Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]2[N:32]=[C:31]3[S:33][C:34]([C:36]([OH:38])=O)=[CH:35][N:30]3[C:29]=2[CH:39]=1.[CH2:40]([NH2:45])[C:41]([CH3:44])([CH3:43])[CH3:42].[OH-].[Na+]>CN(C=O)C>[OH:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]2[N:32]=[C:31]3[S:33][C:34]([C:36]([NH:45][CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:38])=[CH:35][N:30]3[C:29]=2[CH:39]=1
Reactant: O=C(O)c1cn2c(nc3ccc(CO)cc32)s1
Reactant: CC(C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)CNC(=O)c1cn2c(nc3ccc(CO)cc32)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Hydroxybenzotriazole (10.1 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28.8 g) were added to a DMF (500 ml) suspension of 6-hydroxymethylthiazolo[3,2-a]benzimidazole-2-carboxylic acid (12.4 g), and the reaction mixture was stirred at room temperature for 2 hours. Neopentylamine (17.7 ml) was added to the reaction mixture, and the resulting reaction mixture was stirred at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into 0.5 M sodium hydroxide aqueous solution (2 l). The insoluble matter was collected by filtration, washed with water and then with a mixed solvent of hexane and diethyl ether (mixing ratio; 3:1) and then dried by heating under a reduced pressure to obtain the title compound (12.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.N[C@@H]1CCN(C(OC(C)(C)C)=O)C1.[C:41](=O)([O:50][C@H:51]1[CH2:55][CH2:54][O:53][CH2:52]1)[O:42]N1C(=O)CCC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]4[CH2:22][CH2:21][N:20]([C:41]([O:50][C@H:51]5[CH2:55][CH2:54][O:53][CH2:52]5)=[O:42])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: O=C(O[C@H]1CCOC1)N1CC[C@@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 47 %

Procedure:
According to the procedure for compound 398 using (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate and (S)-2,5-dioxopyrrolidin-1-yl tetrahydrofuran-3-yl carbonate afforded 19.8 mg (47% yield) of 424 as a solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CCCCCC.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>S(=O)(=O)(O)O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:15]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: C1=COCCC1
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: Ic1ccc(OC2CCCCO2)cc1
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
4-Iodophenol 10.0 g (45.5 mmol) was dissolved in 20 mL 3,4-dihydro-2H-pyran, then one drop of concentrated sulfuric acid was added, the reaction mixture was stirred for 30 min, then the mixture was poured into 1000 mL of n-hexane, filtered, washed with 300 mL (100 mL×3) hexane, and dried in vacuum to afford the desired product as a white solid (9.1 g, 65.9%).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][N:2]1[C:12]1[CH:21]=[C:20]([NH2:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.N12CCCN=C1CCCCC2.[Cl:34][CH2:35][C:36](Cl)=[O:37]>C(OCC)(=O)C>[Cl:34][CH2:35][C:36]([NH:22][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH:21]=1)=[O:37]
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(CCl)Nc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 22.1 %

Procedure:
To the solution of 2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-amine (500 mg, 1.73 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.52 mL, 3.48 mmol) followed by chloroacetyl chloride (0.21 mL, 2.64 mmol) at room temperature. The resulting solution was heated with stirring at 70° C. for 2 hours under nitrogen. After cooled to room temperature, the reaction was diluted with ethyl acetate (50 mL), and then washed with water (50 mL×3). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1:4) to give 140 mg of product as an off-white solid (yield was 22.1%). MS obsd. (ESI+) [(M+H)+] 366.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])[C:5]([C:6]([NH:8][NH:9][C:10](=O)[C:11]([O:13][CH3:14])=[O:12])=O)=[CH:4][N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[S:31][C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:9][N:8]=2)=[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])[CH:17]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)C(=O)NNC(=O)c1cnc(Cl)cc1NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1nnc(-c2cnc(Cl)cc2NC(C)C)s1

