Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2([NH:19]C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH2:12]1)=O)C1C=CC=CC=1.C(N(CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43]C=1F)[N:41]([C@@H:46]1[CH2:48][C@@H:47]1[F:49])[CH:40]=[C:39]([C:50]([OH:52])=[O:51])[C:38]2=[O:53].[OH-].[Na+]>CO.[C].[Pd]>[NH2:19][C:16]1([C@@H:13]2[CH2:14][CH2:15][N:11]([C:9]3[CH:43]=[C:42]4[C:37]([C:38](=[O:53])[C:39]([C:50]([OH:52])=[O:51])=[CH:40][N:41]4[C@@H:46]4[CH2:48][C@@H:47]4[F:49])=[CH:36][C:35]=3[F:34])[CH2:12]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCN(C(=O)OCc3ccccc3)C2)CC1
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2cc(F)c(F)cc2c1=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: NC1([C@@H]2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4[C@@H]3C[C@@H]3F)C2)CC1
Reaction time: 2 h
Yield: 77 %

Procedure:
A 322 mg (0.89 mmol) portion of (3R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine was dissolved in 10 ml of methanol to which was subsequently added 100 mg of 5% palladium-carbon to carry out 2 hours of hydrogenation under normal pressure with warming by an infrared lamp. After completion of the reaction, 5% palladium-carbon was removed by filtration and methanol was evaporated. The resulting residue was dissolved in 5 ml of acetonitrile to which were subsequently added 0.5 ml of triethylamine and 113 mg (0.4 mmol) of 6,7-difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, followed by 18 hours of heating under reflux. After completion of the reaction, the reaction solution was spontaneously cooled to collect the thus formed crystals by filtration. With cooling in an ice bath, to the thus obtained crystals was added dropwise 5 ml of concentrated hydrochloric acid, followed by 30 minutes of stirring at the same temperature. After completion of the reaction, the reaction solution was adjusted to pH 12 with sodium hydroxide aqueous solution and then to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (50 ml×3). The organic layers were combined and dried on sodium sulfate, and then the solvent was evaporated. Thereafter, the resulting residue was recrystallized from liquid ammonia-ethanol to yield 120 mg (77%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[O:17][C:18]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=2[N:20]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:16]2[O:17][C:18]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=3[N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc2nc(Cl)oc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CNc2nc3ccc(Cl)cc3o2)C1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of 220 mg (1.1 mmol) 3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (commercially available), 188 mg (1 mmol) 2,6-dichloro-benzooxazole (commercially available) and 303 mg (3 mmol) NEt3 in 4 mL DCM was stirred at room temperature over night. After evaporation to dryness the residue was purified with flash column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The product containing fractions were evaporated to yield 351 mg (99%) of the title compound. MS (m/e): 352.4 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[C@@H:3]([NH:7][S:8]([C:11]1[CH:23]=[CH:22][C:14]2[N:15]=[C:16]([S:18][CH2:19][CH2:20][CH3:21])[O:17][C:13]=2[CH:12]=1)(=[O:10])=[O:9])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:28])=O.CN(C=O)C>ClCCl>[CH3:1][CH:2]([CH3:24])[C@@H:3]([NH:7][S:8]([C:11]1[CH:23]=[CH:22][C:14]2[N:15]=[C:16]([S:18][CH2:19][CH2:20][CH3:21])[O:17][C:13]=2[CH:12]=1)(=[O:10])=[O:9])[C:4]([Cl:28])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc2o1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)Cl)C(C)C)cc2o1
Temperature: 0 °C

