Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cn2)cc1
Temperature: 120 °C
Yield: 89.6 %

Procedure:
A mixture of [4-(methylthio)phenyl]boronic acid (66 mg, 0.39 mmol), 1-methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 81, Step 1, 140 mg, 0.39 mmol), PdCl2(PPh3)2 (50 mg), 2M Na2CO3 (1 mL) and DME (2 mL) was stirred and heated in a microwave at 120° C. for 10 min, cooled to ambient temperature, and the organics were separated. The aqueous phase was washed with EtOAc. The organics were combined, dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 50% EtOAc/hexanes to give 140 mg (90%) of 1-methylethyl 4-[({6-[4-(methylthio)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.32 (d, 1H, J=2.8 Hz), 7.84 (d, 2H, J=8.5 Hz), 7.60 (d, 1H, J=8.8 Hz), 7.30 (d, 2H, J=8.5 Hz), 7.22 (bs, 1H), 4.90 (septet, 1H, J=6.3 Hz), 4.20 (bs, 2H), 3.87 (d, 2H, J=6.3 Hz), 2.85-2.70 (m, 2H), 2.50 (s, 3H), 2.04-1.94 (m, 1H), 1.90-1.75 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 401 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([Cl:18])[C:6]2[O:10][CH:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][C:7]=2[CH:17]=1.[C:19](Cl)([Cl:21])=[O:20]>C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([Cl:18])[C:6]2[O:10][CH:9]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][CH3:16])[C:19]([Cl:21])=[O:20])[CH2:8][C:7]=2[CH:17]=1
Reactant: CCCCNCC1Cc2cc(Cl)cc(Cl)c2O1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCN(CC1Cc2cc(Cl)cc(Cl)c2O1)C(=O)Cl
Reaction time: 4 h

Procedure:
A thoroughly stirred suspension of 26 g (0.0838 mole) of N-(5,7-dichloro-2,3-dihydrobenzofuran-2-ylmethyl)-N-butylamine hydrochloride in 250 ml of dry ethyl acetate was gassed with phosgene at 50° C. After 4 hours, the suspended material had dissolved. The mixture was evaporated down under reduced pressure, at 50° C. and under 0.5 mbar in the final stage. 27 g of N-(5,7-dichloro-2,3-dihydrobenzofuran-2-ylmethyl)-N-butylcarbamyl chloride were obtained as a colorless oil, which was reacted further without additional purification.
Reaction SMILES: Cl.[C:2](=[NH:9])(OC)[CH2:3][CH2:4][CH2:5][CH3:6].CN(C)C=O.[NH2:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1>C(N(CC)CC)C>[NH:9]=[C:2]([NH:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:24][CH:25]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CCCCC(=N)OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC(=N)NCc1ccc(C(=O)O)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A 22 L, three-necked round bottom flask equipped with an air-powered mechanical stirrer was placed under a nitrogen atmosphere. The vessel was charged with methyl valerimidate hydrochloride (2.5 kg, 16 mol) and dimethylformamide (9.2 L). A thermometer was attached and the suspension cooled to 0°-15° C. with a cooling bath. Triethylamine (2.3 L) was added to the reaction at such a rate so that the internal temperature did not exceed 25° C. The cooling was stopped and the reaction was allowed to stir 1 hour. The reaction mixture was vacuum filtered using a Buchner funnel and a carboy (20 L). The filter cake was washed with additional dimethylformamide (1.0 L) and force-air dried for 15 min. The combined filtrates were saved. Another clean 22 L, three-necked round bottom flask equipped as above was placed under nitrogen. The vessel was charged with the combined filtrates from above followed by triethylamine (1.6 L) and 4-(aminomethyl)benzoic acid (1.7 kg, 11.5 mol). The thermometer was attached and the suspension was heated to an internal temperature of 65° C. with a heating mantle and a temperature controller. The heating was continued for 20 hours. The reaction was cooled to ambient temperature and filtered to yield 2.5 kg of product; 92% uncorrected yield.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([F:33])[CH:27]=1.[F:34][C:35]([F:50])([F:49])[C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[C:39](O)=[O:40]>>[F:34][C:35]([F:49])([F:50])[C:36]1[CH:37]=[C:38]([C:39]([NH:12][C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:15][C@H:14]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([F:33])[CH:27]=2)=[O:40])[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](c2ccc(Cl)c(F)c2)C1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccc(Cl)c(F)c2)C1

