Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][C:5]([N:7]1[CH:11]([CH3:12])[CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:8]1=[O:19])=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:34]([O:38][C:39](=[O:42])[CH2:40]Br)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39](=[O:42])[CH2:40][C@@H:4]([C:5]([N:7]1[C@@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:9][C:8]1=[O:19])=[O:6])[CH2:3][C:2]([CH3:1])([CH3:23])[CH2:20][CH2:21][CH3:22])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCCC(C)(C)CCC(=O)N1C(=O)OC(c2ccccc2)C1C
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CCCC(C)(C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Yield: 49.2 %

Procedure:
According to example 1, 5.07 g (16 mmol) of 3-(4,4-dimethyl-heptanoyl)-4-methyl-5-phenyl-oxazolidin-2-one, 18 mL (1N, 18 mmol) of NaHMDS solution and 4.72 mL (32 mmol) of bromo-acetic acid tert-butyl ester gave 3.40 g (49.3%) of the title compound as a crystalline solid. m.p.: 83-85° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[C:20](OC)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:21]1([C:20](=[O:27])[CH2:13][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccccc1
Reactant: Cc1cnccn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(Cc1cnccn1)c1ccccc1
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
To a mixture of diisopropyl-amine (1.29 g, 12.7 mmol) in anhydrous THF (10 mL) was added n-BuLi (2.5 M/L in hexane, 4.7 mL, 11.7 mmol) at −78° C., after being stirred for 30 minutes, a solution of 2-methylpyrazine (1 g, 10.6 mmol) in THF (5 mL) was added, and the mixture was stirred at −78° C. for 30 minutes, a solution of methyl benzoate (1.4 g, 10.6 mmol) in THF (5 mL) was added, and the mixture was stirred at this temperature for 3 hours. When TLC indicated that the starting material was consumed, the reaction mixture was diluted with EtOAc, and the mixture was washed with water and brine, and concentrated. The residue was purified by column chromatography (PE:EtOAc=30:1) to give Intermediate 26 (700 mg, yield 33.3%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C@H:48]1[C:56]2[C:51](=[CH:52][CH:53]=[C:54]([C:57]([O:59][CH3:60])=[O:58])[CH:55]=2)[CH2:50][CH2:49]1>ClCCl>[C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:47][C@H:48]1[C:56]2[C:51](=[CH:52][CH:53]=[C:54]([C:57]([O:59][CH3:60])=[O:58])[CH:55]=2)[CH2:50][CH2:49]1)=[O:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccccc1C(=O)O
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1C(C)(C)C)CC2
Reaction time: 0.5 h
Yield: 57 %

Procedure:
2-tert-Butylbenzoic acid (0.75 g, 4.2 mmol, 1 eq) was dissolved in dichloromethane (40 ml), and at 0° C. HATU (1.5 g, 4.2 mmol, 1 eq) and DIPEA (1.7 ml, 10.52 mmol, 2.5 eq) were added and stirring was carried out for 30 min. Then (R)-methyl 3-amino-2,3-dihydro-1H-indene-5-carboxylate (A-07) (804 mg, 4.2 mmol, 1 eq) dissolved in dichloromethane (20 ml) was added and stirring was carried out for 16 h at RT. After monitoring by thin-layer chromatography, the reaction solution was diluted with dichloromethane (250 ml), washed with sat. sodium hydrogen carbonate solution (50 ml), sat. ammonium chloride solution (50 ml), water (50 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 8-10% ethyl acetate in hexane). Yield: 57% (1.6 g, 4.56 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([CH3:33])[CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][C:26]=2[CH3:33])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccccc2)c1Cl
Reactant: Cc1cc(F)ccc1B(O)O
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccccc2)c1-c1ccc(F)cc1C
Temperature: 75 °C
Reaction time: 15 h
Yield: 84.5 %

Procedure:
A solution of 1-benzyl-4-chloro-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (4.56 g, 0.0144 mol) in toluene (80 mL) and EtOH (40 mL) was degassed 3 times before Pd(PPh3)4 (0.834 g, 0.722 mmol), 4-fluoro-2-methylphenylboronic acid (2.67 g, 0.0173 mol) and an aqueous solution of Na2CO3 (2N, 14.4 mL, 0.0288 mol) were added. The reaction mixture was stirred at 75° C. for 15 hours, cooled down to RT, filtered and the volatiles evaporated under vacuo. The residue was taken up in EtOAc and washed with aqueous NaOH (1N). The organic phase was dried over Na2SO4, concentrated under vacuo, before a purification on column chromatography (SiO2, EtOAc/Heptane, 1/4) yielded 4.74 g (84%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16]O)[N:6]=1.P(Br)(Br)[Br:20]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16][Br:20])[N:6]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)Cc1nn(CO)c(=O)c2ccccc12
Solvent: ClCCl
Product: COC(=O)Cc1nn(CBr)c(=O)c2ccccc12

