Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:14].[CH2:24](I)[CH:25]=[CH2:26]>>[CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:26][CH:25]=[CH2:24])[CH:16]=1)=[O:14]
Reactant: C=CCI
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Product: C=CCn1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21

Procedure:
eq-Quinolizidin-2-ylmethylindole-3-carboxylate (E9b) was alkylated with allyl iodide using the method in Example 18. The product was chromatographed on silica gel eluting initially with ether, then with ethyl acetate, to afford the title compound (E19) as a colourless oil. This was converted to its hydrochloride salt mp 190°-192° C. (acetone)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a 3-neck round-bottomed flask were added zinc powder (1.96 g, 30 mmol) followed by anhydrous THF (40 mL). To the stirred suspension was slowly added, via syringe, TiCl4 (1.6 mL, 2.77 g, 14.6 mmol) at room temperature. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 2 h. To the refluxing reaction mixture was added a solution of (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (1.1 g, 3.61 mmol) and cyclohexanone (1.1 mL, 1.04 g, 10.6 mmol) in anhydrous tetrahydrofuran (40 mL). The stirred reaction mixture was heated at reflux under a nitrogen atmosphere for 2 h. The oil bath was removed and the reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added water (24 mL) followed by 10% aqueous K2CO3 (24 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was transferred to a separatory funnel with the aid of water and EtOAc and the layers were separated. The organic phase was washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 60:40) to give 1.17 g (95%) of compound 6 as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.52 (m, 6H), 2.12 (m, 4H), 6.65 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 9.32 (s, 1H). HRMS (EI) Calcd for C19H19BrO: 342.0619 (M+). Found: 342.0627.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH2:17][S:18][CH3:19])[NH2:15].[CH3:21][N:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:35][C:34](=[O:36])[C:33]3([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[N:32]=2)=[CH:27][CH:26]=1)[CH3:23]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH2:17][S:18][CH3:19])[NH:15][C:34]([C:33]1([NH:32][C:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][N:22]([CH3:23])[CH3:21])=[CH:26][CH:27]=2)=[O:35])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:36]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CN(C)Cc1ccc(C2=NC3(CCCCC3)C(=O)O2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)C1(NC(=O)c2ccc(CN(C)C)cc2)CCCCC1
Reaction time: 8 h
Yield: 59.1 %

Procedure:
129 mg (1 mmol) of diisopropylethylamine was added to a suspension of 84 mg (0.42 mmol) of L-methionine methyl ester hydrochloride and 100 mg (0.35 mmol) of 2-[4-[(dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 3 ml of toluene, and the mixture was refluxed under heating overnight. After the solvent was distilled off under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with saturated brine and dried with sodium sulfate. After the solvent was distilled off under reduced pressure, diethyl ether was added thereto, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 93 mg (59%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH2:19][N:20]2[C@@H:24]([CH3:25])[C@@H:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:22][C:21]2=[O:32])[CH:3]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1>>[CH3:25][C@H:24]1[C@@H:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:22][C:21](=[O:32])[N:20]1[CH2:19][C:4]1[CH:3]=[C:2]([C:37]2[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=2)[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(-c2cnn(C)c2)ccc1Oc1cccc(CC(=O)O)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[4-bromo-2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].I[CH2:22][C:23]([CH3:32])([CH3:31])[CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][C:23]([CH3:32])([CH3:31])[CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Reactant: CC(C)(CI)CN1CCCCC1
Product: CC(C)(CN1CCCCC1)CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In analogy to the procedure described for intermediate 4A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and 1-(3-iodo-2,2-dimethyl-propyl)-piperidine stirred 2 h at RT, gave the title compound as white solid. MS: 466.3 (MH+, 2Cl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: CC(N)c1nc2ccc(F)cc2n1-c1ccncc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccncc1
Temperature: 100 °C
Yield: 13.9 %

