Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:48][C@H:49]1[CH2:54][CH2:53][C@H:52]([OH:55])[CH2:51][CH2:50]1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:48][C@H:49]4[CH2:54][CH2:53][C@H:52]([OH:55])[CH2:51][CH2:50]4)=[O:26])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)N[C@H]3CC[C@H](O)CC3)c2n1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K, 30 mg, 0.084 mmol) in anhydrous CH2Cl2 (2 mL) was added HOBt (34 mg, 0.25 mmol) followed by EDCI (48 mg, 0.25 mmol). The solution was stirred for 30 minutes, then treated with (trans)-4-aminocyclohexanol (29 mg, 0.25 mmol) followed by triethylamine (35 μL, 0.25 mmol). After stirring at ambient temperature for 5 hours, the reaction mixture was diluted with EtOAc, washed with saturated NH4Cl (20 mL), saturated NaHCO3, and brine, then dried (Na2SO4), filtered and concentrated. The crude material was purified by silica chromatography (4% MeOH/CH2Cl2) to yield the final product as white solid (23 mg, 60%). LCMS (apci) m/z=455.1 (M+H).
Reaction SMILES: C([C:9]1[C:10]([NH:14][C:15](=[O:34])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[C:17]=2[Cl:33])=[N:11][O:12][N:13]=1)(=O)C1C=CC=CC=1.ClC1C(COCC(F)(F)F)=C(S(C)(=O)=O)C=CC=1[C:38](O)=[O:39].NC1C(C(C2C=CC=CC=2)=O)=NON=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>ClCCl.CN(C1C=CN=CC=1)C>[Cl:33][C:17]1[C:18]([CH2:26][O:27][CH2:28][C:29]([F:31])([F:30])[F:32])=[C:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=[CH:21][C:16]=1[C:15]([NH:14][C:10]1[C:9]([O:39][CH3:38])=[N:13][O:12][N:11]=1)=[O:34]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1COCC(F)(F)F
Reactant: CS(=O)(=O)c1ccc(C(=O)Nc2nonc2C(=O)c2ccccc2)c(Cl)c1COCC(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Agent: Nc1nonc1C(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1nonc1NC(=O)c1ccc(S(C)(=O)=O)c(COCC(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Synthesis of N-(4-benzoyl-1,2,5-oxadiazol-3-yl)-2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]benzamide (example No. 11-5 in the tables) 204 mg (0.59 mmol) of 2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]-benzoic acid and 111 mg (0.59 mmol) of (4-amino-1,2,5-oxadiazol-3-yl)(phenyl)-methanone are dissolved in 10 ml of dichloromethane at RT and treated with 59 mg (0.599 mmol) of triethylamine, 14 mg (0.19 mmol) of DMAP and 561 mg (0.882 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF). The reaction mixture is stirred for 30 h at RT and subsequently washed twice with in each case 5 ml of water. The organic phase is dried over Na2SO4 and evaporated. The residue is purified by column chromatography (silica gel, heptane/ethyl acetate). Yield 50 mg (15%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH2:24])[CH2:7][C:6]2=1.[CH2:25](N(CC)CC)[CH3:26].Cl.O.CCO[C:37]([CH3:39])=[O:38]>ClCCl>[Br:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:24][C:37]([CH:39]3[CH2:26][CH2:25]3)=[O:38])[CH2:7][C:6]2=1
Reactant: CCOC(C)=O
Reactant: CCN(CC)CC
Reactant: NC1CCc2c(c3cc(Br)ccc3n2Cc2cccc(F)c2)C1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(NC1CCc2c(c3cc(Br)ccc3n2Cc2cccc(F)c2)C1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
Mix 6-bromo-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylamine hydrochloride (195 mg, 0.48 mmol), triethylamine (210 μL, 1.5 mmol), cyclopropanecarbonyl chloride chloride (55 μL, 0.6 mmol) in dichloromethane (10 mL) and stir at room temperature for 18 h. Shake the reaction with dilute HCl/water/EtOAc. Dry (MgSO4) the organic layer and concentrate to give 120 mg crude product. Recrystallize (EtOH) to give 50 mg (24%) of the title compound. MS (ES): m/z 441, 443 (M+1); 1H NMR (CDCl3): δ 7.63 (s, 1H), 7.27 (m 2H), 7.08 (d,1H), 6.92 (t, 1H), 6.75 (d, 1H), 6.63 (d, 1H), 5.58 (br d, 1H), 5.23 (s, 2H), 4.44 (br m, 1H), 3.13 (dd, 1H), 2.74 (m, 2H), 2.64 (dd,1H), 2.23 (m,2H), 2.16 (m,1H), 2.02 (m,1H), 1.09 (m,4H); HPLC: Rt=3.55 min, (95%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[CH:6]=[C:7]([C:9]3[C:18]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:24]([O:26]C)=[O:25])[CH:15]=4)[N:10]=3)[O:8][C:4]=2[CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[CH:6]=[C:7]([C:9]3[C:18]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:24]([OH:26])=[O:25])[CH:15]=4)[N:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccc(F)cc4o3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccc(F)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a solution of methyl 2-(6-fluoro-1-benzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (55 mg, 0.14 mmol) in methanol (20 mL) and water (1 mL) was added sodium hydroxide (12 mg, 0.30 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted the pH value to 5 with 3N HCl and filtered to give 2-(6-fluoro-1-benzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a light yellow solid (28.8 mg, 54%).
