Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:17][C:18]([O:21][C:22](=[O:28])[NH:23][CH2:24][CH2:25][CH2:26][NH2:27])([CH3:20])[CH3:19]>C(#N)C>[C:18]([O:21][C:22](=[O:28])[NH:23][CH2:24][CH2:25][CH2:26][NH:27][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)([CH3:20])([CH3:17])[CH3:19]
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of 5-bromo-2,4-dichloro-pyrimidine (1.4 g) in acetonitrile (10 mL) at 0° C. was added triethylamine (0.94 mL) and 3-aminopropylcarbamic acid-1,1-dimethylethyl ester (1.0 g). After removing the cooling bath the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and to the residue water (20 mL) was added. The precipitate was collected, washed with water and ether to afford the title compound (1.8 g).
Reaction SMILES: [OH:1][C:2]1([CH2:5][CH2:6][N:7]2[C:15](=[O:16])[C:14]3[NH:13][C:12]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)=[N:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[CH2:4][CH2:3]1.Cl.Cl[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[OH:1][C:2]1([CH2:5][CH2:6][N:7]2[C:15](=[O:16])[C:14]3[N:13]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=4)[C:12]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=4)=[N:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[CH2:4][CH2:3]1
Reactant: Cc1ccc(CCl)nc1
Reactant: Cn1c(=O)n(CCC2(O)CC2)c(=O)c2[nH]c(Oc3cccc(OC(F)(F)F)c3)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c(Oc3cccc(OC(F)(F)F)c3)nc3c2c(=O)n(CCC2(O)CC2)c(=O)n3C)nc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
To a solution of 1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (50 mg, 0.117 mmol, intermediate 58) in DMF (3 mL) was added 2-(chloromethyl)-5-methylpyridine hydrochloride (24.9 mg, 0.176 mmol, intermediate 50), followed by potassium carbonate (48.6 mg, 0.351 mmol) and TBAI (10 mg, 0.027 mmol). The reaction was stirred at 65° C. overnight. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product, which was purified by preparative HPLC to give 1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (21 mg, 33.7% yield) as white solid.
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[CH:5]([O:8][C@H:9]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[NH2:19])[C@H:4]([O:20][CH:21]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([O:28][C@H:29]3[O:34][C@@H:33]([CH2:35][NH2:36])[C@@H:32]([OH:37])[C@H:31]([OH:38])[C@H:30]3[NH2:39])[C@H:22]2[OH:40])[C@@H:3]([OH:41])[C@@H:2]1[NH2:42].C(Cl)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>>[CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@H:9]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[NH2:19])[C@H:4]([O:20][C@@H:21]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([O:28][C@H:29]3[O:34][C@@H:33]([CH2:35][NH2:36])[C@@H:32]([OH:37])[C@H:31]([OH:38])[C@H:30]3[NH2:39])[C@H:22]2[OH:40])[C@@H:3]([OH:41])[C@@H:2]1[NH2:42]
Reactant: NC[C@@H]1O[C@H](O[C@@H]2[C@@H](CO)OC(O[C@H]3C(O[C@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4N)[C@@H](N)C[C@@H](N)[C@@H]3O)[C@@H]2O)[C@H](N)[C@@H](O)[C@@H]1O
Agent: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Product: NC[C@@H]1O[C@H](O[C@H]2[C@@H](O)[C@H](O[C@@H]3[C@@H](O)[C@H](N)C[C@H](N)[C@H]3O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3N)O[C@@H]2CO)[C@H](N)[C@@H](O)[C@@H]1O