Procedure:
Using the compound obtained in step 1 and 3,5-bis(trifluoromethyl)benzoic acid, and by the reaction and purification in the same manner as in Reference Example 1, step 5, the title compound was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH2:17][CH2:16]1)=[N:11][C:10]([C:35]1[CH:40]=[C:39]([Cl:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[ClH:41].[ClH:41].[ClH:41].[Cl:41][C:39]1[CH:40]=[C:35]([C:10]2[N:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:13]3[NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[CH2:17][CH2:16]2)[CH:36]=[C:37]([Cl:43])[C:38]=1[OH:42]
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1NC1CCC(CN2CCN(C(=O)OC(C)(C)C)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN2CCNCC2)CC1
Product: Cl

Procedure:
Following general procedure IV-2, tert-butyl 4-((4-((3-acetyl-6-(3,5-dichloro-4-hydroxy-phenyl)-1,5-naphthyridin-4-yl)amino)cyclohexyl)methyl)piperazine-1-carboxylate (0.298 mmol) was reacted with TFA (2 mL) followed by formation of the trihydrochloride salt to afford the desired product (84 mg, 47% over two steps) as a yellow solid: 1H NMR (500 MHz, D2O) δ 9.00 (s, 1H), 8.22-8.11 (m, 2H), 7.59 (s, 2H), 5.06 (m, 1H), 4.76-4.71 (m, 1H), 4.66 (s, 1H), 3.60 (s, 8H), 3.15 (d, J=6.7 Hz, 2H), 2.74 (s, 3H), 2.25-2.23 (m, 2H), 2.02-1.97 (m, 2H), 1.60-1.58 (m, 2H), 1.24-1.20 (m, 2H); ESI MS m/z 528 [M+H]+; HPLC 98.0% (AUC), tR=9.29 min.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br[CH2:19][C:20]([CH3:22])=[CH2:21].[In]>C1COCC1.O.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH2:21][C:20]([CH3:22])=[CH2:19])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: C=C(C)CBr
Agent: [In]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)CC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (609 mg) in THF (4 mL) and H2O (12 mL) at room temperature were added 3-bromo-2-methyl-propene (0.31 mL), followed by indium powder (279 mg, −100 mesh). The resulting mixture was then stirred at room temperature for 18 hr. The resulting mixture was filtered through a pad of Celite®, rinsed with EtOAc, the layers separated, the aqueous layer extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield an orange gum. The orange gum was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as an orange solid.
Reaction SMILES: [OH-].[Na+].[Br-].[CH3:4][O:5][C:6]([C:8]1[CH:33]=[CH:32][C:11]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:10][CH:9]=1)=[O:7].[N:34]1[CH:39]=[CH:38][C:37]([CH:40]=O)=[CH:36][CH:35]=1.O>CS(C)=O>[N:34]1[CH:39]=[CH:38][C:37](/[CH:40]=[CH:12]/[C:11]2[CH:10]=[CH:9][C:8]([C:6]([O:5][CH3:4])=[O:7])=[CH:33][CH:32]=2)=[CH:36][CH:35]=1.[N:34]1[CH:39]=[CH:38][C:37](/[CH:40]=[CH:12]\[C:11]2[CH:10]=[CH:9][C:8]([C:6]([O:5][CH3:4])=[O:7])=[CH:33][CH:32]=2)=[CH:36][CH:35]=1
Reactant: O=Cc1ccncc1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(/C=C/c2ccncc2)cc1
Product: COC(=O)c1ccc(/C=C\c2ccncc2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of sodium hydroxide (830 mg) in dimethylsulfoxide (100 ml) was added (4-methoxycarbonylbenzyl)triphenylphosphonium bromide (10.0 g), and after 30 minutes, 4-pyridinecarbaldehyde (2.22 g) was added thereto under ice-cooling. The mixture was stirred overnight. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (n-hexane—ethyl acetate) to give methyl 4-[(E)-2-(4-pyridyl)vinyl]benzoate (1.18 g) and methyl 4-[(Z)-2-(4-pyridyl)vinyl]benzoate (2.67 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1.[CH3:15][O:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1.CS(C)=O>C(#N)C>[CH3:15][O:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[S:22]([NH:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1)(=[O:24])=[O:23]
Reactant: COc1ccsc1S(=O)(=O)Cl
Reactant: COc1cnc(OC)n2nc(N)nc12
Solvent: CS(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccsc1S(=O)(=O)Nc1nc2c(OC)cnc(OC)n2n1
Reaction time: 96 h
Yield: 50.9 %