Procedure:
A mixture of 1-(6-fluoro-1-pyridin-4-yl-1H-benzoimidazol-2-yl)ethylamine (60 mg, 0.23 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (59 mg, 0.25 mmol) and DIPEA (125 μL, 0.70 mmol) in n-butanol (0.5 mL) was heated at 100° C. in a sealed vial for 23 h. After cooling to RT, the resulting mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-60%, 0.1% NH4OH in acetonitrile/water) to afford 303 as a pale orange solid (12 mg, 14%). LCMS (Method K): RT 2.70 min [M+H]+ 375.05. 1H NMR (DMSO-d6, 400 MHz): δ 12.90 (1H, s), 8.72-8.66 (2H, m), 8.09-8.01 (2H, m), 7.73-7.67 (3H, m), 7.19-7.01 (2H, m), 5.68-5.11 (1H, m), 1.62 (3H, d, J=7.26 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[C:8]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11]>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[C:8]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)c1-c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)c(Cc2cccc(C(=O)O)c2-c2cccnc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
Methyl 3-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoate (231 mg, 0.5286 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (10 ml) and 1,4-dioxane (10 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (200 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (170 mg, 0.4018 mmol, 76%).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26]([NH:28][CH3:29])=[O:27].C(N(C(C)C)CC)(C)C.[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[NH:25][C:26](=[O:27])[NH:28][CH3:29])[CH:10]=1
Reactant: CNC(=O)Nc1ccc(Cl)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CNC(=O)Nc1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 26.3 %

Procedure:
(Step 3) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (2.3 g), 1-[2-(aminomethyl)-4-chlorophenyl]-3-methylurea hydrochloride obtained in Step 2 (2.45 g) and diisopropylethylamine (5 ml) were stirred in ethanol (15 ml) overnight at 70° C. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in ethanol, 4N hydrogen chloride-ethyl acetate solution (3 ml) was added, and the mixture was crystallized from ethanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.52 g).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=[C:33]=[N:34][CH2:35][CH3:36].O.ON1C2C=CC=CC=2N=N1.N1CC1>CN(C)C=O.C(Cl)(Cl)Cl.O>[N:34]1([C:23]([C:20]2[CH:21]=[CH:22][N:18]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[CH:17][CH:16]=3)[CH:19]=2)=[O:24])[CH2:33][CH2:36][CH2:35]1
Reactant: O=C(O)c1ccn(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)c1
Reactant: CCN=C=NCCCN(C)C
Agent: C1CN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccn(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)c1)N1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.2 %

Procedure:
A suspension of 1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrole-3-carboxylic acid (0.1 g) synthesized in Example 2, 1-{3-(dimethylamino)propyl}-3-ethylcarbodiimide hydrochloride (0.085 g), 1-hydroxybenzotriazole hydrate (0.067 g) and aziridine (0.034 g) in N,N-dimethylformamide (0.1 ml) was stirred at room temperature for 16 hours. Water was added to the reaction mixture and extraction was conducted with chloroform. The organic layer was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (NH form silica gel; eluent: n-hexane/ethyl acetate=88/12-0/100) to give the titled compound as a colorless solid (0.056 g).
Reaction SMILES: [CH3:1][C:2]1([O:19][C@H:18]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C@H:5]1[OH:6])[O:3][CH3:4].[CH3:31][C:32](OC(C)=O)=[O:33].O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1([O:19][C@H:18]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C@H:5]1[O:6][C:32](=[O:33])[CH3:31])[O:3][CH3:4]
Reactant: COC1(C)O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: COC1(C)O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1OC(C)=O

Procedure:
To the solution of raw oil from Step 2 above (173.6 g, 0.3600 mol) in 1.379 L pyridine, were added Ac2O (33.970 mL, 0.3600 mol) and DMAP (1.3766 g, 0.01127 mol). After 21 hours of stirring at room temperature 1.4 L H2O were added. The solution was acidified with 1.45 L concentrated HCL. The acidified product was extracted with EtOAc, dried with MgSO4 and concentrated in vacuo. The residue was isolated as 85.75 g (0.1636 mol) of clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=[O:15].[Br:16][CH2:17][CH2:18]Br.C(Cl)(Cl)Cl.CO>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]([CH2:18][CH2:17][Br:16])[C:6]2=[O:15]
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Reactant: BrCCBr
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cc2ncn(CCBr)c(=O)c2cc1OC