Procedure:
(2R)-3-methyl-2-[(2-propylthiobenzoxazol-6-sulfonyl)amino]butanoic acid (112 mg, 0.3 mmol) prepared in Example 19 was dissolved in dichloromethane (2 mL) and cooled down to 0° C., and, oxalylchloride (0.08 mL, 3 equi.) and DMF of catalytic amount were added. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent and dried under reduced pressure. Then, (2R)-3-methyl-2-[(2-propylthiobenzoxazol-6-sulfonyl)amino]butanoic chloride thus obtained was dissolved in THF (1 mL). Hydroxylamine hydrochloride (0.21 g, 10 equi.) and NaHCO3 (0.303 g, 12 equi.) was dissolved in THF/H2O (2 mL/2 mL) and cooled down to 0° C. to prepare a hydroxylamine solution. Then, acid chloride THF solution was slowly added to the hydroxylamine solution while maintaining the temperature of 0° C. After 1 hour, the solvent was removed from the reaction solution. Then, the product was extracted with ethylacetate (5 mL), washed with H2O and 0.1N HCl and dried over MgSO4. The dried material was distilled under reduced pressure and vacuum-dried to prepare the titled compound, (2R)-N-hydroxy-3-methyl-2-[(2-propylthiobenzoxazol-6-sulfonyl)amino]butyric amide (100 mg, 85%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[CH2:2]2.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>CCO>[C:11]1([NH:10][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CN2CCC1CC2
Reactant: Nc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(NC2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
(Method 1B) A mixture of 1.26 g of 1-azabicyclo[2.2.2]octan-3-one and 0.93 g of aniline and 4.4 mL of Ti(/PrO)4 was stirred overnight at room temperature. The reaction mixture was diluted with EtOH and then NaBH4 pellets (0.8 g) were added until reaction was judged complete by TLC. The solvent was evaporated in vacuo. The residue was diluted with 3N NaOH, water and EtOAc and the mixture was filtered through dicalite. The filter pad was washed with additional EtOAc. The filtrate was transferred to a separatory funnel and the aqueous layer was extracted with an additional portion of EtOAc. The combined organic extracts were washed with water and then brine and then dried over K2CO3. The solution was filtered and the solvent was evaporated in vacuo. The residue was chromatographed on silica (90/7.5/2.5 CHCl3/MeOH/7.0 M NH3 in MeOH) to give N-Phenyl-1-azabicyclo[2.2.2]octan-3-amine (1.5 g, 75%) as a white solid. 1H NMR (CDCl3) is consistent with the one from Method 1A.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C@H:11]1[CH2:16][NH:15][C:14]2[CH:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[CH:20][C:13]=2[N:12]1[C:31](=[O:33])[CH3:32].[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>ClCCl>[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39]([N:15]1[CH2:16][C@H:11]([CH3:10])[N:12]([C:31](=[O:33])[CH3:32])[C:13]2[CH:20]=[N:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[CH:17][C:14]1=2)=[O:40]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(=O)N1c2cnc(-c3ccc(S(C)(=O)=O)cc3)cc2NC[C@@H]1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2cnc(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)c2ccco2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
N,N-Diisopropylethylamine (0.3 mL, 1.718 mmol) was added to a solution of (S)-1-(3-methyl-7-(4-(methylsulfonyl)phenyl)-2,3-dihydropyrido[4,3-b]pyrazin-4(1H)-yl)ethanone (0.004 g, 0.012 mmol) and furan-2-carbonyl chloride (0.2 mL, 2.029 mmol) in dichloromethane (1.0 mL), and the mixture stirred at room temperature for 2 h. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-1-(1-(furan-2-carbonyl)-3-methyl-7-(4-(methylsulfonyl)phenyl)-2,3-dihydropyrido[3,4-b]pyrazin-4(1H)-yl)ethanone (0.0038 g, 75%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.13-1.22 (m, 3 H), 2.25 (br s, 1 H), 2.31 (s, 3 H), 3.02 (s, 3 H), 3.88 (br s, 1 H), 4.05-4.18 (m, 1 H), 5.03 (br s, 1 H), 6.55 (dd, J=3.52, 1.76 Hz, 1 H), 7.20-7.26 (m, 1 H), 7.45 (dd, J=1.76, 0.88 Hz, 1 H), 7.78 (s, 1 H), 7.89-8.02 (m, 4 H). MS (ESI, pos. ion) m/z 440.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[C:14]2[C:10]=1[C:11]1[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][C:12]=1[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(S(C1C=C(C2C=C([C:46]([N:48]3[CH2:53]C[N:51](C)[CH2:50][CH2:49]3)=O)C=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:8][C:9]1[CH:17]=[C:16]([C:18]([NH:51][CH2:50][CH2:49][N:48]([CH3:53])[CH3:46])=[O:20])[CH:15]=[C:14]2[C:10]=1[C:11]1[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][C:12]=1[NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnc2[nH]c3cc(C(=O)O)cc(SCc4ccccc4)c3c2c1
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)N3CCN(C)CC3)cc3[nH]c4ncc(C)cc4c23)c1
Product: Cc1cnc2[nH]c3cc(C(=O)NCCN(C)C)cc(SCc4ccccc4)c3c2c1

