Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25](O)=[O:26])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8].C(OC(Cl)=O)C(C)C.[NH2:39][C@H:40]([C:48]([N:50]1[CH2:88][CH2:87][CH2:86][C@H:51]1[C:52]([NH:54][C@H:55]([C:61]([NH:63][C@H:64]([C:69]([N:71]1[CH2:85][CH2:84][CH2:83][C@H:72]1[C:73]([N:75]1[CH2:82][CH2:81][CH2:80][C@H:76]1[C:77]([OH:79])=[O:78])=[O:74])=[O:70])[C@H:65]([CH2:67][CH3:68])[CH3:66])=[O:62])[CH2:56][CH2:57][C:58](=[O:60])[NH2:59])=[O:53])=[O:49])[CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:47])[NH2:46].CCOC(C)=O>CN(C=O)C.CC(O)=O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH:39][C@H:40]([C:48]([N:50]1[CH2:88][CH2:87][CH2:86][C@H:51]1[C:52]([NH:54][C@H:55]([C:61]([NH:63][C@H:64]([C:69]([N:71]1[CH2:85][CH2:84][CH2:83][C@H:72]1[C:73]([N:75]1[CH2:82][CH2:81][CH2:80][C@H:76]1[C:77]([OH:79])=[O:78])=[O:74])=[O:70])[C@H:65]([CH2:67][CH3:68])[CH3:66])=[O:62])[CH2:56][CH2:57][C:58](=[O:60])[NH2:59])=[O:53])=[O:49])[CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:46])[NH2:47])=[O:26])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8]
Reactant: O=C1CC[C@@H](C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)N2CCC[C@H]2C(=O)O)N1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.29 h

Procedure:
The tripeptide, from part C, Pyr-Trp-Pro (23.3 mmoles) is dissolved in DMF (85 ml) and 3.27 ml (23.3 mmoles) TEA, the solution cooled to -20° (inside the flask, or -35° to -40° in the cooling bath) and kept at this temperature for 15-20 minutes. To this cold solution 3.19 ml of isobutyloxycarbonyl chloride is added and then a time of 30 minutes is allowed for the mixed anhydride to be formed at the same temperature. A solution of Arg-Pro-Gln-Ile-Pro-Pro (16.5 g) in DMF (100 ml) is precooled to about 0° and then added into the solution of the mixed anhydride. At this moment, the pH value is adjusted to 8 with TEA (8.5 ml) while the temperature of 0° is maintained. After 20 to 24 hours at room temperature, the volume of the solvents is reduced to 1/3-1/4 and poured into 20-25 volumes of EtOAc containing 3 % of AcOH. The precipitate is washed thoroughly with EtOAc and then dried in vacuo over KOH overnight to yield the title compound. This material is dissolved in water, sterilized by filtration, and the sterile aqueous solution freeze-dried to a free flowing powder. The powder is reconstituted for injection with water for injection or saline.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.FC1C(F)=C(C#CC2C=C(C=CC=2)N)C(F)=C(F)N=1.[O:25]=[C:26]([NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]#[C:56][C:57]2[C:62]([F:63])=[C:61]([F:64])[N:60]=[C:59]([F:65])[C:58]=2[F:66])[CH:50]=1)[C@@H:27]([NH:40]C(=O)OC(C)(C)C)[CH2:28][CH2:29][CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C>N1C=CC=CC=1.Cl>[ClH:3].[ClH:3].[NH2:40][C@@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[C:26]([NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]#[C:56][C:57]2[C:62]([F:63])=[C:61]([F:64])[N:60]=[C:59]([F:65])[C:58]=2[F:66])[CH:50]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(C#Cc2c(F)c(F)nc(F)c2F)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: Nc1cccc(C#Cc2c(F)c(F)nc(F)c2F)c1
Solvent: c1ccncc1
Product: NCCCC[C@H](N)C(=O)Nc1cccc(C#Cc2c(F)c(F)nc(F)c2F)c1
Temperature: -25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
L-Boc-Lys(Boc)-OH (0.26 g, 0.75 mmol) was dissolved in 3 mL of pyridine. The solution was cooled to −25° C. and phosphorus oxychloride (0.12 g, 0.75 mmol) was added dropwise with vigorous stirring. After stirring for 15 min. at −25° C., 3-((perfluoropyridin-4-yl)ethynyl)aniline, (13b) (0.10 g, 0.36 mmol) in pyridine (3 mL) was added slowly. The reaction mixture was stirred for 0.5 h at −25° C. and then at room temperature for 10 h. The reaction mixture was quenched with ice/water and extracted with EtOAc. The organic layer was washed with sat. NaHSO4 three times, dried with Na SO4 and was concentrated in