Procedure:
A solution of methyl-3-hydroxymethyl-4-oxo-phthalazin-1-ylacetate (0.49 g), phosphorous tribromide (0.54 g) and methylene chloride (10 ml) was stirred at room temperature for 2 hours. The solution was poured onto ice-water (5 ml) and the separated methylene chloride layer was collected, dried and evaporated to obtain a light yellow solid (yield: 0.43 g; m.p. 98°-104° C.).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:19]([O:21][CH:22]([CH:24]4[CH2:26][CH2:25]4)[CH3:23])=[O:20])[C:15]([CH3:18])([CH3:17])[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:29]O.O>C(O)(=O)C.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:19]([O:21][CH:22]([CH:24]4[CH2:25][CH2:26]4)[CH3:23])=[O:20])[C:15]([CH3:18])([CH3:17])[S:16](=[O:29])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(OC(=O)C1N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1(C)C)C1CC1
Reactant: OO
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(OC(=O)C1N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1(C)C)C1CC1
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
1-cyclopropylethyl 6-(2-phenylacetamido)-2,2-dimethylpenam-3-carboxylate (1.55 g.) was dissolved in acetic acid (8 cc) and sodium tungstate (10 mg.) was added thereto. To the stirred mixture was added, dropwise, 30% hydrogen peroxide (0.53 g.) while cooling in an ice bath and the mixture was stirred for a period of 30 minutes at this temperature. Water was added to the mixture and the aqueous solution was extracted with ethyl acetate. The ethyl acetate layer was washed in turn with a saturated aqueous solution of sodium bicarbonate, water, and a saturated aqueous solution of sodium chloride, dried and concentrated. The residue was dissolved in ether and the ether solution was allowed to stand. The precipitate was collected by filtration to yield crystals (1.53 g.) of 1-cyclopropylethyl 6-(2-phenylacetamido)-2,2-dimethylpenam-3-carboxylate-1-oxide, m.p. 158°-159° C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:22][NH2:23]>C(O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]3[CH2:15][CH2:16][C:17](=[O:19])[NH:22][N:23]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NN
Reactant: O=C(O)CCC(=O)/C=C/c1ccc(-n2ccnc2)cc1
Solvent: CCO
Solvent: O
Product: O=C1CCC(C=Cc2ccc(-n3ccnc3)cc2)=NN1

Procedure:
A solution of 2 g of (E)-6-[4-(1H-imidazol-1-yl)phenyl]-4-oxo-5-hexenoic acid in 60 ml of ethanol containing 0.5 g of 80% hydrazine hydrate is heated to reflux for three hours. The solution is concentrated to a small volume (ca 10 ml) and filtered. The residue is crystallized from THF/methanol to give 0.6 g of the 4,5-dihydro-pyridazinone, mp 230°-231° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[S:19](Cl)(=[O:21])=[O:20]>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:10]=1[S:19]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Br
Reactant: CN1CCNCC1
Product: CN1CCN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CC1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate EU using 1-methylpiperazine and 2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride. 1H NMR (500 MHz, CDCl3) δ 8.37-8.28 (d, J=2.2, 1H), 7.98-7.86 (d, J=8.2, 1H), 7.73-7.59 (d, J=8.2, 1H), 3.45-3.31 (t, J=5.0, 4H), 2.60-2.42 (t, J=4.9, 4H), 2.40-2.20 (d, J=1.5, 3H).
Reaction SMILES: F[C:2]1[CH:7]=C[CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[C:17]([N:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=O)[CH3:18]>O>[CH3:5][C:4]1[CH:18]=[C:17]([N:20]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:2][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(=O)N1CCCNCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(N2CCCNCC2)ccc1[N+](=O)[O-]
Temperature: 95 °C
Yield: 53.6 %

