6.06-6.07 (d, 1H, J=2.4 Hz), 7.12 (s, 1H), 7.32-7.34 (dd, 1H, J=8.4, 1.6 Hz), 7.38.-7.42 (t, 2H, J=8.8 Hz), 7.48.-7.49 (d, 2H, J=2.34 Hz), 7.59 (s, 1H), 7.71-7.73 (d, 1H, J=8.4 Hz), 7.97-7.97-8.01 (m, 2H), 8.47-8.48 (d, 1H, J=4.8 Hz), 8.69 (s, 1H). LCMS: (ES+) m/z=553.2 (M+H).: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)=O.[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][CH2:25][C:26]([CH3:28])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:31][O:30][C:23](=[O:29])[CH2:24][C:25]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:26]=1[CH3:28]
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1OC
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCCC3
Yield: 80.2 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3,4-dimethoxyphenyl)methanone (0.317 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane furnished 0.330 g (80%) of the title compound as a yellow solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH:7]([C:11]([O:13]C)=O)[CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:15]1[CH2:20][CH:19]=[CH:18][CH2:17][CH2:16]1>>[O:4]1[C:5]2([CH2:10][CH2:9][NH:8][CH:7]([C:11]([N:15]3[CH2:16][CH:17]=[CH:18][CH2:19][CH2:20]3)=[O:13])[CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: C1=CCNCC1
Reactant: COC(=O)C1CC2(CCN1)OCCO2
Product: O=C(C1CC2(CCN1)OCCO2)N1CC=CCC1
Temperature: 150 °C

Procedure:
A mixture of the product of Example 1 stage (iv) (1 g) and 1,2,3,6-tetrahydropyridine (2.8 ml) was heated at 150° C. in a reactivial for 2 h. After cooling the mixture was evaporated in vacuo and the solid residue (800 mg) was purified by flash chromatography eluting with dichloromethane/methanol/ammonia (200:10:1) to give the title compound as an oil (260 mg). T.l.c. Silica, dichloromethane/methanol/ammonia (150:8:1) Rf 0.25.
Reaction SMILES: [S:1]([C:4]1[S:8][C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)=[N:6][CH:5]=1)[C:2]#[N:3].[CH3:18]O>O=P(Cl)(Cl)Cl>[CH3:18][O:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:7]2[S:8][C:4]([S:1][C:2]#[N:3])=[CH:5][N:6]=2)=[N:15][CH:14]=1
Reactant: N#CSc1cnc(Nc2ccc(CO)cn2)s1
Reactant: CO
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1ccc(Nc2ncc(SC#N)s2)nc1
Temperature: 85 °C

Procedure:
(6-(5-Thiocyanatothiazol-2-ylamino)pyridin-3-yl)methanol (0.094 g, 0.356 mmol) was dissolved in POCl3 (3 mL) and the reaction was heated at 85° C. for 3 hours. POCl3 was then evaporated and the resulting oil was washed with water to give a gummy solid. Methanol (10 mL) was added to the solid and the resulting suspension was stirred at 23° C. for over a month. Methanol was evaporated to almost dryness and water was added to precipitate the oil. The resulting solid was filtered and dried under vacuum to give the crude title material (0.109 g, quant.) which was used as such in the next reaction. HPLC ret. time (Condition A): 1.603 min. LC/MS (M+H)+: 279.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[C:5]([O:9][CH3:10])=[CH:6][C:7]=1[F:8].OS(O)(=O)=O.[CH3:20]O>O>[F:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:20])=[O:13])[C:5]([O:9][CH3:10])=[CH:6][C:7]=1[F:8]
Reactant: CO
Reactant: COc1cc(F)c(F)cc1CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1cc(F)c(F)cc1OC