vacuo. The crude product was subjected to chromatography with CH2Cl2:CH3CN=1:30 and the product was obtained in 36% yield. (S)-Di-tert-butyl (6-oxo-6-((3-((perfluoropyridin-4-yl)ethynyl)phenyl)amino)hexane-1,5-diyl)dicarbamate (97 mg, 0.16 mmol) was dissolved in gaseous HCl saturated MeOH (4 mL) at 0° C. and the solution was stirred for 10 hours at room temperature. The solvent was evaporated and the product (65 mg, 86%) was purified by recrystallization with isopropanol: 1H-NMR (600 MHz, CD3OD) δ 8.07 (dd, J=1.74 Hz, J=1.68 Hz, 1H), 7.75 (ddd, J=7.98 Hz, J=1.92 Hz, J=1.14 Hz, 1H), 7.48 (dd, J=7.8 Hz, J=7.8 Hz, 1H), 7.43 (ddd, J=7.68 Hz, J=1.32 Hz, J=1.32 Hz, 1H) 4.12 (t, J=6.6 Hz, 1H), 2.97 (t, J=7.56 Hz, 2H), 2.00-2.07 (m, 1H), 1.97-2.00 (m, 1H), 1.74-1.77 (m, 2H), 1.56-1.60 (m, 2H); 13C-NMR (150 MHz, CD3OD) δ 168.7, 144.9 (dm, J=224 Hz), 143.5 (dm, J=262 Hz), 139.7, 130.8, 129.4, 124.2, 123.3, 122.4, 117.9 (m), 106.5 (m), 74.2 (m), 54.9, 40.3, 32.2, 28.2, 23.0; m.p. >250° C. (decomp.)
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:29])[C:12]([OH:28])=[C:13]([C:15]3[NH:16][CH:17]=[C:18]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[N:19]=3)[N:14]=[C:3]21.C(N(CC)CC)C.[CH3:37][C:38]1[O:42][N:41]=[C:40]([C:43](Cl)=[O:44])[CH:39]=1.CNC.CO>C(Cl)Cl.CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:18]2[N:19]=[C:15]([C:13]3[N:14]=[C:3]4[C:2]5([NH:1][C:43]([C:40]6[CH:39]=[C:38]([CH3:37])[O:42][N:41]=6)=[O:44])[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]5)[CH2:5][N:4]4[C:11](=[O:29])[C:12]=3[OH:28])[NH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: NC12CCC(CC1)Cn1c2nc(-c2nc(Cc3ccc(F)cc3)c[nH]2)c(O)c1=O
Agent: CNC
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NC23CCC(CC2)Cn2c3nc(-c3nc(Cc4ccc(F)cc4)c[nH]3)c(O)c2=O)no1
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of 10-amino-2-(4-(4-fluorobenzyl)-1H-imidazol-2-yl)-3-hydroxy-7,8,9,10-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-4(6H)-one, Example 1 (30 mg, 0.076 mmol) in CH2Cl2 (3 mL) was added triethylamine (0.063 mL, 0.455 mmol) followed by 5-methylisoxazole-3-carbonyl chloride (55.2 mg, 0.379 mmol) and the resulting mixture stirred at room temperature. After 16 h the reaction mixture was concentrated to give the crude product which was treated with 2M dimethylamine/MeOH (0.5 mL) in MeOH (2 mL) at 60° C. for 2 h. The mixture was then cooled and purified by preparative HPLC to afford the title compound (15 mg, 39%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 13.4 (1H, br. s.), 9.0 (1H, s), 7.4 (1H, br. s.), 7.4 (2H, dd, J=8.24, 5.80 Hz), 7.2 (2H, t, J=8.85 Hz), 6.6 (1H, s), 4.1 (2H, d, J=3.36 Hz), 4.1 (2H, s), 2.7-2.8 (2H, m), 2.5 (1H, br. s.), 2.0-2.0 (2H, m), 1.9-1.9 (2H, m), 1.7-1.8 (2H, m). LCMS (M+H)=505.49.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:30](O)(=[O:32])[CH3:31]>C(OC(=O)C)(=O)C>[C:30]([O:17][C:13]1[CH2:14][CH2:15][CH2:16][C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:32])[CH3:31]
Reactant: CCOC(=O)CCCCCCC1CCCC1=O
Reactant: CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)CCCCCCC1=C(OC(C)=O)CCC1
Reaction time: 16 h

Procedure:
A stirred solution of 100 g. of 2-(6-carbethoxyhexyl)cyclopentan-1-one (Example 9) in 250 ml of acetic anhydride containing 0.940 g. of p-toluenesulfonic acid monohydrate is heated to boiling under partial reflux allowing distillate at 118° C. or less (i.e., acetic acid) to escape through a Vigreaux column equipped with a condenser to collect the distillate. After 16 hours, during which period active anhydride is added in portions in order to keep the solvent level at at least 100 ml., the solution is cooled and poured cautiously into a stirred cold mixture of saturated sodium bicarbonate solution (400 ml.) and hexane (250 ml.). The resulting mixture is stirred for an additional 30 minutes during which period solid sodium bicarbonate is added periodically to insure a basic solution. The hexane layer is separated and washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation of the residual oil gives 102 g. (87%) of pale yellow oil, b.p. 118° C. (0.07 mm).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C>O1CCOCC1>[OH:4][CH2:3][C:2]([NH:1][S:13]([C:11]1[S:12][C:8]([CH3:7])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:15])=[O:14])([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: Cc1sc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1sc(S(=O)(=O)NC(C)(C)CO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 58 %

