Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][C:5]=2[O:4][N:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(Cl)(Cl)Cl>[C:18]([N:3]1[C:2](=[O:1])[C:10]2[CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][C:5]=2[O:4]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCc2c(O)noc2C1
Solvent: ClC(Cl)Cl
Product: CC(=O)n1oc2c(c1=O)CCN(C(=O)OC(C)(C)C)C2

Procedure:
t-BOC THIP (7.2 g) was refluxed with acetic acid anhydride (5.0 g) in 50 ml of CHCl3 for 2 hours. 2-Acetyl-6-(t-butyloxycarbonyl)-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-one was isolated as an oil in 6.4 g (76%) yield by column chromatography (Silicagel 60 "Merck") (eluted with ether/CH2Cl2 (1:3)). The t-BOC group was split off as above, yielding 73% of the oxalate. M.P. 177°-178° C. (dec.) (Found: C 44.32; H 4.70; N (10.58); C10H12N2O7 requires C 44.12; H 4.45; N 10.29%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[N:9][CH:10]=1)(=O)C.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[N:9][CH:10]=1
Reactant: COc1ccc(OC(C)=O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
To a solution of the 5-acetoxy-2-methoxypyridine(600 mg, 3.59 mmol) in MeOH(10 mL) was added 1M aq. NaOH(10 mL, 10 mmol). After stirring at r.t. for 30 min, volatile solvent was removed in vacuo, acidified with HOAc and extracted with CHCl3(3 x). The combined CHCl3 extracts were washed with H2O, dried(anhydrous MgSO4) and evaporated to give the title compound as a brown oil(240 mg, solidified on standing).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][NH:8][C:9]1[CH:14]=[C:13](F)[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:23])[CH2:7][NH:8][C:9]1[CH:14]=[C:13]([N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CNc1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNc1cc(-n2ccnc2)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture of 9.36 g (27.7 mmol) of N-(5-fluoro-2-nitro-4-trifluoromethylphenyl)glycine tert-butyl ester, 7.54 g of imidazole and 30 ml of DMF was stirred for 2 hours on an oil bath at 60° C. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was poured into water and the compound so precipitated was collected by filtration. The resulting compound was washed successively with water and ethyl ether and then dried under reduced pressure to give 8.95 g (84%) of N-[5-(1H-imidazol-1-yl)-2-nitro-4-trifluoromethylphenyl)glycine tert-butyl ester.
Reaction SMILES: C(OC(C1NC=CC=1)=O)C.C(I)C.[CH2:14]([N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([OH:23])=[O:22])[CH3:15].[CH2:24]([O:26][C:27](=[O:35])[CH2:28][C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[CH3:25]>>[CH2:14]([N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([OH:23])=[O:22])[CH3:15].[CH2:24]([O:26][C:27](=[O:35])[CH2:28][C:29]1[N:30]=[C:31]([NH:34][C:21]([C:17]2[N:16]([CH2:14][CH3:15])[CH:20]=[CH:19][CH:18]=2)=[O:23])[S:32][CH:33]=1)[CH3:25]
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: CCOC(=O)c1ccc[nH]1
Agent: CCn1cccc1C(=O)O
Solvent: CCI
Product: CCOC(=O)Cc1csc(NC(=O)c2cccn2CC)n1