Procedure:
4.04 g of 2-(3,4-difluoro-6-methoxyphenyl)acetic acid (D3) are dissolved in 34 ml of methanol. 1.54 ml of H2SO4 (95-98%, extra pure) are subsequently added, and the reaction solution is heated under reflux for 3 h. For work-up, the mixture is diluted with 100 ml of water and extracted twice with 150 ml of ethyl acetate each time. The combined organic phases are washed with 50 ml of saturated NaHCO3 solution, dried over Na2SO4, filtered off with suction and evaporated to dryness in vacuo. The residue is recrystallised from cyclohexane, giving 4.0 g of the title compound as a colourless solid having a melting point of 48.3° C.; MS: 216.1 (M+); TLC: Rf=0.60 (cyclohexane/diethyl ether 1:1 parts by volume).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C1(P(=[CH:32][CH:33]=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5](/[CH:6]=[CH:32]/[CH:33]=[O:34])[CH:8]=[CH:9][CH:10]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: O=C/C=C/c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Trifluoromethylbenzaldehyde (20.0 g, 0.115 mol) was taken up in 500 mL of CH3CN along with (triphenylphosphoranylidene)acetaldehyde (35 g, 0.115 mol). The reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in 800 mL of 1:1 pentane/EtOAc and filtered. The filtrate was concentrated under reduced pressure to afford crude (E)-3-(3-(trifluoromethyl)phenyl)acrylaldehyde as a dark red oil. This material was taken up in 30 mL of CH2Cl2. The resulting mixture was slowly added to a suspension of 2-nitroaniline (4 g, 0.029 mol) in concentrated HCl (50 mL) at 90° C. over a period of 30 min. The resulting reaction mixture was stirred at 90° C. for an additional 1 h. The reaction mixture was cooled to room temperature and washed with CH2Cl2 (2×100 mL). The aqueous layer was neutralized with 5% aqueous NaOH and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (pentane/EtOAc) to afford 800 mg of 8-nitro-2-(3-(trifluoromethyl)phenyl)quinoline. MS (ESI) calcd for C16H9F3N2O2 (m/z): 318.06. found: 319 [M+1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33](=[O:46])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:35]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:31][C:30]1[CH:29]=[CH:28][C:27]([NH:32][C:33](=[O:46])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]3)[CH:35]=2)=[CH:26][C:25]=1[NH:24][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:16]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCCCC3)c2)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Product: Cc1ccc(NC(=O)c2cccc(N3CCCCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 57 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 25, 3-(1-tert-butoxycarbonylpiperidin4-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-piperidinobenzamide to give N-[2-methyl-5-(3-piperidinobenzamido)phenyl]-3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzamide in 57% yield; NMR Spectrun: (DMSOd6) 1.39 (s, 9H), 1.54 (m, 4H), 1.62 (m, 4H), 1.91 (m, 2H), 2.19 (s, 3H), 3.2 (m, 4H), 3.65 (m, 2H), 4.64 (m, 4H), 7.09 (m, 1H), 7.19 (m, 2H), 7.27 (m, 2H), 7.41 (t, 2H), 7.58 (m, 2H), 7.79 (m, 1H), 9.83 (s, 1H), 10.09 (s, 1H); Mass Spectrum: M—C3H7+ 557.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:6]3[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(Br)n2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(-c3ccc(F)cc3)n2n1
Temperature: 80 °C
Yield: 88.4 %

Procedure:
To a stirred mixture of 3-bromo-6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.100 g, 0.275 mmol), 4-fluorophenylboronic acid (0.412 mmol), Na2CO3 (0.825 mmol) in 2-propanol (6 mL) and water (2 mL) that has been degassed with N2 (5 minutes) is added PdCl2(PPh3)2(0.0275 g). The reaction mixture is heated at 80° C. for 6 hours, cooled, diluted with sat. aqueous NaHCO3 (50 mL) and extracted with EtOAc (3×25 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography (hexanes to EtOAc) to afford 0.092 g (88%) of the title compound as a yellow solid: Rf 0.47 (1:1 EtOAc:hexanes); LCMS (m/z)=379.4 [M+H]+, tR=3.07 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:21][OH:22].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:21][OH:22])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ncc(Cl)cc1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(=NO)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.8 %

Procedure:
To a solution of 10.6 g of tert-butyl N-[2-(3,5-dichloropyridin-2-yl)-2-oxoethyl]carbamate and 4.8 g of hydroxylamine hydrochloride in 87 ml of ethanol, 6.1 g of pyridine was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 50 ml of water and extracted with ethyl acetate (100 ml×2), the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 40:60) as the eluent to obtain 10.1 g of the desired product as a pale yellow resinous substance.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=[CH:10][C:2]=1[F:1]
Reactant: CO
Reactant: CC(C)Oc1cc(C(=O)O)c(F)cc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC(C)C)c(O)cc1F