Procedure:
To a stirred solution of methyl 2-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-2-oxoacetate (11) (1 g, 3.1 mmol) in THF (30 mL), Lawesson's reagent (6.3 mmol, 2 equiv) was added and heated to reflux for 3 h. The reaction mixture was diluted with EtOAc and washed twice with 10% NaHCO3 solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography through silica gel and MeOH: DCM as eluent afford methyl 5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:20]=3[N:19]=[CH:18]2)=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.C(N=C=NC(C)C)(C)C.[NH2:48][CH2:49][CH2:50][OH:51].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[OH:51][CH2:50][CH2:49][NH:48][C:26]([C:24]1[CH:23]=[CH:22][C:21]2[N:17]([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:16][CH:15]=3)[CH:18]=[N:19][C:20]=2[CH:25]=1)=[O:27]
Reactant: NCCO
Reactant: O=C(O)c1ccc2c(c1)ncn2-c1ccc(OCCOc2ccccn2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCCO)c1ccc2c(c1)ncn2-c1ccc(OCCOc2ccccn2)cc1
Reaction time: 0.08 h

Procedure:
To a 20 mL Bohdan MiniBlock 12-position glass reaction tube, 1-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxylic acid (100 mg, 0.27 mmol), PS-HOBt (HL; 269 mg, 0.24 mmol), DMAP (18 mg, 0.15 mmol), CH2Cl2 (1 mL), and DMF (0.25 mL) were added. The reaction mixture was shaken for 5 min. 1,3-Diisopropylcarbodiimide (138 mg, 1.09 mmol) was added to the reaction mixture and shaken for 4 h. The solution was filtered and the resin was washed with CH2Cl2 (3×3 mL), DMF (3×3 mL), and THF (3×3 mL). The resin was resuspended in DMF (1 mL) and 2-aminoethanol (15 mg, 0.24 mmol) and DIEA (31 mg, 0.24 mmol) were added. The reaction mixture was allowed to shake overnight. The reaction mixture was then filtered, and washed with CH2Cl2 (3×3 mL), DMF (3×3 mL), and THF (3×3 mL). The filtrate and the washes were combined and concentrated in vacuo. The crude product was purified by using the Waters mass-directed HPLC purification system to yield N-(2-hydroxyethyl)-1-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxamide as a yellowish white powder. 1H NMR (d6-DMSO, 400 MHz): δ 8.57 (s, 1H), 8.49 (t, J=4.4 Hz, 1H), 8.32 (d, J=1.2 Hz, 1H), 8.19 (ddd, J=5.2, 2.0, 0.8 Hz, 1H), 7.85 (dd, J=8.4, 1.6 Hz, 1H), 7.74 (ddd, J=9.2, 7.2, 2.0 Hz, 1H), 7.61 (ddd, J=5.6, 3.6, 3.6 Hz, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.23 (ddd, J=6.0, 3.6, 3.6 Hz, 2H), 7.01 (ddd, J=7.2, 5.2, 0.8 Hz, 1H), 6.88 (ddd, J=8.4, 0.8, 0.8 Hz, 1H), 4.63 (m, 2H), 4.43 (m, 2H), 2.82 (d, J=4.8 Hz, 3H). MS(ES+): m/z 419 (60) [MH+].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:6][N:5]=[C:4]2[NH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[C:3]=12.[CH3:30]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]3[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=3)[C:11]([N:13]([CH3:14])[CH3:15])=[O:12])[C:2]=2[CH3:30])[NH:19][CH:20]=1
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)N(C)C)c3)c(Cl)c12
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)N(C)C)c3)c(C)c12
Yield: 6.7 %

Procedure:
Into a 5 mL Personal Chemistry microwave reaction vial were added 3-[4-Chloro-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (37 mg, 0.09 mmol), trimethylboroxine (15 μL, 0.11 mmol), tetrakis(triphenylphosphine)palladium (7 mg, 0.009 mmol), potassium carbonate (52 mg, 0.27 mmol), and dioxane (1 mL). The vial was purged with nitrogen, sealed, and irradiated in a Personal Chemistry Optimizer at 140° C. for 60 min. The reaction mixture was diluted with ethylacetate, filtered over Celite and concentrated. The crude product was purified by mass triggered reverse phase HPLC to afford the title compound (2.4 mg, 0.006 mmol, 7% yield). 