Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]C[Si](C)(C)C.[Mg].[SiH4].CCOCC.[C:14]1([CH3:33])[C:15]([S:20]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1>C(OCC)C.C(I)C.O1CCCC1>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][OH:23])=[CH:27][CH:28]=1.[C:14]1([CH3:33])[C:15]([S:20]([Cl:1])(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)CCl
Reactant: Cc1ccccc1S(=O)(=O)OCCc1ccc(Cl)cc1
Agent: [Mg]
Agent: [SiH4]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCI
Product: Cc1ccccc1S(=O)(=O)Cl
Product: OCCc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
About 12.3 g (0.1 Mol) of commercially available chloromethyltrimethylsilane were dissolved in 100 ml of diethyl ether, and 2 ml of this solution were added under an inert gas to a mixture containing 3 g of magnesium turnings and one drop of ethyl iodide. After the reaction had been initiated by warming, the remainder of the silane/ether mixture was added dropwise at 20° C. with stirring over a period of one hour. When the addition was complete, the mixture was refluxed for an additional 30 minutes, then cooled and decanted from the excess magnesium. The resultant solution was added dropwise over a period of 30 minutes with stirring at 20° to 30° C. to a solution containing 22.7 g (0.1 Mol) of 2-(4-chlorophenyl)ethyl toluene sulfonate (obtained from commercially available 2-(4-chlorophenyl)ethanol by the known reaction with toluene sulfonyl chloride) in 100 ml of tetrahydrofuran. When the addition was complete, 100 ml of the solvent mixture were removed by distillation and replaced by 50 ml of tetrahydrofuran. The mixture was heated at an internal temperature of 60° C. for 60 minutes, during which time magnesium tosylate precipitated. After cooling, the mixture was poured over ice and acidified with a little hydrochloric acid, and the aqueous phase was extracted twice with tert-butyl methyl ether. The collected organic phases were washed with NaCl solution, dried and evaporated. About 17.1 g (75.4 percent yield) of 1-chloro-4-(1-trimethylsilylpropyl)benzene were obtained by fractional distillation of the residue at 16 hPa and at 115° to 118° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:22]3[NH:26][CH2:25][CH2:24][S:23]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][N:28]=[C:29]=[O:30]>O1CCCC1>[CH3:27][NH:28][C:29]([N:26]1[CH2:25][CH2:24][S:23][CH:22]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1)=[O:30]
Reactant: c1ccc(N2CCN(CCOc3ccccc3C3NCCS3)CC2)cc1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2ccccc2)CC1
Reaction time: 2 h
Yield: 89.7 %

Procedure:
3.69 g of 2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine are dissolved in 40 ml of tetrahydrofuran, and 0.62 g of methyl isocyanate is added thereto at room temperature. The mixture is stirred at the same temperature for 2 hours. The mixture is concentrated under reduced pressure to remove solvent. Water is added to the residue, and crystalline precipitates are collected by filtration. The crystals are washed with ethanol and ether, and then recrystallized from a mixture of ethyl acetate and n-hexane. 3.82 g of N-methyl-2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidin-3-carboxamide are obtained. Yield: 89.7%.
Reaction SMILES: [C:1]([C:5]1[CH:32]=[CH:31][C:8]([NH:9][C:10]2[CH:29]=[CH:28][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]=2[F:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.CN(C)C=O>O>[C:1]([C:5]1[CH:32]=[CH:31][C:8]([NH:9][C:10]2[CH:29]=[CH:28][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:41][CH2:42][N:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]=2[F:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)c(F)c3)ccnc2cc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)c(F)c3)ccnc2cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
4-{4-[4-(Tert-butyl)anilino]-3-fluorophenoxy}-6-methoxy-7-quinolinol (starting compound 6) (1.75 g), potassium carbonate (2.80 g), and 4-(2-chloroethyl)morpholine hydrochloride (1.13 g) were added to N,N-dimethylformamide (20 ml), and the mixture was stirred at 80° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and was dried over sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude thus obtained was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (1.44 g, yield 64%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: ClCCCN1CCCCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a three-necked flask fitted with an overhead mechanical stirrer, a mixture of 1-(3-chloropropyl)piperidine (49.8 g, 0.308 mol), 4-nitrophenol (42.8 g, 0.308 mol) and potassium carbonate (212 g, 1.53 mol), in anhydrous DMF (200 mL) was heated to 94° C. and stirred for 18 h. The mixture was cooled to room temperature, then diluted with 2 L water. The organics were taken up in ethyl acetate and washed twice with 2N sodium hydroxide and then brine. The combined organics were dried over magnesium sulfate then concentrated under reduced pressure to give the title compound as a yellowish oil.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][O:7][C:8](=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=O)[NH:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])=O>C(O)(=O)C>[CH3:6][O:7][C:8](=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[NH:5][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[CH:17][N:16]=1
Reactant: [NH4+]
Reactant: COC(=O)CCCCCCC(=O)NCC(=O)c1ccccc1OC
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COC(=O)CCCCCCc1ncc(-c2ccccc2OC)[nH]1
Yield: 43.8 %