Procedure:
Starting with paromomycin I, the procedure described in WO2007/064954 is followed to generate the aldehyde 212L. b) Reductive amination is performed using general procedure 15 to generate the amine 212M. c) Fmoc protection of the amine is performed in the standard manner with Fmoc-Cl to generate 212N. d) 212N is deprotected as described in WO2007/064954 to generate 212O. e) 212O is sulfated using general procedure 1 to yield 212P. f) The sulfated paramomycin 212P is deprotected and converted to the azide as described in example 19 to generate 212Q.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([N:10]2[C@H:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][O:12][C:11]2=[O:22])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(N(CC)CC)C.[C:47]1([CH2:53][CH2:54][CH:55]=[O:56])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([C@@H:55]([OH:56])[CH2:54][CH2:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:8]([N:10]2[C@H:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][O:12][C:11]2=[O:22])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CCCc1ccccc1
Reactant: O=C(CCC1CCCC1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@H](CC1CCCC1)[C@@H](O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of acyloxazolidinone 2 (1.57 g, 5.00 mmol) in 20 mL of dichloromethane, cooled to −78° C. under nitrogen atmosphere, dibutylboron triflate (1.40 mL, 5.50 mmol) was added dropwise, followed by the addition of triethylamine. The mixture was warmed slowly to 0° C. and was stirred at 0° C. for an additional hour. The resultant boryl enolate solution was then cooled to −78° C., and 3-phenylpropanal (0.80 mL, 5.5 mmol) was added over a 5-min period time. The solution was stirred for 1 h at −78° C., then for 1 h at 0° C. The reaction mixture was quenched by the addition of 4 mL of a pH 7 aqueous phosphate buffer and 12 mL of methanol. To this cloudy solution was added 8 mL of methanol and 10 mL of 30% aqueous hydrogen peroxide at such a rate as to keep the internal temperature below 10° C. After the solution was stirred for one additional hour, the volatile material was removed in a rotary evaporator. The resulting slurry was extracted with three 20 mL portions of diethyl ether. The combined organic layers was washed with 20 mL of 5% aqueous sodium bicarbonate and 20 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (25% ethyl acetate-hexane) provided 1.11 g (56%) of aldol 3 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.15-7.38 (m, 10 H), 4.72 (m, 1 H), 4.12-4.28 (m, 3 H), 3.85 (m, 1 H), 3.34 (1 H, dd, J=13.4, 3.1 Hz), 2.80-2.95 (1 H, m), 2.60-2.78 (2 H, m), 1.95-2.05 (1 H, m), 1.40-1.90 (10 H, m), 1.10 (2 H, m).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:27])=[C:12]([C:19]([NH:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:20])[C:13](=[O:18])[N:14]3[CH3:17])=[CH:9][CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:27])=[C:12]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[C:13](=[O:18])[N:14]3[CH3:17])=[CH:9][CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COC(=O)CNC(=O)c1c(O)c2ccc(-c3c(C)noc3C)cc2n(C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)n(C)c2c1
Temperature: 24 °C
Reaction time: 4 h

Procedure:
Suspended Methyl 2-(7-(3,5-dimethylisoxazol-4-yl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate in 3 ml MeOH, 1 ml THF, and 2 ml 1M aqueous NaOH and stirred at 24° C. for 4 hours. The mixture was acidified to pH=1 using 2M aqueous HCl and the solids collected by filtration, washed with H2O and dried in vacuo: 50 mg white solids.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](Cl)(Cl)=[S:10].C(N(C(C)C)C(C)C)C>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[C:9]=[S:10]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: S=C=Nc1ccccc1Cl
Yield: 37.5 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2-chloro aniline (2.0 g, 15.74 mmol), thiophosgene (1.81 g, 15.73 mmol), and N-ethyl di-isopropyl amine (4.0 g, 31.00 mmol) to afford 1.0 g of the desired product. 1HNMR (DMSO-d6): δ 7.62 (m, 3H), 7.39 (t, J=7.8 Hz, 1H).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O+](CC)CC)[CH3:7].[C:13]1([C:19]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:27]3[CH:23]([CH2:24][N:25]([C:28](=[O:38])[CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])[CH2:26]3)[C:22](=[O:39])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOCC>ClCCl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O:38][C:28](=[N+:25]1[CH2:24][CH:23]2[CH:27]([C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:20][CH2:21][C:22]2=[O:39])[CH2:26]1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[CH3:7]
Reactant: COc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(Cc1ccccc1OC)=[N+]1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
Triethyloxonium tetrafluoroborate (2.35 g) is added to a solution of (3aRS,7aRS)-7,7-diphenyl-2-[(2-methoxyphenyl)acetyl]perhydro-4-isoindolone (5 g) in dichloromethane (10 cc). The reaction mixture is left stirring for 20 hours at room temperature; it is then treated with ether (100 cc) and the precipitate obtained is drained, washed with ether (100 cc) and dried. (3aRS,7aRS)-2-[1-Ethoxy-2-(2-methoxyphenyl)ethylidene]-4-oxo-7,7-diphenylperhydroisoindolium tetrafluoroborate (5.75 g) is obtained in the form of a yellow powder, which is used in the crude state for the following manipulation.
Reaction SMILES: BrC(CC)[C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9])=O.COC1C=CC=CC=1N1CCNCC1.[OH-].[K+].[Cl-].[NH4+]>C(Cl)(Cl)Cl.CCOCC>[N:5]1[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[NH:10][CH:3]=1
Reactant: CCC(Br)C(=O)Nc1ccccc1C(N)=O
Agent: COc1ccccc1N1CCNCC1
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=c1[nH]cnc2ccccc12