Procedure:
1-Ethylpyrrole-2-carboxylic acid (90 mg) was prepared from ethyl-pyrrole-2-carboxylate (140 mg, 1.0 mmol) and ethyl iodide (0.12 mL, 1.5 mmol) following the general procedures A and B. (2-{[1-Ethylpyrrole-2-carbonyl]-amino}-thiazol-4-yl)acetic acid ethyl ester (46 mg) was prepared from 1-ethylpyrrole-2-carboxylic acid (90 mg, 0.53 mmol) and 2-aminothiazol-4-yl acetic acid ethyl ester (95 mg, 0.53 mmol) following the general procedure F.
Reaction SMILES: [ClH:1].C(OC([NH:9][C:10]([NH:19][O:20][CH2:21][CH2:22][NH2:23])=[N:11]C(OC(C)(C)C)=O)=O)(C)(C)C>>[ClH:1].[ClH:1].[NH2:23][CH2:22][CH2:21][O:20][NH:19][C:10]([NH2:11])=[NH:9]
Reactant: CC(C)(C)OC(=O)N=C(NOCCN)NC(=O)OC(C)(C)C
Agent: Cl
Product: N=C(N)NOCCN
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The HCl salt of ({[(tert-butoxycarbonyl)amino-(tert-butoxycarbonyl)iminomethyl]aminooxy}ethyl)amine (90.5 mg, 255 μmol) (WO 2004/091613 A2) was treated with 12 M HCl (aq) (210 μL, 2.5 mmol) in one portion at rt, and was then stirred at rt for 20 min. The resulting thick white slurry was concentrated under rotary evaporation at rt, and the residue was taken up in toluene (3×3 mL) with repeated rotary evaporation and high vacuum to yield the title compound as an off-white powder (52.9 mg, quantitative yield).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[N:16]=[CH:17][C:18]=2[O:19][CH3:20])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:23]OC(OC)(C)C.Cl>CO.O1CCOCC1>[CH3:23][O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[N:16]=[CH:17][C:18]=2[O:19][CH3:20])=[CH:11][CH:12]=1
Reactant: COC(C)(C)OC
Reactant: COc1cnn(C)c(=O)c1-c1ccc(C[C@H](N)C(=O)O)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C(N)Cc1ccc(-c2c(OC)cnn(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(S)-Amino-3-[4-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-propionic acid (0.40 g, 1.0 mmol) was dissolved in MeOH (2.6 mL). Dimethoxypropane (0.26 mL) and 1N HCl in dioxane (0.33 mL) were added and stirred at room temperature for 24 h. The mixture was concentrated in vacuo to give 2-Amino-3-[4-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-propionic acid methyl ester. MS (ES+) 318.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC#N)C(=O)COC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)=[CH:52][C:53]4[N:58]([CH:59]([C:61]#[N:62])[CH3:60])[C:57](=[O:63])[CH2:56][O:55][C:54]=4[N:64]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)(C)(C)C>>[NH2:39][C:40]1([C:44]2[CH:45]=[CH:46][C:47]([C:50]3[C:51]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)=[CH:52][C:53]4[N:58]([CH:59]([CH3:60])[C:61]#[N:62])[C:57](=[O:63])[CH2:56][O:55][C:54]=4[N:64]=3)=[CH:48][CH:49]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: CC(C#N)N1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Agent: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Product: CC(C#N)N1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 99.7 %

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(1-(1-cyanoethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (7 mg, 0.013 mmol) was reacted to afford the title compound (5.5 mg). 1H NMR (500 MHz, CH3OD) 7.77 (1H, s), 7.44 (2H, d), 7.40 (2H, d), 7.30-7.34 (3H, m), 7.25-7.28 (2H, m), 6.03 (1H, q), 4.99 (2H, s), 2.7-2.85 (2H, m), 2.55-2.65 (2H, m), 2.2-2.3 (1H, m), 1.9-2.1 (1H, m), 1.81 (3H, d), LCMS (Method A): RT=4.11 min, M+H+=426.1.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36].S>C(O)C>[C:1]1([C:7]2[S:36][C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)=[CH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(CC(C(=O)c1ccccc1)c1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: S
Solvent: Cc1ccccc1C
Solvent: CCO
Product: Clc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1Cl
Yield: 177.8 %

Procedure:
In a 1-liter stainless steel autoclave equipped with electrically-driven stirrer were placed 38.3 g. (0.100 mole) of 1,2-diphenyl-4-(3,4-dichlorophenyl)butane-1,4-dione, 100 ml of xylene, 20 g of phosphorus pentasulfide and 140 g of hydrogen sulfide. The reactor was heated for three hours at 160°-164° C. The crude product remaining after cooling and venting the reactor was stirred with ethanol. Filtration gave 30.5 g (80%) of solid m.p. 101°-103° C. Recrystallization from 30 ml of dioxane and 60 ml of ethanol gave 22.5 g (59%) of pure product, m.p. 106.2°-107.8° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([Cl:27])[CH:19]=2)[S:5][C:6]=1[C:7](=[O:16])[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15].[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[O:23])=[C:20]([Cl:27])[CH:19]=2)[S:5][C:6]=1[C:7](=[O:16])[C:8]1[C:9]([F:15])=[CH:10][CH:11]=[CH:12][C:13]=1[F:14]
Reactant: Nc1nc(Nc2ccc(C(=O)O)c(Cl)c2)sc1C(=O)c1c(F)cccc1F
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1ccc(Nc2nc(N)c(C(=O)c3c(F)cccc3F)s2)cc1Cl