Procedure:
The title compound was synthesized from Compound 150 using an analogous procedure to that described in the preparation of Compound 140. 1H NMR (400 MHz, MeOD) δ ppm 2.53 (s, 3H) 3.02 (s, 6H) 3.43 (t, J=5.81 Hz, 2H) 3.82 (t, J=5.81 Hz, 2H) 4.42 (s, 2H) 7.16-7.26 (m, 3H) 7.31 (d, J=7.83 Hz, 2H) 7.82 (d, J=1.26 Hz, 1H) 7.96 (s, 1H) 8.30 (s, 1H) 8.80 (s, 1H) [M+H] calc'd for C24H26N4OS, 419; found, 419.
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[CH:28]=[N:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=34)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:36][CH3:37])[CH:12]=1.[CH3:38][N:39]1[CH2:43][C@@H:42]2[NH:44][CH2:45][CH2:46][C@@H:41]2[CH2:40]1>FC(F)(F)CO>[CH3:38][N:39]1[CH2:40][C@@H:41]2[C@@H:42]([N:44]([C:11]3[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]4[N:26]=[C:25]([C:27]5[CH:28]=[N:29][N:30]6[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=56)[CH:24]=[CH:23][N:22]=4)=[C:13]([O:36][CH3:37])[CH:12]=3)[CH2:45][CH2:46]2)[CH2:43]1
Reactant: CN1C[C@H]2CCN[C@H]2C1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: OCC(F)(F)F
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 140 °C
Yield: 60.9 %

Procedure:
DIPEA (0.583 mL, 3.35 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 127, 515 mg, 1.34 mmol) and (3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole (Intermediate 37, 186 mg, 1.47 mmol) in 2,2,2-trifluoroethanol (5 mL) and the mixture was heated in a microwave at 140° C. for 1 h. After cooling, the mixture was part-purified by ion exchange chromatography, using an SCX column, eluting with 7M methanolic ammonia, and then concentrated in vacuo onto silica. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (400 mg, 61%) as an orange/red foam; 1H NMR (CDCl3): 1.87 (1H, dd), 1.90-1.98 (2H, m), 2.03-2.14 (3H, m), 2.20 (3H, s), 2.28 (1H, dd), 2.45 (2H, ddd), 2.60-2.67 (1H, m), 2.97-3.07 (1H, m), 3.18-3.34 (3H, m), 3.48-3.58 (1H, m), 3.96 (3H, s), 4.20 (2H, t), 4.40 (1H, ddd), 6.43 (1H, s), 6.86 (1H, d), 7.35 (1H, s), 7.95 (1H, s), 8.30 (1H, d), 8.92 (1H, s); m/z: ES+ MH+ 491.15.
Reaction SMILES: [I-].[C:2]([CH2:4][C:5]1[S:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[N+:9]=1[CH2:10][CH3:11])#[N:3].CO/[CH:18]=[CH:19]/[CH:20]=[C:21]1\[S:22](=[O:32])(=[O:31])[C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]\1=[O:26].C(Cl)(Cl)Cl.CO.C([O-])(=O)C.[Na+]>CO>[O:31]=[S:22]1(=[O:32])[C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25](=[O:26])/[C:21]/1=[CH:20]/[CH:19]=[CH:18]/[C:4](=[C:5]1\[S:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[N:9]\1[CH2:10][CH3:11])/[C:2]#[N:3]
Reactant: CO/C=C/C=C1/C(=O)c2ccccc2S1(=O)=O
Reactant: CC[n+]1c(CC#N)sc2ccccc21
Agent: CC(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCN1/C(=C(C#N)/C=C/C=C2/C(=O)c3ccccc3S2(=O)=O)Sc2ccccc21
Temperature: 25 °C

Procedure:
In a one-necked round bottom 100-mL flask equipped with magnetic stir bar and reflux condenser were added 2-(cyanomethyl)-3-ethyl-1,3-benzothiazol-3-ium iodide (1.00 g, 3.03 mmol), (2Z)-2-[(2E)-3-methoxyprop-2-en-1-ylidene]-1-benzothiophen-3-(2H)-one 1,1-dioxide (1.00 g, 4.00 mmol) and CHCl3-MeOH mixture (1:1, 20 mL). The flask was heated on an oil bath with stirring until boiling began, and a solution of sodium acetate (320 mg, 4.00 mmol) in 10 mL of methanol was added to the flask. The stirring was continued under reflux for an additional 30 min. The flask was cooled to room temperature and the precipitated solid was filtered, washed with methanol and dried. Green crystals. The yield was 730 mg (57% of theory).
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([C:14]#[N:15])=[C:5]([Cl:16])[N+:4]=1[CH2:17][CH2:18][CH2:19][CH3:20].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[Cl-:16].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([C:14]#[N:15])=[C:5]([S:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N+:4]=1[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: SCc1ccccc1
Reactant: CCCCNc1cc(N)[n+](CCCC)c(Cl)c1C#N
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNc1cc(N)[n+](CCCC)c(SCc2ccccc2)c1C#N
Temperature: 100 °C
Yield: 49.4 %