Procedure:
19.2 g (0.06 moles) of 2-(2-bromobutyrylamino) benzamide and 35.7 g (0.186 moles) of 1-(2-methoxyphenyl)piperazine are heated to 70° C for 2 hours whilst stirring, and then mixed with a solution of 6.4 g of potassium hydroxide in 70 mls. of glycolmonoethyl ether and then heated to 70° C for a further 30 minutes. The reaction mixture is distributed between saturated ammonium chloride solution and chloroform, the chloroform phase is separated and after drying over calcined potassium carbonate is concentrated by evaporation in vacuo. The oily residue is boiled up with ethyl acetate, allowed to cool slowly and the crystal mass is filtered off at the pump. By redissolving in a 9:1 mixture of ethyl acetate and methyl alcohol it is possible to purify the crude product. In this way one obtains 21.3 g (83.5% of theory) of 2-(α-(1-2-methoxyphenyl)-piperazinyl-4)-n-propyl)- 4(3H)-quinazolone with a melting point of 180°-181° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10](O)=[O:11])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=[C:6]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:5]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][CH:62]=1)[CH2:58][NH2:59]>C1COCC1>[CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:59][CH2:58][C:57]2[CH:60]=[CH:61][CH:62]=[C:55]([F:54])[CH:56]=2)=[O:11])=[C:8]([C:13]([F:15])([F:14])[F:16])[CH:7]=[C:6]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:5]=1)[CH3:2]
Reactant: NCc1cccc(F)c1
Reactant: CCSc1nc(N2CCOCC2)cc(C(F)(F)F)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSc1nc(N2CCOCC2)cc(C(F)(F)F)c1C(=O)NCc1cccc(F)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 26 %