Procedure:
The title compound was prepared from 4-{4-amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino}-2-chloro-benzoic acid (12) and N,N-dimethyl-ethylene-diamine in a manner similar to Step 3 in Method A.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[N:13]([C@@H:14]3[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]3)[C:12]3[CH:24]=[C:25]([CH2:28]O)[CH:26]=[CH:27][C:11]=3[N:10]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl.CS(C)=O>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:27]=[CH:26][C:25]([CH2:28][N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:24][C:12]=3[N:13]\2[C@@H:14]2[CH2:15][CH2:16][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:19]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: COC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccc(F)cc3)nc3ccc(CO)cc32)CC1
Solvent: CS(C)=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCCCC4)cc32)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
cis-Methyl 4-(2-(4-fluorobenzamido)-6-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (0.19 g, 0.447 mmol) was suspended in DCM (4.47 mL) and cooled to 0° C. under a nitrogen atmosphere. To this mixture was added thionyl chloride (0.652 mL, 8.93 mmol) dropwise, and the reaction mixture was stirred at 0° C. for 1 hour. The ice bath was removed, and the mixture was stirred at RT for 2 hours. The reaction mixture was concentrated under reduced pressure and dried under high vacuum to afford a yellow foam. The foam was suspended in 2 mL of DMSO and treated with piperidine (0.441 mL, 4.47 mmol) followed by TEA (0.248 mL, 1.786 mmol). The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with DCM (2-20 mL) and washed with water (2-20 mL). The organic layer was collected, dried over sodium sulfate, and concentrated. The residue was purified by HPLC (10-70% ACN/H2O; 0.1% TFA) to afford cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate as a white solid (150 mg, 68.2% yield). MS m/z=493.2 [M+H]. Calc'd for C28H33FN4O3: 492.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.45 (m, 2H) 1.44-1.61 (m, 4H) 1.66-1.93 (m, 4H) 2.19-2.32 (m, 2H) 2.29-2.43 (m, 4H) 2.53-2.65 (m, 2H) 2.81-2.94 (m, 1H) 3.51 (s, 2H) 3.78 (s, 3H) 4.57-4.89 (m, 1H) 7.10-7.18 (m, 1H) 7.21-7.32 (m, 2H) 7.42-7.52 (m, 2H) 8.02-8.48 (m, 2H) 12.78 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1.[Cl:28][C:29]1[CH:30]=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[C:34](B1OC(C)(C)C(C)(C)O1)[CH:33]=2.B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[C:34]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]3[CH2:26][CH2:25][C:15]4([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]5[CH2:24][CH2:23]5)[CH2:16]4)[CH2:14][CH2:13]3)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1)[CH:33]=2
Reactant: NC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: CC1(C)OB(c2ccc3cc(Cl)cnc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)C(c1ccc(-c2ccc3cc(Cl)cnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Yield: 4 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (137 mg, 0.31 mmol), crude 3-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline/boronic acid mixture (45.0 mg), and 2M aq potassium carbonate (0.17 mL, 0.342 mmol) in 1,4-dioxane (0.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (10.2 mg, 0.012 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in the microwave at 110° C. for 25 min, at which point the reaction had proceeded to completion. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with 5 mL of 1M aq HCl. The organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered through a pad of celite, and concentrated to dryness. Purification of the residue by reverse phase HPLC (5-45% acetonitrile+0.1% TFA:water+0.1% TFA) followed by resolution of the racemate by chiral HPLC (Chromegachiral CC4, methanol) afforded the title product in >98% ee (9 mg, 4% yield over the two steps). αD=+41 deg (c=0.02, methanol); MS(ES)+ m/e 523.5 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.65 (br. s., 2 H) 0.82 (d, J=5.81 Hz, 2 H) 1.59 (br. s., 4 H) 1.92 (br. s., 1 H) 2.72 (br. s., 3 H) 3.16 (br. s., 3 H) 4.01 (br. s., 2 H) 4.53 (br. s., 1 H) 5.58 (s, 1 H) 7.27 (br. s., 1 H) 7.63 (br. s., 1 H) 7.92 (d, J=7.07 Hz, 2 H) 8.25 (d, J=2.02 Hz, 1 H) 8.35 (s, 1 H) 8.89 (d, J=2.27 Hz, 1 H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:31]4[S:32][C:28]([CH3:27])=[CH:29][N:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cncs1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3ncc(C)s3)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and 5-methylthiazole
Reaction SMILES: [O:1]=[C:2]([N:12]1[CH2:17][CH2:16][C:15](=[C:18]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:25][C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:14][CH2:13]1)[CH2:3][NH:4]C(=O)OC(C)(C)C.[ClH:32].O1CCOCC1.C(=O)([O-])O.[Na+]>O1CCOCC1>[ClH:32].[CH:20]1[C:19]2[C:18](=[C:15]3[CH2:16][CH2:17][N:12]([C:2](=[O:1])[CH2:3][NH2:4])[CH2:13][CH2:14]3)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[S:25][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC(=C2c3ccccc3Sc3ccccc32)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: NCC(=O)N1CCC(=C2c3ccccc3Sc3ccccc32)CC1
Reaction time: 8 h