1H NMR (500 MHz, DMSO-d6) δ 11.74 (d, J=2 Hz, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.50 (t, J=8 Hz, 1H), 7.41 (dt, J1=9.5 Hz, J2=1.5 Hz, 1H), 7.37 (dt, J=7.5 Hz, J2=1.5 Hz, 1H), 7.33 (m, 4H), 7.26 (dd, J1=7 Hz, J2=2 Hz, 1H), 7.04 (d, J=7.5 Hz, 1H), 6.97 (td, J=7.5 Hz, J2=1 Hz, 1H), 3.70 (s, 3H), 2.97 (bs, 3H), 2.93 (bs, 3H), 2.04 (s, 3H). MS: m/z 386.2 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3](=[N:16][NH:17][C:18]([NH2:20])=[O:19])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.[P:21]([O:26]C)([O:24][CH3:25])[O:22][CH3:23]>C1(C)C=CC=CC=1>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C:3](=[N:16][NH:17][C:18]([NH2:20])=[O:19])[CH2:2][P:21](=[O:26])([O:24][CH3:25])[O:22][CH3:23]
Reactant: NC(=O)NN=C(CCl)COc1cccc(C(F)(F)F)c1
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(CC(COc1cccc(C(F)(F)F)c1)=NNC(N)=O)OC
Temperature: 0 °C
Yield: 58.3 %

Procedure:
A mixture of 1-chloro-3-[3-(trifluoromethyl)phenoxy]-2-propanone semicarbazone (36.5 g, 0.12 mol), P(OMe)3 (18.6 g, 0.15 mol) and toluene (100 mL) was refluxed for 3 h and cooled to 0° C. The precipitate was filtered off, washed on the filter with cold toluene and recrystallized from toluene to afford 26.8 g (59%) of dimethyl 3-[3-(trifluoromethyl)phenoxy]-2-semicarbazonopropylphosphonate as about 10:1 mixture of two isomers: mp 132–133° C. 1H NMR (CDCl3) (major isomer) δ: 9.40 (s, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.15 (s, 1H), 7.07 (d, J=8.0 Hz, 1H), 5.80 (br.s, 2H), 4.68 (s, 2H), 3.76 (s, 3H), 3.73 (s, 3H), 3.11 (d, J=12 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:14])=[C:7]([CH3:13])[C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].CCOC(C)=O.CCCCCCC>CC#N.O.CC(OC)(C)C>[C:1]([C:5]1[C:6](=[O:14])[C:7]([CH3:13])=[C:8]([CH3:12])[C:9](=[O:11])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(O)cc(C(C)(C)C)c(O)c1C
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Solvent: COC(C)(C)C
Product: CC1=C(C)C(=O)C(C(C)(C)C)=CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 500 ml round bottom flask equipped with a stir-bar was added crude 5-tert-butyl-2,3-dimethyl-benzene-1,4-diol as a solution in MeCN (200 ml). To the stirring solution at room temperature was added CAN (114 g, 220 mmole) as a solution in water (200 ml) in one portion. The biphasic reaction mixture was stirred vigorously at room temperature for one hour, after which time no further reaction was detected by TLC analysis (20% EtOAc:heptane). The reaction mixture was poured into MTBE (500 ml). The organic layer was separated, then washed with water until the aqueous phase remained colorless (3×200 ml). The solution was then washed with brine (2×200 ml), dried over sodium sulfate, and concentrated to a red oil. A portion of the crude product was further purified by silica gel chromatography (120 g, 0-20% EtOAc:heptane) to give 5-tert-butyl-2,3-dimethyl-[1,4]benzoquinone (213) as a volatile yellow oil. 1H NMR (400 MHz; C6D6; ppm): 6.42 (s, 1H), 1.66 (q, J=1.2 Hz, 3H), 1.61 (q, J=1.2 Hz, 3H), 1.12 (s, 9H).
Reaction SMILES: [CH3:1]S(N)(=O)=O.[NH:6]1[CH2:10][CH2:9][N:8]=[C:7]1[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17](N)=[CH:18][CH:19]=2)[C:14]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:13]1.CS(Cl)(=O)=O>N1C=CC=CC=1>[NH:6]1[CH2:10][CH2:9][N:8]=[C:7]1[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[CH3:1])[C:14]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:13]1
Reactant: CS(=O)(=O)c1cn(CC2=NCCN2)c2ccc(N)cc12
Reactant: CS(N)(=O)=O
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cccc2c(S(C)(=O)=O)cn(CC3=NCCN3)c12

Procedure:
N-1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-3-methanesulfonyl-1H-indol-5-yl]-methanesulfonamide, mp 232-233° C., was prepared from 1-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-3-methanesulfonyl-1H-indol-5-ylamine by treatment with methane sulfonylchloride and pyridine.