Procedure:
To a solution of 170 mg (0.5 mmol) 2-(ethylsulfanyl)-6-morpholin-4-yl-4-(trifluoromethyl)-pyridine-3-carboxylic acid in THF (3 ml) were added 192 mg (0.5 mmol) HATU and 210 μl (1.5 mmol) NEt3 and the RM was stirred at 50° C. for 90 min. Then 69 μl (0.6 mmol) 3-fluorobenzylamine were added and stirring was continued at 50° C. for 5 d. After cooling to RT the mixture was partitioned between water and EtOAc. The organic layer was separated, washed with a 4N aq. NH4Cl sol. and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:1) provided 57 mg (0.13 mmol, 26%) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-morpholin-4-yl-4-(trifluoromethyl)-pyridine-3-carboxylic acid amide (example 11). [M+H]+ 444.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]1(=O)[O:12][C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.C(OCC)(=O)C>CCCCCC>[C:7]1(=[O:12])[N:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12
Reactant: NCCC(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)CCN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A mixture of β-alanine (89 g) and phthalic anhydride (148 g) was heated at 180° C. to 190° C. for 30 min. The mixture was cooled to 60° C. and ethyl acetate (500 ml) was added, and the mixture was stirred at 0° C. for 1 hr. n-Hexane is added to the reaction mixture and the reactant crystals were collected filteration to afford 219.5 g of 3-phthalimidopropionic acid in colorless crystals.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>C(OCC)(=O)C>[OH:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@H:3]([NH:2][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=3)=[O:32])[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]2)=[O:5])=[CH:19][CH:18]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-3-(4-hydroxy-phenyl)-1-(4-hydroxy-piperidin-1-yl)-propan-1-one hydrochloride (0.68 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.65 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) with the following workup: the reaction mixture was diluted with ethyl acetate, the resulting solution washed with 1N NaOH (2 ml), the aqueous layer extracted three times with ethyl acetate, the combined organic extracts washed with 1N HCl, dried and concentrated. The residue was purified by chromatography on silica gel eluted with 1-16% ethanol in dichloromethane. Yield, 150 mg, 52%; HPLC (60/40) 3.53 minutes (99%); PBMS 442/444 (MH+, 100%);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:19]=[C:11]3[CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH2:20]([NH:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23].O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C=O)C.ClCCl>[CH2:26]([N:25]([CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:16]([C:13]1[CH:14]=[CH:15][N:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[CH:19]=[C:11]2[CH:12]=1)=[O:18])[CH2:27][CH:28]([CH3:29])[CH3:30]
Reactant: O=C(O)c1ccn2nc(-c3ccc(Br)cc3)cc2c1
Reactant: CC(C)CCNCCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(-c3ccc(Br)cc3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
2-(4-bromophenyl)pyrazolo[1,5-a]pyridine-5-carboxylic acid (2.20 g, 7.0 mmol), diisopentylamine (2.13 mL, 1.64 g, 10.4 mmol) and hydroxybenzotriazole hydrate (1.59 g, 10.4 mmol) were dissolved in DMF (50 mL) and CH2Cl2 (25 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.0 g, 10.4 mmol) was added and the mixture was stirred at room temperature overnight. A saturated solution of ammonium chloride (20 mL) was added and the mixture was diluted with dichloromethane (20 mL). The separated aqueous layer was then extracted with dichloromethane (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford a residue which was purified by column chromatography using 20% to 30% EtOAc in hexanes as eluant to provide 2.89 g of the title compound. LCMS m/z 456.2, 4582 (M+H)+, ret. time=3.33 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]#C)[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.[F-].[Cs+].[CH2:16](N(CC)C1C=CC=CC=1)C>CC(OC)(C)C>[Br:1][C:2]1[C:3]2[CH:16]=[C:11]([CH3:12])[O:10][C:4]=2[C:5]([F:9])=[C:6]([F:8])[CH:7]=1
Reactant: C#CCOc1cc(Br)cc(F)c1F
Reactant: CCN(CC)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COC(C)(C)C
Product: Cc1cc2c(Br)cc(F)c(F)c2o1

Procedure:
51.9 g (0.21 mol) of 5-bromo-1,2-difluoro-3-prop-2-ynyloxybenzene are heated at 205° C. for 4 h together with 20.7 g (0.14 mol) of caesium fluoride in 300 ml of N,N-diethylaniline. The batch is diluted with MTBE and washed a number of times with 1 N HCl. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:1-chlorobutane=3:1), giving 4-bromo-6,7-difluoro-2-methylbenzofuran as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])([CH3:17])[C:7](=[O:16])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][C:3]=1[NH:19][CH:20]([CH3:22])[CH3:21].Br[C:24]#[N:25]>O.C1COCC1>[NH2:25][C:24]1[N:19]([CH:20]([CH3:21])[CH3:22])[C:3]2=[CH:4][C:5]3[C:6]([CH3:18])([CH3:17])[C:7](=[O:16])[N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:9]=3[CH:10]=[C:2]2[N:1]=1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(NC(C)C)c(N)cc21
Reactant: N#CBr
Solvent: C1CCOC1
Solvent: O
Product: CCCCCN1C(=O)C(C)(C)c2cc3c(cc21)nc(N)n3C(C)C
Yield: 97.5 %