Procedure:
To a stirred solution of 2-amino-2-methyl-1-propanol (1.11 g, 12.4 mmol) in dioxane (20 ml) was added at 0° C. (ice water bath) 5-methyl-4-nitrothiophene-2-sulfonyl chloride [CAS No. 61714-77-0] and triethylamine (0.63 ml, 4.56 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate/MeOH) and subsequent crystallization (ethyl acetate/heptane) to yield 5-methyl-4-nitro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (0.71 g, 58%) as a light brown solid. MS (ISP) 293.0 [(M−H)−]; mp 126° C.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][C@@H:5]1[C:23](=[O:24])[N:7]2[C:8]([C:20]([O-:22])=[O:21])=[C:9]([CH2:12][N+:13]3[N:14]([CH3:19])[C:15]([NH2:18])=[CH:16][CH:17]=3)[CH2:10][S:11][C@H:6]12.C[Si](C)(C)NC(=O)C.Cl.[NH2:34][C:35]1[S:39][N:38]=[C:37](/[C:40](=[N:44]/[O:45][C:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])([CH3:48])[CH3:47])/[C:41]([Cl:43])=[O:42])[N:36]=1.C(OCC)C>O1CCCC1>[ClH:43].[ClH:1].[ClH:43].[NH2:34][C:35]1[S:39][N:38]=[C:37]([C:40](=[N:44][O:45][C:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])([CH3:47])[CH3:48])[C:41]([NH:4][C@@H:5]2[C:23](=[O:24])[N:7]3[C:8]([C:20]([O-:22])=[O:21])=[C:9]([CH2:12][N+:13]4[N:14]([CH3:19])[C:15]([NH2:18])=[CH:16][CH:17]=4)[CH2:10][S:11][C@H:6]23)=[O:42])[N:36]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)Cl)c1nsc(N)n1
Reactant: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c3nsc(N)n3)[C@H]2SC1
Reaction time: 1 h
Yield: 194.8 %

Procedure:
To a solution of 7β-amino-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate trihydrochloride (2 g) and N-(trimethylsilyl)acetamide (6.28 g) in tetrahydrofuran (40 ml) was added (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetyl chloride hydrochloride (1.84 g) under ice-cooling. After being stirred for 1 hour, the reaction mixture was added dropwise to ethyl ether (300 ml), and the resulting precipitate was collected by filtration to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate trihydrochloride (syn isomer) (3.4 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.Cl.[CH3:13][N:14]1[C:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[O:25][C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:17]=2[CH:16]=[N:15]1.C(N(CC)CC)C>CN(C=O)C>[CH3:13][N:14]1[C:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[O:25][C:26]3([CH2:31][CH2:30][N:29]([C:5]([C:4]4[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=4)=[O:6])[CH2:28][CH2:27]3)[C:17]=2[CH:16]=[N:15]1
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3-Methylbenzoyl chloride (14 mg, 0.09 mmol) was added to a mixture of 1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride (30 mg, 0.09 mmol), triethylamine (64 μL, 0.46 mmol), and DMF (0.7 mL) at 25° C. The mixture was allowed to stir at 50° C. overnight before it was cooled to 25° C. The mixture was filtered and then purified by reverse phase-HPLC to give (1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)(m-tolyl)methanone. ESI-MS m/z calc. 373.2. found 374.2 (M+1)+. Retention time: 2.04 minutes (4 min run).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].O>CN(C=O)C>[Br:8][C:21]1[C:22]([NH2:25])=[N:23][CH:24]=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([S:10]([CH3:9])(=[O:11])=[O:12])=[CH:18][CH:17]=2)[N:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1ccc(-c2cnc(N)cn2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