Reaction SMILES: [CH:1]([C:3]1(O)[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)=[CH2:2].[C:14](OC)([O:18]C)([O:16][CH3:17])[CH3:15]>C(O)(=O)CC>[CH:4]12[CH2:12][CH:8]3[CH2:7][CH:6]([CH2:11][CH:10]([CH2:9]3)[C:3]1=[CH:1][CH2:2][CH2:15][C:14]([O:16][CH3:17])=[O:18])[CH2:5]2
Reactant: C=CC1(O)C2CC3CC(C2)CC1C3
Reactant: COC(C)(OC)OC
Solvent: CCC(=O)O
Product: COC(=O)CCC=C1C2CC3CC(C2)CC1C3
Temperature: 115 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A distillation column-provided four-necked flask having a volume of 100 mL, which was equipped with a dropping funnel, a thermometer, a stirring device and a reflux ratio regulator, was charged with 25.0 g (140.2 mmoles) of 2-vinyl-2-adamantanol, 30.3 g (280.5 mmoles) of trimethyl orthoacetate and 0.2 g (2.8 mmoles) of propionic acid, and the internal temperature was raised to 115° C. Heating was continued for 16 hours while removing a fraction of not higher than 65° C. from a column top of the distillation column. At that time, 0.2 g (2.8 mmoles) of propionic acid was added 16 times every one hour. The reaction mixture was concentrated at 110° C. under atmospheric pressure to obtain 26.9 g (115.0 mmoles) of methyl 4-adamantylidenebutanoate. The yield was 82.0%.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[O:10])([O-:5])=[O:4].Br[CH2:20][CH2:21][CH2:22][CH3:23].C(OCC)(=O)C>CN(C)C=O>[CH2:20]([N:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9](=[O:10])[C:8]1[CH:16]=[CH:17][CH:18]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[CH2:21][CH2:22][CH3:23]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1ccc[nH]1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCn1cccc1C(=O)c1cccc([N+](=O)[O-])c1
Yield: 95.8 %

Procedure:
4 G (160 mmol) of 50% sodium hydride were suspended, under nitrogen atmosphere, in 250 ml of anhydrous dimethylformamide. A solution of 15 g (69 mmol) of 2-(3-nitrobenzoyl)pyrrole, prepared, for example, as described in Preparation 3A, in 50 ml of anhydrous dimethylformamide was added thereto, in a dropwise fashion and under stirring, maintaining the temperature at 20°-25° C. The resulting mixture was stirred for 2 additional hours and then a solution of 18 ml (170 mmol) of 1-bromobutane in 50 ml of dry dimethylformamide was added. The reaction mixture was stirred at room temperature for 18 hours further and then poured into 2000 ml of ethyl acetate. The organic extract was washed with water (5×500 ml), dried and evaporated in vacuo. The residue was purified by column chromatography on 1 Kg of silica gel, using hexane-acetone (90:10) as eluant, thus obtaining 18 g (95%) of 1-butyl-2 -(3'-nitrobenzoyl)pyrrole, the title compound, as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:3]([C:14]([Cl:20])=[O:16])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: O=C(O)c1noc(-c2ccc(Cl)cc2)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1noc(-c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a suspension of 4-chloro-5-(4-chlorophenyl)isoxazole-3-carboxylic acid (0.66 g, 2.58 mmol) and oxalyl chloride (0.9 mL, 10.32 mmol) in dichloromethane (30 mL) was added 2 drops of N,N-dimethylformamide. After the mixture was stirred 16 hours at room temperature, the volatiles were removed in vacuo to obtain 4-chloro-5-(4-chlorophenyl)isoxazole-3-carbonyl chloride (0.71 g, 2.53 mmol).