Procedure:
1-(6,7-Dimethoxy-4(3H)-quinazolinone-3-yl)-2-bromo-ethane was prepared analogous to Example 1 (a) by reaction of 6,7-dimethoxy-4(3H)-quinazolinone with 1,2-dibromoethane in dimethylformamide. Viscous oil. Rf -value (chloroform/methanol = 9/1) : 0.85.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:13]=2)=[N:4][C:3]=1[NH:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].C(OCC)(=O)C.C(OC(C)C)(C)C>ClCCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N:20]3[CH2:21][CH2:22][CH:23]([N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[CH2:24][CH2:25]3)[CH:13]=2)=[N:4][C:3]=1[NH:27][C@H:28]1[CH2:29][CH2:30][C@H:31]([OH:34])[CH2:32][CH2:33]1
Reactant: CN1CCNCC1
Reactant: COc1ccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(Cl)nc2C(N)=O)cc1N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(C)OC(C)C
Product: COc1ccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(Cl)nc2C(N)=O)cc1N1CCC(N2CCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-methoxy-3-(4-oxopiperidin-1-yl)phenyl]amino}pyrazine-2-carboxamide (Example 495) (0.346 mg), N-methylpiperazine (0.12 mL) and 1,2-dichloroethane (10 mL), sodium triacetoxyborohydride (225 mg) was added and stirred at room temperature for 5 hours. After addition of saturated aqueous sodium hydrogen carbonate, the reaction liquid was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia=100:0:0 to 20:1:0.1) to give a crude product. The crude product was solidified with ethyl acetate-diisopropyl ether and then washed with ethyl acetate to give 6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-methoxy-3-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (39 mg) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.P(Br)(Br)[Br:11]>>[Br:11][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: BrP(Br)Br
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(Br)nc1
Temperature: 145 °C
Yield: 81 %

Procedure:
6-Chloronicotinonitrile (13.8 g, 100 mmol) was heated at 145° C. in phosphorus tribromide (150 mL) for 32 h. After cooling, the mixture was concentrated in vacuo. To the residue was added phosphorus tribromide (150 mL), and the mixture was heated at 145° C. for another 32 h. After cooling, the mixture was concentrated in vacuo, and an ice-water mixture (500 mL) was added. Sodium bicarbonate was added to neutralize the mixture, and the product was extracted with ethyl acetate (3×250 mL). The combined organic extracts were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo, and the residue was chromatographed (hexanes-ethyl acetate) to give 14.9 g (81 %) of 6-bromonicotinonitrile as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=11.0 Hz, 1H), 7.80 (dd, J=3.1, 11.0 Hz, 1H), 8.67 (d, J=3.1 Hz, 1H); MS (M+H)+ m/z=183.0, 185.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[CH3:15][NH:16][CH2:17][CH2:18][CH2:19][OH:20].C(N(CC)C(C)C)(C)C>O>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[N:16]([CH3:15])[CH2:17][CH2:18][CH2:19][OH:20]
Reactant: Brc1ccn2c(n1)nc1ccccc12
Reactant: CNCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(CCCO)c1ccn2c(n1)nc1ccccc12
Temperature: 25 °C
Yield: 100.2 %

Procedure:
2-Bromobenzo[4,5]imidazo[1,2-a]pyrimidine (0.2 g, 0.806 mmol), 3-(methylamino)propan-1-ol (0.072 g, 0.806 mmol) and N,N-Diisopropylethylamine (0.141 ml, 0.806 mmol) were heated to 100° C. for 10 minutes in a microwave. Let the reaction cool to room temperature. Diluted reaction with water, extracted with ethyl acetate, combined organics, dried, filtered and concentrated to afford crude 3-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl(methyl)amino)propan-1-ol (0.207 g, 0.808 mmol, 100% yield).
Reaction SMILES: [C:1]([O-:4])(O)=[O:2].[Na+].Cl.Cl.[Cl:8][CH2:9][CH2:10][N:11]([CH2:19][CH2:20][Cl:21])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Cl:8][CH2:9][CH2:10][N:11]([CH2:19][CH2:20][Cl:21])[C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:1]=[O:4])=[CH:14][CH:13]=1.[N-:11]=[C:19]=[O:2]
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(N(CCCl)CCCl)cc1
Product: [N-]=C=O