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:22]([OH:24])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(Br)(Br)(Br)[Br:31]>>[Br:31][CH2:26][CH2:27][CH2:28][CH2:29][O:23][C:22](=[O:24])[C@H:15]([CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)[NH:14][C:12](=[O:13])[CH2:11][CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(CCNC(=O)c1cccnc1)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: BrC(Br)(Br)Br
Reactant: C1CCOC1
Product: O=C(CCNC(=O)c1cccnc1)N[C@@H](Cc1c[nH]cn1)C(=O)OCCCCBr

Procedure:
To a solution of N-nicotinoyl-β-alanyl-(L)-histidine (9.9 g, 30.1 mmoles) in tetrahydrofuran (200 ml) triphenylphosphine (23.7 g, 90.3 mmoles) and carbon tetrabromide (28.85 g, 90.3 moles) are added under stirring. The reaction mixture is left under stirring at room temperature for 24 hours. Lastly the solvent is removed by evaporation at reduced pressure. The obtained crude product is purified by chromatography on silica gel column eluting with n-hexane/ethyle acetate 1/1. N-nicotinoyl-β-alanyl-(L)-histidine 4-bromobutyl ester is obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([CH:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[C:31](=[O:32])[CH2:30][O:29][C:28]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:27]3)=[CH:21][CH:20]=2)[C:16](O)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.[NH2:39][CH:40]([CH3:54])[CH2:41][CH2:42][CH2:43][C:44]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:46][CH2:45]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:10]1([CH:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[C:31](=[O:32])[CH2:30][O:29][C:28]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:27]3)=[CH:21][CH:20]=2)[C:16]([NH:39][CH:40]([CH3:54])[CH2:41][CH2:42][CH2:43][C:44]2([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:45][CH2:46]2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(N)CCCC1(C(=O)OC(C)(C)C)CC1
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(CCCC1(C(=O)OC(C)(C)C)CC1)NC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
At RT, 253 μl (1.45 mmol) of DIEA were added to a solution of 517.9 mg (1.32 mmol) of (+)-cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetic acid and 450 mg (about 1.98 mmol, crude material) of tert-butyl 1-(4-aminopentyl)cyclo-propanecarboxylate in 2.5 ml of DMF. The resulting mixture was cooled to 0° C., and four portions of altogether 186.4 mg (0.49 mmol) of HATU were then added. The reaction mixture was slowly warmed to RT, stirred at RT for 16 h and then added to water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. Purification of the crude product by preparative RP-HPLC (acetonitrile/water gradient) gave 540.0 mg (68.0% of theory) of the target compound as a diastereomer mixture.
Reaction SMILES: C([O-])(=O)C.[Na+].[Br:6]Br.[Br:8][C:9]1[C:17]2[C:12](=[N:13][C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=2)[O:11][CH:10]=1.N12CCCN=C1CCCCC2>C(Cl)Cl>[Br:6][C:10]1[O:11][C:12]2=[N:13][C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[C:17]2[C:9]=1[Br:8]
Reactant: BrBr
Reactant: CCOC(=O)c1cc2c(Br)coc2nc1C(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc2c(Br)c(Br)oc2nc1C(=O)OCC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Sodium acetate (2.40 g, 0.0292 mol) and bromine (7.5 mL, 0.146 mol) are added to a solution of diethyl 3-bromofuro[2,3-b]pyridine-5,6-dicarboxylate (5.00 g, 0.0146 mol) in methylene chloride (150 mL). The mixture is stirred at room temperature for four days then washed with aqueous sodium bisulfate to remove unreacted bromine. The aqueous solution is then back extracted with methylene chloride. The organic solution is combined, dried over sodium sulfate and filtered. To the filtrate is added 1,8-diazabicyclo[5.4.0]undec-7-ene(4.4 mL, 0.032 mol), and the mixture is stirred at room temperature for one hour. The solution is then concentrated in vacuo. The residue is chromatographed over silica gel eluting with 20% ethyl acetate in hexane, yielding the crude 2,3-dibromofuro[2,3-b]pyridine as a white solid in 95% yields recrystallization from a methylene chloride-hexane mixture affords diethyl 2,3-dibromofuro[2,3-b]pyridine-5,6-dicarboxylate mp 96°-98° C. in 75.9% recrystallized yield.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CCCCCC>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:39]([NH:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:40])[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Solvent: CCCCCC
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Nc1ccccc1
Yield: 375 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine (1.0 g, 0.0024 mol) in hexane (50 mL) was added, dropwise, a solution of phenylisocyanate (0.27 mL, 0.298 g, 0.0025 mol) in hexane (25 mL) and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated under vacuum and the residue was chromatographed with 6:4 hexane-ethyl acetate to give the title compound (0.5 g, 0.009 mol) as a yellow amorphous solid. 1H NMR (CDCl3) δ 11.0(s,1H), 7.7-6.9(m,14H), 6.4(s,1H), 3.4(t,2H,J=7 Hz), 3.2(t,2H,J=7 Hz), 3.0(t,2H,J=7 Hz), 1.9-1.1(m,16H), 0.9(t,3H,J=8 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=2[CH2:12][CH3:13])=[C:5]([CH3:17])[CH:4]=[N:3]1.[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])=[O:16])[S:10][C:11]=2[CH2:12][CH3:13])=[C:5]([CH3:17])[CH:4]=[N:3]1
Reactant: CCc1sc(C(=O)O)cc1-c1c(C)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(C)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (130 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [prepared according to Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (278 mg, 0.43 mmol, 82% yield) as a yellow oil: LCMS (ES) m/e 581 (M+H)+.