Procedure:
Fluoronitrobenzene (9.1 g, 0.0586 mol) is dissolved in water (50 ml) and then potassium carbonate (9.7 9, 0.0703 mol) and 1-acetyl-[1,4]diazepane (10 g, 0.0703 mol) are added. The medium is heated at 95° C. for 6 hours, and an orange-coloured solution is obtained. The medium is then cooled to room temperature, and an orange-coloured sticky paste then appears. The maximum amount of water is removed from the reaction medium. Isopropanol is then added to the paste until a yellow solid precipitates. The medium is filtered and, after drying in a vacuum oven at 45° C., a yellow powder is obtained which corresponds to 1-(3-methyl-4-nitrophenyl)-[1,4]diazepane (1). (8.7 g; Yield=53.6%)
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C@:11]12[N:27]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=4[C:34]4[C:35]5[CH2:40][NH:39][C:37](=[O:38])[C:36]=5[C:24]5=[C:25]([C:26]=43)[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=35)[C@H:15]([O:16]1)[CH2:14][C@@H:13]([NH:41][CH3:42])[C@H:12]2[O:43][CH3:44].C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[CH3:10][C:11]12[N:27]3[C:26]4=[C:25]5[N:17]([C:18]6[C:23]([C:24]5=[C:36]5[C:37](=[O:38])[NH:39][CH2:40][C:35]5=[C:34]4[C:33]4[C:28]3=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:22][CH:21]=[CH:20][CH:19]=6)[CH:15]([O:16]1)[CH2:14][CH:13]([N:41]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:42])[CH:12]2[O:43][CH3:44]
Reactant: CN[C@@H]1C[C@H]2O[C@@](C)([C@@H]1OC)n1c3ccccc3c3c4c(c5c6ccccc6n2c5c31)C(=O)NC4
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC1C(N(C)C(=O)c2ccccc2)CC2OC1(C)n1c3ccccc3c3c4c(c5c6ccccc6n2c5c31)C(=O)NC4
Reaction time: 0.17 h

Procedure:
0.035 ml (0.3 mmol) of benzoyl chloride is added at room temperature to a solution of 116.5 mg (0.25 mmol) of staurosporine and 0.065 ml (0.38 mmol) of N,N-diisopropylethylamine in 2 ml of chloroform and the whole is stirred for 10 minutes. The reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated by evaporation. The crude product is chromatographed on silica gel (eluant:methylene chloride/ethanol 30:1); m.p. 235°-247° with colour turning brown.
Reaction SMILES: Cl[Si:2]([CH3:23])([CH3:22])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]1[CH3:21].CCN(CC)CC.C[SiH]([N:34](C1C2C(=C(C)C=C(C)C=2)C(C)=C1C)[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)C>CCCCCC>[CH:35]1([NH:34][Si:2]([CH3:23])([CH3:22])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[CH3:21])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC1=C(C)C(N(C2CCCCC2)[SiH](C)C)c2cc(C)cc(C)c21
Reactant: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)NC1CCCCC1)CCC3
Reaction time: 24 h
Yield: 89.9 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2-methyl-3-phenyl-s-indacen-1-yl) silane (9c)) (5.6340 g, 0.01633 moles) was stirred in hexane (100 mL) as NEt3 (2.9673 g, 0.02932 moles) and cyclohexylamine (1.6373 g, 0.01651 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (5.8969 g, 89.9 percent).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1)[NH2:3].C(N(CC)CC)C.[CH2:19]([O:21][C:22](=[O:35])[C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=O)[CH3:20]>C(O)C>[CH2:19]([O:21][C:22]([C:23]1[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=2)[N:2]([C:4]2[CH:9]=[N:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)[N:3]=1)=[O:35])[CH3:20]
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(C)c1
Reactant: COc1ccc(NN)cn1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2cccc(C)c2)n(-c2ccc(OC)nc2)n1