Procedure:
To a slurry of 0.8 g (4.5 mmol) of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine in 7 mL of acetonitrile was added 1.3 g (6.1 mmol) of 3-methoxythiophene-2-sulfonylchloride, 0.6 mL of dry pyridine and 0.003 mL of dry DMSO. After 96 hr, the reaction mixture was partitioned with CH2Cl2 and water. The organic phase was separated, washed with dilute aqueous HCl, dried over MgSO4, filtered and concentrated. The residue was taken into a small amount of CH2Cl2 before ether was added slowly with stirring to precipitate a fine tan solid. The solid was collected by filtration and dried under vacuum to give 0.85 g (50%) of the desired product. mp 227-228° C. 1H NMR (300 MHz, DMSO-d6): δ 12.1 (s, 1H); 7.8 (d, 1H, J=5.6); 7.6 (s, 1H); 7.0 (d, 1H, J=5.6); 4.1 (s, 3H); 3.9 (s, 3H); 3.8 (s, 3H). Calc'd for C12H13N5O5S2: C, 38.81; H, 3.53; N, 18.86; S, 17.27. Found: C, 38.32; H, 3.49; N, 18.91; S, 17.34.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([CH3:29])[N:21]=2)=[CH:16][CH:15]=1.Cl>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]4)=[CH:4][CH:3]=3)=[O:25])=[C:22]([CH3:29])[N:21]=2)=[CH:16][CH:15]=1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Reactant: Cc1ccc2ccc(N)cc2n1
Agent: Cl
Product: Cc1ccc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)nc3C)cc2n1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-2-methylquinoline (D66) (20 mg, 0.13 mmol) and 6-(4-fluorophenyl)-2-methylnicotinic acid (D24) (30 mg, 0.13 mmol) then converted to the HCl salt as a beige solid by treatment with ethereal HCl. 1H NMR (400 MHz, DMSO) (HCl salt) δ (ppm): 11.39 (br.s, 1H), 9.04 (s, 1H), 8.96 (d, 1H), 8.30 (d, 1H), 8.23 (dd, 2H), 8.12 (d, 1H), 8.00 (m, 2H), 7.84 (d, 1H), 7.37 (t, 2H), 2.94 (s, 3H), 2.71 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:21]=[O:22])=[N:6][CH:7]=1.[CH3:23][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:21]([OH:22])[CH3:23])=[N:6][CH:7]=1
Reactant: O=Cc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Temperature: 25 °C

Procedure:
To a solution of 5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazole-4-carbaldehyde (intermediate B4.1, 0.05 g, 0.15 mmol) in THF (1.3 ml) was added 3M methylmagnesium bromide (0.06 ml, 0.18 mmol) at 0° C. The reaction was allowed to warm to rt and satd. aq. NH4Cl was added. Extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, concentrated and purified by flash chromatography (silica, 20-50% EtOAc/hexanes) to give 1-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}ethanol. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, 2.5 Hz, 1H), 8.06 (m, 2H), 7.52 (dd, J=8.4, 2.5 Hz, 1H), 7.12 (m, 3H), 5.02 (m, 1H), 3.22 (d, J=5.2 Hz, 1H), 1.56 (m, 3H); LCMS [M+H]+=351.3.
Reaction SMILES: [CH3:1][S:2][C:3]([S:22][CH3:23])=[N:4][CH2:5][C:6]([N:8]1[CH:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C:11]2([CH2:16][CH2:15]3)[CH2:10][S:9]1(=[O:21])=[O:20])=[O:7].C([Li])CCC.CCCCCC.CN(P(N(C)C)(N(C)C)=O)C.I[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH:54]=[CH2:55]>O1CCCC1>[CH3:23][S:22][C:3]([S:2][CH3:1])=[N:4][CH:5]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH:54]=[CH2:55])[C:6]([N:8]1[CH:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C:11]2([CH2:16][CH2:15]3)[CH2:10][S:9]1(=[O:20])=[O:21])=[O:7]
Reactant: C=Cc1ccccc1CI
Reactant: CSC(=NCC(=O)N1C2CC3CCC2(CS1(=O)=O)C3(C)C)SC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C=Cc1ccccc1CC(N=C(SC)SC)C(=O)N1C2CC3CCC2(CS1(=O)=O)C3(C)C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 43.5 %