Procedure:
Heat a mixture of ammonium acetate (16.5 g, 214 mmol) and 7-[2-(2-methoxyphenyl)-2-oxoethylcarbamoyl]heptanoic acid methyl ester (14.2 g, 42.3 mmol) in acetic acid (300 mL) at reflux under nitrogen for 15 hours. Remove the solvent under reduced pressure. Dilute the residue in ethyl acetate (500 mL) and adjust to pH 8 with saturated aqueous sodium bicarbonate solution. Extract the aqueous layer with additional. ethyl acetate (200 mL) and dry the combined organic extracts over sodium sulfate and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate, to afford 7-[5-(2-methoxyphenyl)-1H-imidazol-2-yl]heptanoic acid methyl ester (5.86 g, 44%): APCI mass spectrum m/z 317 [C18H24N2O3+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][C:14]1[N:15]=[C:16]([OH:25])[C:17]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C:18]=2[N:24]=1.C(N(CC)CC)C>[Pd].CN(C)C=O>[OH:9][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([N:21]2[CH2:22][CH2:23][C:17]3[C:16]([OH:25])=[N:15][C:14]([CH3:13])=[N:24][C:18]=3[CH2:19][CH2:20]2)[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1nc(O)c2c(n1)CCNCC2
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(O)c2c(n1)CCN(c1nc(C)nc(O)c1[N+](=O)[O-])CC2

Procedure:
In analogy to the procedure described in example 1c 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (example. 1a) was treated with the 2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (prepared from the corresponding N-benzyl derivative [Bull. Chem. Soc. Jap. (1971), 44(1), 153-8] by catalytic hydrogenation with palladium on charcoal) in N,N-dimethylformamide in the presence of triethylamine at room temperature to yield the title compound as yellow solid; m.p.>200° C.; MS: [M+H]+=333.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Br:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH:27]([NH2:29])[CH3:28])[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>>[Br:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH:27]([NH:29][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:2]=3[Cl:1])[CH3:28])[CH2:20][CH2:21][C:22]([F:25])([F:26])[CH2:23][CH2:24]2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: CC(N)C1(c2ccc(Br)nc2)CCC(F)(F)CC1
Product: CC(NC(=O)c1cccc(Cl)c1Cl)C1(c2ccc(Br)nc2)CCC(F)(F)CC1

Procedure:
From 2,3-dichlorobenzoic acid and 1-(1-(6-bromopyridin-3-yl)-4,4-difluorocyclohexyl)ethanamine. LCMS (MH+): m/z=493.1, tR (minutes, Method D)=0.83
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:34]=2)[N:31]=1.C(N(C(C)C)C(C)C)C.[Cl-].[Na+].CN(C)[CH:53]=[O:54]>>[C:9]([OH:8])(=[O:54])/[CH:32]=[CH:33]/[C:35]([OH:37])=[O:36].[C:53]([OH:54])(=[O:8])/[CH:32]=[CH:33]/[C:35]([OH:37])=[O:36].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)c1cn2nc(Cl)ccc2n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Product: O=C(O)/C=C/C(=O)O
Temperature: 80 °C
Reaction time: 18.5 h