Procedure:
5-Hydrazino-2-methoxypyridine hydrochloride (0.380 g) obtained from Referential Example 1 and triethylamine (0.30 mL) were added to a solution of the above-obtained 4-(3-methylphenyl)-2,4-dioxobutanoic acid ethyl ester (1.014 g) dissolved in ethanol (20 mL) at room temperature. The resultant mixture was refluxed under heat for 14 hours, and then cooled in air. The solvent was evaporated under reduced pressure, and the residue was partitioned between chloroform and water. The aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate: 20%), to thereby give the title compound as an oily substance (0.451 g, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7](=O)[CH:8]([CH3:18])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[H-].[Na+].P(Cl)(OCC)(OCC)=O.[N+:33]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])#[C-:34].[H-].[Na+].C1COCC1>C1COCC1>[CH2:39]([O:38][C:36]([C:35]1[N:33]=[CH:34][N:6]2[C:7]=1[CH:8]([CH3:18])[N:9]=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[C:4]1[CH:3]=[C:2]([Br:1])[CH:21]=[CH:20][C:5]2=1)=[O:37])[CH3:40]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CC1N=C(c2ccccc2F)c2cc(Br)ccc2NC1=O
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1F)c1cc(Br)ccc1-2
Temperature: -10 °C
Reaction time: 3 h

Procedure:
7-Bromo-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 117 (3.78 g, 10.88 mmol) was suspended in dry THF (150 mL) and cooled to −10° C. Sodium hydride (60% dispersion in mineral oil, 0.52 g, 13.07 mol) was added into the suspension in one portion. The reaction mixture was allowed to stir and then warm to rt over a 3 h period. The reaction mixture was again cooled to −10° C. and diethyl chlorophosphate (2.65 mL, 17.42 mmol) was added. The cooling bath was then removed and stirring continued for 3 h. During this time, sodium hydride (60% dispersion in mineral oil, 0.61 g, 15.24 mmol) was suspended in dry THF (60 mL) at −10° C. in another flask. Ethyl isocyanoacetate (1.43 ml, 13.07 mnol) was added to the NaH/THF suspension and this mixture allowed to stir for 3 h. After 3 h the first flask was cooled to −30° C. with a cooling bath and the mixture in the second reaction flask was added to the first flask via a cannula. The reaction mixture was allowed to stir for 24 h, after which it was cooled to 0° C. with an ice-water bath and slowly quenched with acetic acid (5 mL). Water was then added to the reaction mixture and this was extracted with EtOAc. The EtOAc layers were combined, washed with aq NaHCO3, brine and dried (Na2SO4). After removal of the solvent under reduced pressure, the solid was purified by flash chromatography (silica gel, EtOAc:hexane: gradient elution 1:2, 1:1, 2:1). The ethyl ester 118 was a white solid (1.82 g, 38%). mp 190-192° C.; IR (KBr, cm−1) 3316, 2925, 1693, 1621, 1485, 1448, 1371; 1H NMR (CDCl3) δ 7.92 (s, 1 H), 7.72 (dd, J=8.5, 1.5 Hz, 1 H), 7.6 (t, J=6.9 Hz, 1 H), 7.48 (d, J=8.5 Hz, 1 H), 7.42-7.49 (m, 2 H), 7.23-7.29 (m, 1 H), 7.05 (t, J=9.3 Hz, 1 H), 6.71 (q, J=7.3 Hz, 1 H), 4.41 (m, 2 H), 1.42 (t, J=7.1 Hz, 3 H), 1.29 (d, J=7.2, 3 H). MS (EI) m/e (relative intensity) 442 (M+, 5), 428 (7), 381 (58), 355 (100), 303 (37); [α]26D=10.6 (c 0.53, EtOAc).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Sn](C)(C)C)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[C:25]1[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=1)(=O)=O>[Pd]>[CH2:1]([O:8][C:9]1[NH:10][CH2:11][C:12]([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: C[Sn](C)(C)c1ccc(OCc2ccccc2)nc1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CC=C(C2=CC=C(OCc3ccccc3)NC2)CC1