Procedure:
Analogously to general procedure (III) 6-amino-5-isopropylamino-3,3-dimethyl-1-pentyl-1,3-dihydro-indol-2-one (180 mg) is cyclized using BrCN (3 M; 0.2 ml; 600 μmol) at RT in water (2.5 ml) and THF (1 ml). After aqueous work-up the desired compound (190 mg) is obtained.
Reaction SMILES: [N+:1]([C:4]1C=C[C:12]2[C:15]3[C:5]=1[CH2:6][CH2:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)([O-])=O.C(O[CH2:20][CH3:21])(=O)C>[Pd]>[CH2:15]1[C:12]2=[C:20]3[C:21](=[CH:9][CH:10]=[CH:11]2)[C:4]([NH2:1])=[CH:5][CH:6]=[C:7]3[CH2:8]1
Reactant: O=[N+]([O-])c1ccc2cccc3c2c1CC3
Reactant: CCOC(C)=O
Agent: [Pd]
Product: Nc1ccc2c3c(cccc13)CC2

Procedure:
A mixture of 5 and 3-nitroacenaphthene was reduced with Pd/C in ethyl acetate under hydrogen at 40 psi pressure and the resulting amines were separated by recrystallization from cyclohexane/ethyl acetate.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][C@H:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1.Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:24]=[CH:25][C:18]=12.CCN(CC)CC>CN(C=O)C.O>[CH3:1][C@@H:2]1[CH2:7][N:6]([C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:24]=[CH:25][C:18]=23)[CH2:5][C@H:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1
Reactant: C[C@@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: C[Si](C)(C)CCOCn1ncc2c(Cl)ncnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(c2ncnc3c2cnn3COCC[Si](C)(C)C)C1
Temperature: 80 °C

Procedure:
A mixture of tert-butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate (150 mg, 0.7 mmol), 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 0.7 mmol) and Et3N (195 μL, 1.4 mmol) in DMF (5 mL) was heated at 80° C. for 16 h. The solution was cooled, diluted with water, extracted with EtOAc, washed with aq. citric acid and aq. NaHCO3, dried (Na2SO4), filtered, and concentrated in vacuo to afford a residue, which was purified by column chromatography (silica gel, gradient EtOAc in hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:14]=[C:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][C:21](OC)=[O:22].[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:21](=[O:22])[CH2:20][N:16]2[CH2:17][CH2:18][CH2:19][C:15]2=[O:14])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)CN1CCCC1=O
Reactant: COc1ccc(CC#N)cc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(C#N)C(=O)CN2CCCC2=O)cc1OC
Temperature: 25 °C
Yield: 25.5 %

Procedure:
To a mixture of [3,4-bis(methyloxy)phenyl]acetonitrile (1.0 g, 5.5 mmol) and methyl (2-oxopyrrolidin-1-yl)acetate (1.0 g, 7.0 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 4.2 mL, 11 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3,4-bis(methyloxy)phenyl]-3-oxo-4-(2-oxopyrrolidin-1-yl)butanenitrile as a brown oil (0.43 g, 1.4 mmol, 25% yield), MS (EI) for C16H18N2O4: 303 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccc(F)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-4-fluorobenzene (0.52 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.76 g, 58%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:9]2[O:10]C=CC=2)=[N:5][CH:6]=[N:7][CH:8]=1)[CH3:2].CC(C)=[O:16].[Mn]([O-])(=O)(=O)=O.[K+].C(=O)([O-])O.[Na+]>O>[CH2:1]([C:3]1[C:4]([C:9]([OH:10])=[O:16])=[N:5][CH:6]=[N:7][CH:8]=1)[CH3:2]
Reactant: CC(C)=O
Reactant: CCc1cncnc1-c1ccco1
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CCc1cncnc1C(=O)O
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-ethyl-4-(furan-2-yl)-pyrimidine (2.03 g), acetone (70 ml), and water (35 ml) was stirred at 50° C., potassium permanganate (15 g) was added thereto over 15 minutes, and the reaction mixture was stirred under reflux for 1 hour. After standing to cool the reaction mixture to room temperature, to the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added, and extracted with tert-butyl methyl ether. To the resulting aqueous layer, hydrochloric acid was added, and extracted with tert-butyl methyl ether. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 1.14 g of 5-ethyl-pyrimidine-4-carboxylic acid.