Procedure:
Dissolve 2-(bis-methylsulfanyl-methyleneamino)-1-(10,10-dimethyl-3,3-dioxo-3-thia-4-aza-tricyclo[5.2.1.0 1,5]dec-4-yl)-ethanone (7.91 g, 21.0 mmol) in tetrahydrofuran (100 mL) and cool to -78° C. Treat, by dropwise addition, with 1.6M n-butyllithium in hexane (13.1 mL, 21 mmol). Stir for 1.5 hours, then add hexamethylphosphotriamide (HMPA) (4.25 mL, 24.4 mmol). Stir for 15 minutes and add, via cannula, a solution of 1-iodomethyl-2-vinyl-benzene (6.1 g, 25 mmol) in tetrahydrofuran (100 mL). Stir overnight at room temperature, partition between saturated ammonium chloride (2×75 mL) and ethyl acetate (400 mL). Dry (Na2SO4) and purify by silica gel chromatography (2.5:1 hexane/ethyl acetate) to give the title compound as a white solid (4.5 g).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[C:16]1([CH:26]=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[CH:28](=O)[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>>[CH2:9]([N:8]1[C:3]2=[N:1][N:2]([CH2:26][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[C:28]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[C:4]2[C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: O=Cc1ccncc1
Reactant: O=Cc1cccc2ccccc12
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 1-naphthaldehyde, followed by isonicotinaldehyde. Mass: 439.79 (M+H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(OCC)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 95.1 %

Procedure:
To a stirred solution of 1,4-dioxa-8-azaspiro[4.5]decane (2.00 g, 13.9 mmol) and triethylamine (2.90 mL, 20.9 mmol) in ethyl acetate (50 mL) at 0° C. was added phenyl chloroformate (2.10 mL, 13.9 mmol). The mixture was allowed to warm to room temperature overnight. Then, the mixture was filtered to remove triethylamine hydrochloride salts. The filtrate was concentrated, and the obtained residue was chromatographed (silica gel, hexanes to 50:50 hexanes/ethyl acetate) to give the title compound (3.48 g, 95%) as a white solid:
Reaction SMILES: S1C2C3C=CC=NC=3C=CC=2C=CN1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].[S-:24][C:25]#[N:26].[K+].BrBr>>[NH2:26][C:25]1[S:24][C:17]2[C:16]([Cl:15])=[C:22]([F:23])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(F)c(Cl)c1
Agent: BrBr
Agent: C1=Cc2ccc3ncccc3c2SN1
Agent: [K+]
Product: Nc1nc2ccc(F)c(Cl)c2s1