Procedure:
3.15 gms (0.01 mole) of 2-amino-1-n-butyl-4-n-butylamino-6-chloro-5-cyano pyridinium chloride (compound 6 - Table 1), 1.24 gms (0.01 mole) of benzyl mercaptan and 1.0 gm (0.01 mole) of triethylamine was dissolved in dimethylformamide and heated at 100°C for 1 hour. The dimethylformamide was evaporated off, ethanol added and 2.0 gms (50% yield) of 2-amino-6-benzylmercapto-1-n-butyl-4-n-butylamino-5-cyano pyridinium chloride (compound 75 - Table 5) crystallised out and was recrystallised from ethanol (MPt 145° - 147°C).
Reaction SMILES: Cl.C(N(C1C=CC=CC=1)S(C1C=NC(N2C(=O)C(CC3C=NC=CC=3)=C(C)N2)=CC=1)(=O)=O)C.[CH3:34][O:35][CH2:36][C:37]1[CH:38]=[C:39]([CH2:43]O)[CH:40]=[CH:41][CH:42]=1.P(Br)(Br)[Br:46].CO>CCOCC>[Br:46][CH2:43][C:39]1[CH:40]=[CH:41][CH:42]=[C:37]([CH2:36][O:35][CH3:34])[CH:38]=1
Reactant: COCc1cccc(CO)c1
Reactant: BrP(Br)Br
Agent: CCN(c1ccccc1)S(=O)(=O)c1ccc(-n2[nH]c(C)c(Cc3cccnc3)c2=O)nc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COCc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
To a solution of 5.91 g (38.8 mmol) of 2 [3-(methoxymethyl)phenyl]methanol in 75 mL of Et2O are added dropwise, at 0° C., 9.1 mL (97.1 mmol) of phosphorus tribromide. The reaction mixture is allowed to warm slowly to room temperature and stirring is continued for 4 hours. The crude reaction mixture is then poured cautiously into a mixture of 100 g of ice and 100 mL of MeOH. After evaporating off the MeOH under reduced pressure, the aqueous phase is extracted with DCM (2×200 mL). The organic phases are combined, dried over Na2SO4, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 20% EtOAc. 3.25 g of 1-(bromomethyl)-3-(methoxymethyl)benzene are thus obtained in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:21]2[NH:22][C:23](=[O:25])[O:24][C:20]=2[CH:19]=1>O1CCOCC1.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=c1[nH]c2ccc(CCBr)cc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccccc1N1CCN(CCc2ccc3[nH]c(=O)oc3c2)CC1
Yield: 66.5 %

Procedure:
0.025 mol (4.82 g) of 1-(2-methoxyphenyl)-piperazine and 0.02 mol (4.85 g) of 6-(2-bromoethyl)-benzoxazolinone, dissolved beforehand in 50 cm3 of dioxane, were introduced into a 100 cm3 flask with a ground glass neck, fitted with a reflux condenser, and the mixture was then heated under reflux for 72 hours, with stirring. After cooling, filtration and drying, the precipitate formed was dissolved in a sufficient amount of a 3% aqueous solution of sodium hydroxide. A stream of carbon dioxide was then bubbled and the precipitate was filtered off, washed and dried. Recrystallisation from toluene gave 4.7 g of the title product having a melting point of 182°-184° C.
Reaction SMILES: C(Cl)CCCCC.[CH3:8][N:9]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N:11]=[C:10]1[C:17]1[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH2:28]CN)[CH3:27])=[CH:20][O:19][N:18]=1.C[N:32](C)C=O>>[CH3:8][N:9]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N:11]=[C:10]1[C:17]1[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH2:28][NH2:32])[CH3:27])=[CH:20][O:19][N:18]=1
Reactant: CC(CCN)CCCCc1conc1-c1ncc([N+](=O)[O-])n1C
Reactant: CN(C)C=O
Solvent: CCCCCCCl
Product: CC(CN)CCCCc1conc1-c1ncc([N+](=O)[O-])n1C