Reaction SMILES: [C:1]([C:6]([OH:8])=[O:7])#[C:2][C:3](O)=[O:4].[CH2:9]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[S:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CO>[CH2:21]([N:20]1[C:3](=[O:4])[C:2](=[CH:1][C:6]([OH:8])=[O:7])[S:19][C:18]1=[N:17][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCNC(=S)NCCCCCCCC
Reactant: O=C(O)C#CC(=O)O
Solvent: CO
Product: CCCCCCCCN=C1SC(=CC(=O)O)C(=O)N1CCCCCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
A mixture of acetylenedicarboxylic acid (7.2 g, 60 mmoles) and N,N'-dioctylthiourea (18 g, 60 mmoles) in methanol (300 mls) is stirred at room temperature for 16 hours. The solvent is removed under reduced pressure to leave a syrupy residue which eventually crystallizes. Recrystallization from acetonitrile gave the product (18 g), mp 57°-61° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:17]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][C:27]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:22][N:21]=1)([CH3:19])[CH3:18].C(OCC)(=O)C>CN(C=O)C.O>[CH:17]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][C:27]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:22]([C:4]2[C:3]([CH3:10])=[CH:2][CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[N:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1n[nH]c2nccc(-c3cnc4ccccc4c3)c12
Reactant: Cc1cc(C#N)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C#N)c1-n1nc(C(C)C)c2c(-c3cnc4ccccc4c3)ccnc21
Temperature: 80 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
4-Fluoro-3-methylbenzonitrile (0.077 g) and cesium carbonate (0.203 g) were added to a solution of compound (6c) (0.150 g) in DMF (1.73 mL), followed by stirring at 80° C. for 18 hr. The reaction solution was distributed between ethyl acetate and water. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to obtain 4-{(3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-methylbenzonitrile (0.154 g, 73%). This 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-methylbenzonitrile was dissolved in DMSO (5.0 mL) and ethanol (5.0 mL). A 4 N aqueous sodium hydroxide solution (0.195 mL) and a 30% hydrogen peroxide solution (0.088 mL) were added to the resulting solution, followed by stirring at room temperature for 30 min. Water was added to the reaction solution, and the precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain compound (80) (0.135 g, 83%) as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:34]1([C:40](=[O:42])[CH3:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[Cl:43][C:44]1[CH:52]=[C:51]2[C:47]([C:48]([N:62]([CH2:69][C:70](O)=[O:71])[CH:63]3[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]3)([CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=3)[C:49](=[O:53])[NH:50]2)=[CH:46][CH:45]=1>ClCCl>[C:40]([N:34]1[CH2:39][CH2:38][N:37]([C:70](=[O:71])[CH2:69][N:62]([CH:63]2[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]2)[C:48]2([CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=3)[C:47]3[C:51](=[CH:52][C:44]([Cl:43])=[CH:45][CH:46]=3)[NH:50][C:49]2=[O:53])[CH2:36][CH2:35]1)(=[O:42])[CH3:41]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)CN(C1CCCCC1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)CN(C2CCCCC2)C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
To the mixture of DIPEA (43 mg, 0.33 mmol), HATU (64 mg, 0.17 mmol) and 1-piperazin-1-yl-ethanone (22 mg, 0.17 mmol) in dichloromethane (3 mL) was added rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-indol-3-yl]-cyclohexyl-amino}-acetic acid (50 mg, 0.11 mmol). After the mixture was stirred at room temperature for 3 h, the crude was washed with water (3×10 mL). The organic solution was concentrated in vacuo and the residue was puritificated by preparative HPLC to give 24 mg of rac-3-{[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethyl]-cyclohexyl-amino}-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a white solid. MS: 557 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1>C(O)C>[CH3:3][O:4][C@H:5]1[C@H:10]([OH:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1
Reactant: COC1CN(Cc2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CO[C@@H]1CN(Cc2ccccc2)CC[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
Sodium borohydride (7.7 g) was added portionwise to a stirred solution of 3-methoxy-1-(phenylmethyl)-4-piperidinone (44.8 g) in ethanol (610 ml). Upon completion, the whole was cooled to room temperature and stirring was continued for 3 hours at room temperature. The reaction mixture was concentrated to a volume of about 150 ml. Water (300 ml) was added to the concentrate and all traces of ethanol were evaporated. After cooling, the mixture was extracted with diethylether. The extract was washed with water, dried, filtered and evaporated. The oily residue was purified by column-chromatography over silica gel (eluent: CHCl3 /CH3OH 96/4). The pure fractions were collected and the eluent was evaporated. The residue was separated by column-chromatography over silica gel (eluent: hexane/CHCl3 /(CH3OH/NH3) 50/50/1). The first fraction was collected and the eluent evaporated, yielding 11.5 g (25.5%) of trans-3-methoxy-1-(phenylmethyl)-4-piperidinol (intermediate 1). The second fraction was collected and the eluent evaporated, yielding 7.7 g (17.1%) of cis-3-methoxy-1-(phenylmethyl)-4-piperidinol (intermediate 2).