Procedure:
Pyrido-benzothiazine compounds having anti-microbial activity are prepared by (a) reacting 3-chloro-4-fluoroaniline with potassium thiocyanate and bromine to produce 2-amino-6-fluoro-7-chlorobenzothiazole, (b) reacting 2-amino-6-fluoro-7-chlorobenzothiazole with sodium hydroxide to produce the disulfide of 2-amino-5-fluoro 6-chlorothiophenol, (c) reacting the disulfide with sodium monochloroacetate to produce 7-fluoro-8-chloro-2H-1,4-benzothiazin-3(4H)-one, (d) reducing 7-fluoro-8-chloro-2H-1,4-benzothiazin-3(4H)-one to produce 7-fluoro-8-chloro-3,4-dihydro-2H-1,4-benzothiazone, (e) reacting 7-fluoro-8-chloro-3,4-dihydro-2-H-1,4-benzothiazone with ethyl ethoxymethylenemalonate and cyclyzing the intermediate formed with polyphosphoric acid to produce ethyl 9-fluoro-10-chloro-7-oxo-2,3-dihydro-7H-pyrido[1,2,3 de] [1,4]-benzothiazine-6-carboxylate and (f) hydrolyizing the ethyl carboxylate to produce the corresponding carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]2[N:20]=[C:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=[C:10]2[N:9]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([N:26]1[CH2:25][CH2:24][CH:23]([C:21]2[CH:22]=[C:10]3[N:9]=[C:8]([NH:7][N:6]=[CH:5][C:4]4[CH:29]=[CH:30][CH:31]=[C:2]([CH3:1])[CH:3]=4)[CH:13]=[C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[N:11]3[N:20]=2)[CH2:28][CH2:27]1)(=[O:34])[CH3:33]
Reactant: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(C4CCNCC4)cc3n2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCC(c2cc3nc(NN=Cc4cccc(C)c4)cc(N4CCOCC4)n3n2)CC1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
There was suspended, in methylene chloride (2 mL), N-(3-methyl-benzylidene)-N′-(7-morpholin-4-yl-2-piperidin-4-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (31.0 mg, 0.0739 mM) and then acetic acid anhydride (1 mL) was added to the suspension. After this reaction liquid was heated to 90° C. and stirred for 15 minutes, the solvent was distilled off, the resulting residue was diluted with a saturated aqueous solution of sodium bicarbonate and then the mixture was extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (25.0 mg, yield: 73%).
Reaction SMILES: [C:1]1([C:7]2([C:20]#[N:21])[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:22].[Na+].C([OH:26])C>>[C:1]1([C:7]2([C:20]([NH2:21]=[O:26])=[O:22])[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Product: O=C([NH2+][O-])C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
4-Phenyl-4-cyano-1-benzyl-piperidine (535 g, 1940 mmol) was combined with aqueous sodium hydroxide (85 mL, 50% by weight) and ethanol (5 L) and the mixture was heated to 50° C. The heating was removed, and a solution of hydrogen peroxide (856 mL, 30% by weight in water) was added at such a rate that the temperature of the reaction mixture does not rise above 50° C. The reaction mixture was then stirred at 50° C. for 20 hours. The reaction mixture was diluted with water (3 L) and the ethanol was removed in vacuo at 350° C. Cooling the reaction mixture to ambient temperature gave a solid which was collected by filtration, rinsed with water, and air dried to give 4-phenyl-1-benzyl-piperidine-4-carboxylic acid amide N-oxide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+]>CO>[CH2:6]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCCO
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCCNCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A solution of 3-aminopropan-1-ol (3 g, 39.9 mmol) and benzaldehyde (4.05 mL, 39.9 mmol) in methanol (200 mL) was stirred at room temperature overnight. The solution was cooled to 0° C., and sodium borohydride (1.813 g, 47.9 mmol) was added slowly in several portions. The resulting mixture was stirred at room temperature for three hours, and then it was partitioned between water and dichloromethane (3x). The organic extracts were combined and dried over Na2SO4, the drying agent was removed by filtration, and the solution was concentrated in vacuo to give the title compound as an oil (6.5 g, 98%).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(=O)(=O)(O)O.[CH3:21]O>>[C:1]12([CH2:11][CH2:12][C:13]([O:15][CH3:21])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CO
Reactant: O=C(O)CCC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Product: COC(=O)CCC12CC3CC(CC(C3)C1)C2

Procedure:
To a solution of Intermediate 46 (2.9 g, 13.98 mmol) in methanol (22.6 mL) was added dropwise sulphuric acid (0.4 mL, 6.94 mmol) during 15 minutes at 0° C. The resulting reaction mixture was refluxed for 2 hours. The solvent was removed under reduced pressure and the crude was partitioned between ethyl acetate and water. The organic layer was washed with a solution of sodium hydrogen carbonate (4%), water and brine. The solvent was removed under reduced pressure and the title compound was obtained as a red oil (2.9 g, 95%) and was used in the next step without further purification.