Procedure:
686 mg of 4-(diphenylmethoxy)-1-piperidinepropanamine and 477 mg of ethyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate were dissolved in 7 ml of N,N-dimethylformamide; 0.73 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (80° C.) for 18.5 hours. After cooling, ice water and sodium chloride were added, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, dissolved in 5 ml of ethyl acetate; a solution of 95 mg of fumaric acid in 5 ml of ethanol was added, followed by concentration. Acetone-ethyl ether (1:2) was added to the residue to cause recrystallization; the crystal precipitate was collected by filtration and washed with ethyl ether to yield 211 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].O.O=[CH:26][C:27]([OH:29])=[O:28]>C(#N)C>[CH2:19]([O:18][C:16]([C:15]1[CH:14]=[C:13]([NH:12][CH:26]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:27]([OH:29])=[O:28])[CH:23]=[CH:22][CH:21]=1)=[O:17])[CH3:20]
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=CC(=O)O
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cccc(NC(C(=O)O)c2ccc(OC)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
A mixture of 6-methoxypyridin-3-ylboronic acid (1.2 g, 7.84 mmol), ethyl 3-aminobenzoate (1.29 g, 7.84 mmol), and 2-oxoacetic acid hydrate (723 mg, 7.84 mmol) in acetonitrile (70 ml) was stirred at room temperature overnight. The solvent was evaporated under vacuum, and the crude product was purified by flash chromatography (DCM/MeOH=9/1) to obtain 2-(3-(ethoxycarbonyl)phenylamino)-2-(6-methoxypyridin-3-yl)acetic acid (0.95 g, 38% yield).
Reaction SMILES: [N:1](=[C:3]1[CH:7]([CH3:8])[O:6][CH2:5][S:4]1)[OH:2].[CH3:9][N:10]=[C:11]=[O:12].C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>C(OCC)C>[CH3:9][NH:10][C:11]([O:2][N:1]=[C:3]1[CH:7]([CH3:8])[O:6][CH2:5][S:4]1)=[O:12]
Reactant: CN=C=O
Reactant: CC1OCSC1=NO
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOCC
Product: CNC(=O)ON=C1SCOC1C

Procedure:
A quantity of 4.3 grams of 4-oximino-5-methyl-1,3-oxathiolane was caused to react with 3.5 ml of methylisocyanate in the presence of dibutyltin diacetate in ethyl ether and worked up as described in Example I to give 6 grams of crude 4-(methylcarbamoyloximino)-5-methyl-1,3-oxathiolane. Recrystallization from isopropyl ether/ethyl acetate afforded pure syn isomer, mp 70.0°-71.5°; structure confirmed by spectral analysis.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[N:7][C:6]([NH2:27])=[N:5]1.CN(C)[CH:30]=[O:31]>>[CH3:3][N:4]1[C:8]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[N:7][C:6]([NH:27][CH:30]=[O:31])=[N:5]1
Reactant: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cn1nc(NC=O)nc1NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C

Procedure:
A mixture of sodium hydride (0.72 g) and 1-methyl-N5 -[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (3.44 g) in dimethylformamide (50 ml) was heated under reflux for 8 h. The reaction mixture was cooled, poured onto water (300 ml) and extracted with ether. Evaporation of the organic extract gave a yellow oil, which was extracted with boiling cyclohexane (500 ml). As the cyclohexane extract was cooled a brown oil precipitated out. This oil was discarded and the supernatant solution was cooled to room temperature to give the title compound which was recrystallised from a mixture of ethyl acetate and light petroleum (b.p. 60°-80°) as a pale yellow solid (0.35 g) m.p. 68°-75° (decomposition). tlc, System C: Rf 0.6.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])[C:9](=[O:21])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH3:12])[C:5]2=[CH:4][N:3]=1>NC1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([N:10]2[CH:11]([CH3:12])[C:5]3[C:6](=[N:7][C:2]([NH:10][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:3][CH:4]=3)[N:8]([C@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])[C:9]2=[O:21])=[CH:18][CH:17]=1
Reactant: COc1ccc(N2C(=O)N([C@@H](C)c3ccccc3)c3nc(Cl)ncc3C2C)cc1
Solvent: Nc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)N([C@@H](C)c3ccccc3)c3nc(Nc4ccccc4)ncc3C2C)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A suspension of crude 7-chloro-3-(4-methoxy-phenyl)-4-methyl-1-[1-(S)-phenyl-ethyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (308 mg, from 0.56 mmol) (from Example 17 supra) in aniline (0.195 mL) (Aldrich) was stirred at 100° C. for 3 hours. Reaction mixture was then cooled to room temperature, diluted with toluene (3 mL) and purified by column chromatography (silica gel) eluting with hexanes-ethyl acetate (1:1) to give 3-(4-methoxy-phenyl)-4-methyl-7-phenylamino-1-[1-(S)-phenyl-ethyl]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 140 mg, 53.7%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].[C-:10]#[N:11]>>[CH3:8][C:5]([CH3:9])([CH2:4][CH2:3][CH2:2][C:10]#[N:11])[C:6]#[N:7]
Reactant: CC(C)(C#N)CCCCl
Reactant: [C-]#N
Product: CC(C)(C#N)CCCC#N