Procedure:
135 mg (0.297 mmol) of t-butyl 2-oxo-2-[4-(9H-thioxanthen-9-ylidene)-1-piperidinyl]ethylcarbamate was dissolved in 2 ml of dioxane. After adding 2 ml of 4 N hydrochloric acid/1,4-dioxane solution, they were stirred overnight. The obtained mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution. After extracting with ethyl acetate twice and drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. 2 ml of dichloromethane and then 2 ml of 4 N hydrochloric acid/1,4-dioxane solution were added to the residue. The resultant precipitates were taken by the filtration, washed with dichloromethane and air-dried. After further drying under reduced pressure, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[F:10][C:4]1[CH:3]=[C:2]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[C:18]([O:19][CH3:20])[CH:17]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2cc(F)c(N)c(F)c2)cc1OC
Yield: 30.6 %

Procedure:
The title compound (39 mg) was prepared from 4-bromo-2,6-difluoroaniline (100 mg, 0.48 mmol) and 3,4-dimethoxyphenylboronic acid (113 mg, 0.62 mmol) as a pale-yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.25 (dd, J 2, 8.3, 2H), 7.18-7.10 (m, 2H), 6.94 (d, J 8.4, 1H), 5.21 (s, 2H), 3.81 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH3:3].Br[C:16]1[S:17][CH:18]=[C:19]([Br:21])[N:20]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.CO>[Br:21][C:19]1[N:20]=[C:16]([N:7]2[CH2:6][CH2:5][C:4]([CH2:2][CH3:3])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8]2)[S:17][CH:18]=1
Reactant: CCOC(=O)C1(CC)CCNCC1
Reactant: Brc1csc(Br)n1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CC)CCN(c2nc(Br)cs2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of ethyl 4-ethylpiperidine-4-carboxylate hydrochloride (140 mg, 0.62 mmol) and 2,4-dibromothiazole (100 mg, 0.41 mmol) in DMF (0.3 mL) was added triethylamine (0.26 mL, 1.9 mmol) at rt and the mixture heated to 100° C. and stirred for 2 h. The mixture was cooled to rt then diluted with EtOAc (2 mL) and MeOH (2 mL) then evaporated to dryness under reduced pressure. The crude residue was purified over silica-gel using EtOAc: cyclohexane (10% to 60%) to obtain the desired product as viscous oil that solidified upon standing (127 mg, 89% yield). MS: 347.03, 349.01 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Br[CH2:14][C:15]1[C:29]([F:30])=[CH:28][C:18]([C:19]([NH:21][S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[O:20])=[C:17]([F:31])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH2:14][C:15]2[C:29]([F:30])=[CH:28][C:18]([C:19]([NH:21][S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[O:20])=[C:17]([F:31])[CH:16]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Reactant: CC(C)Oc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC(C)Oc1ncc(OCc2cc(F)c(C(=O)NS(=O)(=O)N(C)C)cc2F)cc1Cl
Yield: 30 %