NBS (1.807 g, 10.15 mmol) was added to a stirred solution of 5-(4-methylsulfonylphenyl)pyrazin-2-amine (2.53 g, 10.15 mmol) in DMF (40 mL) and the reaction stirred at ambient temperature for 15 hours. The reaction mixture was added slowly to rapidly stirring water and the resultant precipitate was isolated by filtration and dried in vacuo to give the sub-title compound as a beige solid that was used without further purification (2.8 g, 84% Yield).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]3[C:15]([NH2:16])=[N:14][N:13]([CH3:17])[C:9]3=[N:10]2)=[CH:5][CH:4]=1>Br>[NH2:16][C:15]1[C:8]2[C:9](=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[C:3]([OH:2])[CH:12]=3)[N:13]([CH3:17])[N:14]=1
Reactant: COc1ccc2cc3c(N)nn(C)c3nc2c1
Agent: Br
Product: Cn1nc(N)c2cc3ccc(O)cc3nc21
Yield: 63.2 %

Procedure:
A mixture of 20.9 g 7-methoxy-1-methyl-1H-pyrazolo[3,4-b]quinolin-3-amine (Example 7) and 420 ml 48% aqueous hydrobromic acid was stirred at reflux for 21 hours. The reaction mixture was quenched in ice-water and neutralized to pH 7.0 with ammonium hydroxide. The resulting yellow solid was collected by filtration, washed with water and recrystallized from 1100 ml absolute ethanol to provide 12.4 g (63%) 3-amino-1-methyl-1H-pyrazolo[3,4-b]quinolin-7-ol, orange-yellow solid, m.p. 288°-290° C. (decompn).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.[Li]CCCC.[C:22](OCC)(=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[C:12]([O:11][C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:16])([CH3:13])([CH3:15])[CH3:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(NC(=O)OC(C)(C)C)cccc1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 3-methoxyphenylcarbamate (25.6 g, 0.11 mol) in THF (300 mL) was added n-BuLi (0.25 mol, 1.6 M solution in pentane) at −78° C. The resulted solution was stirred at 0° C. for 3 hours and re-cooled to −78° C. followed by the addition of diethyl oxalate (20.1 g, 0.14 mol). The mixture was stirred at −78° C. for 45 min and at ambient temperature for one hour, and quenched with 1 N HCl. The mixture was extracted with ether. The organic solution was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography to give 3.70 g (27% based on recovered starting material) of the title compound: MS (ES+) m/z 324.3 (M+1).
Reaction SMILES: N#N.Cl.[F:4][C@H:5]1[CH2:9][CH2:8][NH:7][CH2:6]1.Br[CH2:11][CH2:12][CH2:13][C:14]#[N:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6]1
Reactant: N#CCCCBr
Reactant: F[C@H]1CCNC1
Agent: Cl
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: NCCCCN1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (S)-3-fluoropyrrolidin hydrochloride (200 mg, 1.54 mmol) and 4-bromobutyronitrile (0.16 mL, 1.54 mmol) in dry CH3CN (8 mL) was added K2CO3 (1.17 g, 8.50 mmol) at rt followed by KI (26 mg, 0.15 mmol). The reaction mixture was stirred at rt for 15 h. The mixture was filtered and the filtrate partitioned between water and CH2Cl2. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude nitrile was redissolved in dry THF (10 mL) and treated with LiALH4 (92 mg, 2.35 mmol) at 0° C. The reaction mixture was warmed up to rt and stirred at this temperature until completion of the reaction. Aq. 1N NaOH (3 mL) was then added, the layers separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (S)-4-(3-fluoropyrrolidin-1-yl)butan-1-amine as a yellow oil. GC-MS-conditions 01: tR=1.70 min; [M+H]+=161.10.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([CH:10]=[O:11])[CH:4]=[N:3]1.[OH-:12].[K+]>CO.[Ag-]=O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10]([OH:12])=[O:11])[CH:4]=[N:3]1
Reactant: [OH-]
Reactant: Cn1ncc(C=O)c1[N+](=O)[O-]
Agent: O=[Ag-]
Agent: [K+]
Solvent: CO