Procedure:
2-Fluoro-4-hydroxy-5-isopropyloxybenzoic acid (5.7 g) is dissolved in methanol (200 mL) and concentrated sulfuric acid (1 mL) and heated at 70° C. for 5 hours. The solution is concentrated and the resultant oil subjected to mplc on silica gel using petroleum ether:ethyl acetate (4:1 v/v) as eluent to give methyl-2-fluoro-4-hydroxy-5-isopropyloxybenzoate (5.7 g). [NMR (CDCl3) 7.38 (d, 1H, J=7 Hz), 6.67 (d, 1H, J=12 Hz), 4.85 (m, 1H), 3.9 (s, 3H), 1.3 (d, 6H, J=7 Hz)].
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH2:25]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH:8]([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
A mixture of (1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl ester (507 mg, 2.04 mmol) and potassium carbonate (367 mg, 2.65 mmol) in ethanol (15 mL) was treated with benzyl bromide (367 mg, 2.14 mmol) and stirred overnight at ambient temperature. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The isolated organic phase was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The resulting oil was chromatographed on silica gel, eluting with 5-to-50% ethyl acetate in hexane to afford the title compound (529 mg, 77%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ: 1.38 (s, 9H), 2.65-2.75 (dd, 1H), 2.83-2.92 (dd, 1H), 3.11-3.22 (dd, 1H), 3.35-3.42 (dd, 1H), 3.77-3.90 (m, 1H), 4.39-4.51 (q, 2H), 6.45-6.52 (m, 2H), 6.82-6.94 (m, 3H), 7.20-7.34 (m, 5H). MS (ESI) m/z 222.2, 283.1, 339.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8](SC)[N:7]=[C:6]([N:12]2[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]2)[C:5]=1[N+:19]([O-:21])=[O:20])[CH3:2].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:7]=[C:6]([N:12]2[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]2)[C:5]=1[N+:19]([O-:21])=[O:20])[CH3:2]
Reactant: CCOc1nc(SC)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
50 gm (0.15 mol) of 6-ethoxy-2-methylthio-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine together with 64.8 gm (0.15 mol) of piperazine, were dissolved in 150 ml of dimethyl sulfoxide and the solution was stirred for 6 hours at room temperature. Then, the reaction mixture was poured into ice-water, the crystals formed thereby were suction-filtered off, and the filter cake was washed with water and recrystallized from ethanol. Yield: 39.3 gm (70.7% of theory); m.p. 222°-223°C.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:29]2[N:30]=[C:31]([NH:34]C(=O)C(F)(F)F)[S:32][CH:33]=2)[C:7]([NH:9][C@@H:10]2[C:27](=[O:28])[N:12]3[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]4[S:20][CH:21]=[N:22][N:23]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1.O.O.O.C([O-])(=O)C.[Na+]>O.O1CCCC1>[NH2:34][C:31]1[S:32][CH:33]=[C:29]([C:6](=[N:5][O:4][CH:1]2[CH2:3][CH2:2]2)[C:7]([NH:9][C@@H:10]2[C:27](=[O:28])[N:12]3[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]4[S:20][CH:21]=[N:22][N:23]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[N:30]=1
Reactant: O=C(O)C1=C(CSc2nncs2)CS[C@@H]2[C@H](NC(=O)C(=NOC3CC3)c3csc(NC(=O)C(F)(F)F)n3)C(=O)N12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Reaction time: 8 h

Procedure:
To a suspension of 7β-[2-cyclopropyloxyimino-2-(2-trifluoroacetamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid syn isomer) (1.1 g) in a mixture of water (23.5 ml) and tetrahydrofuran (2 ml) was added sodium acetate trihydrate (2.35 g) at ambient temperature. The mixture was stirred at the same temperature overnight to give a clear solution. The solution was washed with ethyl acetate and adjusted to pH 2 with 1N hydrochloric acid. The mixture was extracted with tetrahydrofuran twice. The extract was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give 7β-[2-(2-amino- thiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (780 mg) as a solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].[CH2:12](Cl)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O>[CH2:14]([O:13][CH2:12][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCOCc1ccccc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(COCn2cnc3ccccc32)cc1
Reaction time: 0.33 h
Yield: 44.9 %

Procedure:
To a solution of benzimidazole (500 mg, 4.23 mmol) in 10 mL DMF at 0° C., was added NaH (60%, 169 mg, 4.23 mmol). The mixture was stirred for 20 min, then BOM-Cl (802 μL, 4.65 mmol) was added. The mixture was stirred at rt for 4 h, then was diluted with EtOAc. The organic phase was washed with H2O (3×) and brine, dried (Na2SO4), filtered through 1″ SiO2 (eluting with EtOAc). The crude product was purified by flash chromatography (30 to 100% EtOAc/hexanes gradient) to afford 453 mg of Intermediate 10.1 as a white crystalline solid.