Procedure:
A saturated aqueous NaHCO3 solution was added slowly to a suspension of N,N-bis(2-chloroethyl)benzene-1,4-diamine dihydrochloride (37) (918 mg, 3.0 mmol) in dry toluene (30 mL) with stirring to neutralize to pH ˜7. The organic and water layer were separated and the water layer was extracted with toluene (3×10 mL). The organic layer and extracts were combined, dried over Na2SO4, and then added dropwise to a stirred solution of trichlorimethylchloroformate (593 mg, 365 μL, 3.0 mmol) in dry toluene (10 mL) containing active carbon (20 mg) at 0° C. The reaction mixture was stirred at room temperature for 1 h and then refluxed for 30 min to form a clear solution, which was cooled, filtered through a pad of Celite. The filtrate was evaporated in vacuo to dryness to give crude bis(2-chloroethyl)-4-isocyanatophenylamine, 430 mg (39) (1.66 mmol). This intermediate was dissolved in anhydrous DMF (1 mL) and then added dropwise to a solution of 4-amino-6-methoxy-2-(3-methoxyphenyl)quinoline (280 mg, 1.0 mmol) in dry DMF (1 mL). The reaction mixture was stirred at 50° C. for 9 h and the solvent was removed by vacuum distillation. The residue was chromatographed on a silica gel column (2×24 cm) using CHCl3/MeOH/(100:1 v/v) as eluent. The fractions containing the desired product were combined, evaporated and the solid residue was recrystallized from EtOH to give 1-{4-[bis(2-chloroethyl)amino]phenyl-3-[6-methoxy-2-(4-methoxyphenyl)quinolin-4-yl]urea (22, BO-1049); 400 mg (74.2%); mp 112-113° C.; 1H NMR (DMSO-d6) δ3.72 (8H, m, 4×CH2), 3.87 (3H, s, OMe), 4.01 (3H, s, OMe), 6.72 (2H, d, J=8.8 Hz, ArH), 7.07 (1H, dd, J=2.2 and 8.1 Hz, ArH), 7.41 (2H, d, J=8.8 Hz, 2×ArH), 7.47 (2H, m, 2×ArH), 7.65 (3H, m, ArH), 7.99 (2H, d, J=10.3 Hz, 2×ArH), 8.80 (1H, d, J=8.8 Hz, ArH), 9.25 (2H, brs, exchangeable, 2×NH). Anal. Calcd. for (C28H28Cl2N4O3): C, 62.61; H, 5.23; N, 10.39. Found: C, 62.34; H, 4.99; N, 10.59.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[CH:14]([O:27][C:28]([C:30]1[N:35]2[C:36](=[O:49])[C@@H:37]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@H:34]2[S:33][CH2:32][C:31]=1N1CCOCC1)=[O:29])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC=CC=1>C(O)(=O)C>[CH:14]([O:27][C:28]([C:30]1[N:35]2[C:36](=[O:49])[C@@H:37]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@H:34]2[S:33][CH2:32][CH:31]=1)=[O:29])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3CCOCC3)CS[C@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A suspension is prepared from 142 g (3.75 mmols) of sodium borohydride and 2.4 liters of abs. toluene and then 2.2 liters of glacial acetic acid are added over 4 hours at 20° C. The hydrogen formed during the exothermic reaction is drawn off. To the triacetoxy borohydride so formed are then added, at 20° C., 400 g (0.683 mmol) of 7β-phenoxyacetylamino-3-morpholino-3-cephem-4-carboxylic acid benzhydryl ester in 1.2 liters of glacial acetic acid and 600 ml of abs. toluene. The reaction mixture is warmed to 40° C. and then stirred for 24 hours at this temperature. The solvent is then removed completely by vacuum distillation and the oily residue is partitioned between 1.4 liters of water and 1.4 liters of toluene. The phases are separated and the aqueous phase is extracted with 600 ml of toluene. The combined organic phases are neutralised with saturated sodium bicarbonate solution and washed with two 50 ml portions of water. The organic phase is concentrated under reduced pressure and the oily residue is dissolved in 1.5 liters of ethanol at 55° C. Inoculation of the slowly cooling solution results in the crystallisation of 7β-phenoxyacetylamino-3-cephem-4-carboxylic acid benzhydryl ester.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].B(OC)(OC)OC.F[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[B:21]([OH:23])[OH:22].[CH2:24]1[CH2:28][O:27][CH2:26][CH2:25]1>>[F:20][C:19]1[CH:14]=[C:15]([B:21]([OH:23])[OH:22])[CH:16]=[CH:17][C:18]=1[O:27][CH2:26][CH2:25][CH2:24][CH2:28][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: OB(O)c1cccc(F)c1F
Reactant: C1CCOC1
Agent: COB(OC)OC
Product: CCCCCCCCOc1ccc(B(O)O)cc1F

Procedure:
Quantities: compound 11 (10.00 g, 0.033 mol) in anhydrous THF (132 ml), n-butyllithium (16 ml, 2.5M in hexane, 0.04 mol), trimethyl borate (6.87 g, 0.066 mol) in anhydrous THF (50 ml). The experimental procedure was as described for the preparation of compound 2.