Product: Cn1ncc(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 1-methyl-5-nitro-1H-pyrazole-4-carbaldehyde (0.42 g, 2.8 mmol) in methanol (5 mL) was treated with silver (I) oxide (1.29 g, 5.6 mmol) followed by 5N potassium hydroxide (1.5 mL) in 5 mL of methanol and then refluxed for 16 hours. The mixture was cooled to room temperature and quenched with concentrated HCl (8 mL) and ethyl acetate. The mixture was filtered through a layer of celite and concentrated to give crude 1-methyl-5-nitro-1H-pyrazole-4-carboxylic acid: 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 4.22 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]1.C(N(CC)CC)C.[O:28]1C[CH2:31][CH2:30][CH2:29]1.C(Cl)(=O)C=C>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:29](=[O:28])[CH:30]=[CH2:31])[CH2:13][CH2:14]1
Reactant: OCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)OCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Reaction time: 4 h

Procedure:
First, 4.77 g of 2,3-difluoro-1-[trans-4-(5-hydroxypentyl)cyclohexyl]benzene, 1.9 g of triethylamine, and 60 ml of dry tetrahydrofuran were placed in a 100 ml flask. Then, 1.7 g of acryloyl chloride was added dropwise to the reaction mixture under ice water cooling, and the mixture was stirred at the same temperature for 4 hours. Water was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene/hexane=1/1) and recrystallized from hexane to obtain 3 g of 2,3-difluoro-1-[trans-4-(5-propenoyloxypentyl)cyclohexyl]benzene (Y: 52.9%). The compound thus obtained had a purity of 99.8% by GC, 99.2% by HPLC, and 1 spot by TLC. Furthermore, the compound had an m.p. of 29.6° C. to 30.7° C.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[CH2:15]([NH:17][CH3:18])[CH3:16]>>[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2]([N:17]([CH2:15][CH3:16])[CH3:18])=[N:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:11]=1
Reactant: CCNC
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Product: CCN(C)C1=NS(=O)(=O)c2cc(Cl)ccc2N1

Procedure:
Starting from 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (753 mg; 3 mmol) and N-ethyl-N-methylamine (708 mg; 12 mmol) and with the use of same procedure as in example 21 650 mg (79%) of the title compound was prepared; m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 10.4 (s, 1H, NH), 7.69 (d, 1H, H-8), 7.61 (dd, 1H, H-6), 7.55 (d, 1H, H-5), 3.5 (q, 2H, CH2), 3.09 (s, 3H, CH3), 1.10 (t, 3H, CH3); 13C-NMR (DMSO-d6) ppm; 150.21, 134.69, 131.81, 127.27, 123.98, 121.42, 119.54, 44.2, 34.69, 11.91. Analysis C10H12ClN3O2S requires C, 43.88; H, 4.42; N, 15.35; (found C, 43.52; H 4.55; N, 15.30).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.N1CCCCC1>C(O)C>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:23][C:22]3[CH:25]=[CH:26][C:19]([OH:18])=[CH:20][CH:21]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc(O)cc1
Yield: 65 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (4.40 g) was suspended in 125.00 mL of ethanol and 4-hydroxybenzaldehyde (4.273, 1.5 eq.) and piperidine (0.50 eq, 865 μL) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((3-chlorophenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (4.00 g, 65% yield).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: COc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: COc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: CCN(CC)CC.Cl.[NH:9]1[CH2:12][CH2:11][CH2:10]1.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C(Cl)Cl>[N:9]1([C:18]([C:17]2[CH:21]=[CH:22][C:14]([Br:13])=[CH:15][CH:16]=2)=[O:19])[CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Br)cc1)N1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Et3N (2.00 mL, 14.3 mmol) and azetidine hydrochloride (462 mg, 4.94 mmol) were added to a solution of 4-bromobenzoyl chloride (1.07 g, 4.88 mmol) in CH2Cl2 (20 mL). The mixture was stirred at room temperature for 2 hr, diluted with CH2Cl2 (100 mL), and washed with 1N aqueous HCl (100 mL), H2O (100 mL), and brine (100 mL). The organic layer was dried over MgSO4 and concentrated to give a colorless oil (1.10 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ 7.53 (ddd, J=17.43, 6.57, 2.27 Hz, 4 H) 4.21-4.32 (m, 4 H) 2.32-2.40 (m, 2 H);); LCMS for C10H10BrNO m/z 241.00 (M+H)+.