Procedure:
In an analogous manner to that described above, by a palladium catalyzed coupling of 2-benzyloxy-5-trimethylstannyl-pyridine with tert-butyl 4-trifluoromethylsulphonyloxy-3,6-dihydro-2H-pyridine-1-carboxylate [Example 126 (c)] there was obtained tert-butyl 6-benzyloxy-3',6'-dihydro-2H-[3,4']bipyridine-1'-carboxylate as a colourless solid MS: 367 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:14])=[CH:11]/[CH:12]=[O:13].C(N(CC)CC)C.[P:24]([O-:29])([O:27][CH3:28])[O:25][CH3:26]>C(#N)C>[OH:13][CH:12]([P:24](=[O:29])([O:27][CH3:28])[O:25][CH3:26])/[CH:11]=[C:10](\[CH3:14])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:15])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Reactant: COP([O-])OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COP(=O)(OC)C(O)/C=C(\C)CC/C=C(\C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of farnesal (245 mg, 1.11 mmol) in acetonitrile (1.1 ml) under argon at room temperature (r.t), was added triethylamine (0.31 ml, 2.22 mmol) and dimethyl phosphite (0.153 ml, 1.67 mmol) and the resulting mixture stirred at r.t. for 24 hr. The reaction mixture was concentrated in vacuo, the resulting residue was chromatographed over silica gel eluted with ethyl acetate to afford the title compound as a colorless oil: NMR (CDCl3) δ 1.60 (6H, s), 1.68 (3H, s), 1.71 (3H, d, J=3.1 Hz), 1.80-2.30 (9H, m), 3.80 (6H, m), 4.69 (1H, dt, J=9 and 5.4 Hz), 5.00-5.20 (2H, m), 5.34 (1H, m).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH2:34].CO>>[NH2:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH:34][C:10]1[C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[N:24]=[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3ccccc3)nc(Cl)c12
Reactant: CN(CCCN)CCCN
Solvent: CO
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3ccccc3)nc(NCCCN(C)CCCN)c12
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
In a 2-5 mL microwave vial was added methyl 2-benzyl-4-chloro-9H-pyrimido[4,5-b]indole-7-carboxylate (0.050 g, 0.142 mmol) and N1-(3-aminopropyl)-N1-methylpropane-1,3-diamine (0.115 mL, 0.711 mmol) in MeOH (2.000 mL, 49.4 mmol) to give a tan suspension. The vial was placed in the microwave and heated to 140° C. for 30 min. After 30 minutes, the mixture was concentrated to dryness on a rotavap. and the residue was purified by flash chromatography and lyophilized from CH3CN to afford two distinct products: Example 45 as the mono-N-alkylated product: methyl 4-((3-((3-aminopropyl)(methyl)amino)propyl)amino)-2-benzyl-9H-pyrimido[4,5-b]indole-7-carboxylate (44 mg, 67.2% yield) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (dt, J=13.8, 6.6 Hz, 2H) 1.72 (dt, J=13.7, 6.8 Hz, 2H) 2.11 (s, 3H) 2.24-2.30 (m, 2H) 2.33 (t, J=6.7 Hz, 2H) 2.47 (br. s., 2H) 3.51-3.61 (m, 2H) 3.76-3.85 (m, 3H) 3.97 (s, 2H) 7.08-7.15 (m, 1H) 7.17-7.24 (m, 2H) 7.27-7.34 (m, 2H) 7.50 (t, J=5.3 Hz, 1H) 7.76 (dd, J=8.2, 1.6 Hz, 1H) 7.92 (d, J=1.6 Hz, 1H) 8.20 (d, J=8.2 Hz, 1H); MS m/z 461.2 (M+H)+; HPLC >99%, RT=1.63 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[NH:5][CH:6]=[C:7]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1Cl)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[C:15]3[C:14](=[CH:19][CH:18]=[CH:17][N:16]=3)[C:13](=[O:21])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6]2)[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(=CNc1cccc(Br)c1)C(=O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The crude compound from Step 1 was dissolved in tetrahydrofuran (500 mL), the solution was cooled to 0° C., and sodium hydride (as a 60% dispersion in oil, 9.4 g, 235 mmol) was added in portions. After stirring at 0° for 1 hour, the resulting mixture was allowed to warm up to room temperature. After 2 hours, water (400 mL) was added to the resulting suspension and the insoluble solid was filtered and washed copiously with water. When dry, the solid was stirred in ether (150 ML) at room temperature for 24 hours and filtered to afford the ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate compound as a cream-colored solid.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17]>C(O)C.C(OCC)(=O)C>[C:13]([C:14]1[CH:15]=[C:16]([NH2:17])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([S:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1)([CH3:20])([CH3:19])[CH3:12]
Reactant: CSc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Yield: 95 %

Procedure:
Concentrated hydrochloric acid (1 mL) was added dropwise to a mixture of 4-methylthiophenyl hydrazine (2 g, 10.5 mmol) and 4,4-dimethyl-3-oxopentane nitrile (1.44 g, 11.5 mmol) in ethanol (30 mL) and the mixture was heated under reflux for 18 hours. The cooled mixture was then diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 97:3 to afford the title compound as a yellow oil that crystallised on standing (2.59 g, 95% yield).