Procedure:
A solution of 5-chloro-6-isopropoxypyridin-3-ol (Preparation 6, 44 mg, 0.232 mmol), 4-(bromomethyl)-N-[(dimethylamino)sulfonyl]-2,5-difluorobenzamide (Preparation 1, 83 mg, 0.23 mmol) and potassium carbonate (64 mg, 0.47 mmol) in dimethyl sulfoxide (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and acidified to ˜pH 4 using acetic acid (2 mL). The resulting precipitate was filtered, washed with water (20 mL) and dried to afford the title compound as a white solid (32 mg).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3]>Cl>[C:2]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[NH:3])[NH2:4]
Reactant: CCOC(=O)c1ccc(C(=N)N)cc1
Agent: Cl
Product: N=C(N)c1ccc(C(=O)O)cc1

Procedure:
In 1N hydrochloric acid (100 ml), the resulting ethyl 4-amidinobenzoate hydrochloride (3.00 g) was dissolved at room temperature, followed by heating under reflux for 2 hours. The solvent was then distilled off under reduced pressure. Colorless crystalline powder so precipitated was collected by filtration and washed with a small amount of tetrahydrofuran, whereby the title compound (2.69 g, 94%) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH2:14]Cl.[C:16]([O-:19])(=[O:18])[CH3:17].[K+].CN(C=O)C>O>[C:16]([O:19][CH2:14][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:6]2[C:7](=[O:8])[C:2]=1[Br:1])(=[O:18])[CH3:17]
Reactant: Cc1cccc2nc(CCl)c(Br)c(=O)n12
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2cccc(C)n2c(=O)c1Br
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
A mixture of 3-bromo-2-(chloromethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (4.5322 g, 15.76 mmol), potassium acetate (2.320 g, 23.64 mmol), and DMF (60.0 mL) was stirred at 40° C. After 3.5 h, the mixture was concd under reduced pressure. To the residue was added water (100 mL) and the resulting precipitate was collected by filtration, washed with water (100 mL), and dried to give (3-bromo-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1 H, dd, J=9.0, 7.0 Hz), 7.45 (1 H, dd, J=9.0, 0.8 Hz), 7.02-7.08 (1 H, m), 5.12 (2H, s), 2.95 (3 H, s), 2.14 (3 H, s); Mass Spectrum (ESI) m/e=310.9 [M+1 (79Br)] and 313.0 [M+1 (81Br)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32]C3CCCCO3)[CH:27]=2)[S:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])(=[O:15])=[O:14])=[CH:8][CH:7]=1.Cl.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>CO.C(Cl)Cl.O1CCOCC1>[CH3:1][O:2][C:3](=[O:39])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[S:13]([C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])(=[O:15])=[O:14])=[CH:8][CH:7]=1
Reactant: COC(=O)C=Cc1ccc(N(Cc2cccc(OC3CCCCO3)c2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc(N(Cc2cccc(O)c2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-{4-[[3-(tetrahydro-pyran-2-yloxy)-benzyl]-(2,4,6-trimethylbenzenesulfonyl)-amino]-phenyl}-acrylic acid methyl ester in 0.5 mL MeOH and 0.2 mL methylene chloride was added HCl (0.78 mL of a 4.0M solution in 1,4-dioxane, 3.12 mmol) and triethylsilane (0.20 mL, 1.25 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the aqueous solution was washed with methylene chloride. The organic layer was separated, dried (magnesium sulfate), and concentrated. Medium pressure silica gel chromatography (methylene chloride to 5% ethyl acetate/methylene chloride) afforded 0.050 g of 3-{4-[(3-hydroxy-benzyl)-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-acrylic acid methyl ester. MS 466.4 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]1[CH:14]([CH3:16])[S:15][C:7]1=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22].C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[N:8]1[CH:14]([CH3:16])[S:15][C:7]1=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: CCOC(=O)c1c2n(c3c(F)c(F)c(F)cc3c1=O)C(C)S2
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3c(F)c(N4CCNCC4)c(F)cc3c1=O)C(C)S2
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
Ethyl 6,7,8-trifluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate (0.33 g) and 0.14 g of potassium carbonate were suspended in 10 ml of N,N-dimethylformamide, 0.13 g of anhydrous piperazine was added and the mixture was stirred at 60° C. for 2 hours. N,N-Dimethylformamide was evaporated therefrom in vacuo, the residue was dissolved in chloroform, the solution was washed with water, dried over magnesium sulfate, the solvent was evaporated therefrom, the residue was subjected to a silica gel column chromatography (30 g of Wakogel C-300 being used) and eluted with chloroform-methanol (4:1) to give 0.29 g of the title product, m.p. 195°-198° C. (decompn).