Procedure:
The product prepared above is treated in a similar fashion with hexyl chloride in dimethylformamide for 2 hours. The recrystallized product is identified as 1-methyl-2-(5-aminoethylhexylisoxazol-3-yl)-5-nitroimidazole.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.O=[C:11]1[CH2:15][S:14][CH2:13][CH:12]1[C:16](OC)=[O:17]>>[CH2:13]1[C:12]2[C:16](=[O:17])[NH:9][C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=3[NH:8][C:11]=2[CH2:15][S:14]1
Reactant: Nc1ccc(F)cc1N
Reactant: COC(=O)C1CSCC1=O
Product: O=C1Nc2ccccc2NC2=C1CSC2

Procedure:
In a similar fashion 4-fluoro-o-phenylenediamine is condensed with methyl tetrahydro-4-oxo-3-thiophenecarboxylate to give a mixture of 7-fluoro- and 6-fluoro-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=4[F:34])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[C:42](Cl)(=O)[C:43](C)([CH3:45])[CH3:44]>ClCCl>[F:34][C:25]1[CH:26]=[C:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:28]=[CH:29][C:24]=1[NH:23][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:43]([CH3:45])([CH3:44])[CH3:42])[CH2:9][CH2:10]3)[N:15]=[CH:16][C:17]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1

Procedure:
1-{4-[4-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-2,2-dimethyl-propan-1-one was prepared according to General Procedure J by the reaction of 4-[4-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 1) with trifluoroacetic acid in dichloromethane followed by reaction with pivaloyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.23 (s, 9H), 1.98-2.03 (m, 4H), 3.06-3.12 (m, 2H), 3.30 (methyl sulfonyl and water peak), 4.40-4.46 (m, 2H), 4.99-5.03 (m, 1H), 7.79-7.81 (m, 1H), 7.88-7.92 (m, 1H), 8.21-8.25 (m, 1H), 8.30-8.43 (m, 2H), 10.38 (s, 1H). Mass spectrum MH+=475.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH:37]([CH3:39])[CH3:38])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])([CH3:39])[CH3:38]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-isopropyl-benzenesulfonamide [CAS 118837-66-4] according to general procedure II. Light yellow solid. MS (ISP) 552.0 [(M−H−]; mp 229° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:18]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Br:18][C:12]1[NH:11][CH:10]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c[nH]cc1-c1cccc(F)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c(Br)c1-c1cccc(F)c1
Yield: 33.4 %

Procedure:
To a solution of 38.3 g (164 mmol) of ethyl 4-(3-fluoro-phenyl)-1H-pyrrole-3-carboxylate in 380 ml of tetrahydrofuran are added, over 30 minutes, 32.1 g (181 mmol) of N-bromosuccinimide (CAS 128-08-5), and the mixture is then stirred for 3 hours at reflux. After cooling, 200 ml of aqueous 5% sodium thiosulfate solution are added and the reaction product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give 17.1 g of ethyl 5-bromo-4-(3-fluorophenyl)-1H-pyrrole-3-carboxylate in the form of a white powder after recrystallizing from diisopropyl ether, filtering off and drying.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[C:7]([NH:9][C:10]1[C:11]([CH2:19][CH2:20][CH3:21])=[N:12][N:13]([CH3:18])[C:14]=1[C:15]([NH2:17])=[O:16])=O)[CH:2]=[CH2:3].[OH-].[Na+].O>C(O)C>[CH2:1]([O:4][C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[C:7]1[NH:17][C:15](=[O:16])[C:14]2[N:13]([CH3:18])[N:12]=[C:11]([CH2:19][CH2:20][CH3:21])[C:10]=2[N:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1C(=O)Nc1c(CCC)nn(C)c1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 41.9 %

Procedure:
A mixture of 4-(2-allyloxybenzamido)-1-methyl-3-n-propyl-pyrazole-5-carboxamide (1.2 g, 0.0035 mol), sodium hydroxide (0.70 g, 0.018 mol), water (34 ml) and ethanol (8 ml) was refluxed for 5 hours. After cooling, the solution was exhaustively extracted with ethyl acetate. The combined extracts were washed with brine (30 ml), dried (Na2SO4), filtered and the solvent evaporated under vacuum to give a crude product which was crystallised from ethyl acetate/hexane to afford the title compound (0.476 g, 37%), m.p. 116°-119° C. Found: C,67.00; H,6.21; N,17.23. C18H20N4O2 requires C,66.65; H,6.21; N,17.27%.