Procedure:
treating said 5-chloro-2,2-dimethylpentanenitrile with a cyanide-delivering reagent in the presence of a phase-transfer catalyst to form 2,2-dimethyladiponitrile;
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:21](=[O:23])[NH2:22])[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:9][CH:8]=1.[CH:24]([O-])([O-])OCC.CN(C)C=O>C(OCC)(=O)C>[OH:23][C:21]1[N:3]2[N:4]=[CH:5][C:6]([C:7]3[CH:12]=[CH:11][C:10]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=4)=[CH:9][CH:8]=3)=[C:2]2[N:1]=[CH:24][N:22]=1
Reactant: Cc1cccc(Cc2ccc(-c3cnn(C(N)=O)c3N)cc2)c1
Reactant: CCOC([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(Cc2ccc(-c3cnn4c(O)ncnc34)cc2)c1
Reaction time: 1 h

Procedure:
A mixture of 3-amino-2-carbamoyl-4-{4-(3-methylphenylmethyl) phenyl}pyrazole (3.0 g), ethyl orthoformate (2 ml) and N,N-dimethylformamide (4 ml) was heated and stirred at 100° C. to 110° C. After 1 hour, to the mixture was added ethyl acetate (50 ml). The precipitate was separated by filtration, washed with ethyl acetate, dried to give the title compound (2.0 g).
Reaction SMILES: C(Cl)CCl.[NH:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:6]([C:8]([OH:10])=O)[CH3:7].[CH3:18][O:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:25])[CH3:24])[NH2:22].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:6]([C:8]([NH:22][C@H:21]([C:20]([O:19][CH3:18])=[O:26])[CH:23]([CH3:25])[CH3:24])=[O:10])[CH3:7]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
EDC (1.521 g, 7.93 mmol) was added to Boc-Ala (1.500 g, 7.93 mmol) in 25 mL chloroform at 0° C. and the mixture was allowed to stir 30 minutes. Valine methyl ester (1.329 g, 7.93 mmol), triethylamine (1.11 mL, 7.93 mmol) and 25 mL chloroform were combined in a separate 50-mL flask and stirred. This mixture was transferred to the solution of activated Boc-alanine and stirred at 0° C. for 3 h. The ice bath was removed and the reaction mixture stirred an additional 27 h. Three drops of acetic acid were added and the stirring continued for 15 minutes. The mixture was concentrates in vacuo and then redissolved in EtOAc (50 mL). The organic portion was washed with 10% NaHCO3 (2×25 mL), 1N HCl (2×25 mL), water (25 mL), dried over sodium sulfate, and concentrated in vacuo to 1.848 g (81%) of product. 1H NMR (CDCl3, 300 MHz) δ 6.68 (br d, J=5.4 Hz, 1H), 4.99 (br s, 1H), 4.53 (dd, J=4.8, 8.7 Hz, 1H), 4.19 (br t, J=7.5 Hz, 1H), 3.74 (s, 3H), 2.18 (septet, J=6.9 Hz, 1H), 1.45 (s, 9H), 0.93 (d, J=6.9 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.[CH3:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2.N1CCCCC1.C(O)(=O)C>C(O)C>[CH3:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:1][C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: Cc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Cc1ccc2c(c1)C(=Cc1[nH]c3c(c1CCC(=O)O)CCCC3)C(=O)N2
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (5.4 g), 3.2 g of 5-methyl-2-oxindole and 2.7 g of piperidine in 25 mL of ethanol was refluxed for 4 hours. Upon addition of acetic acid (8 mL), a precipitate formed. The mixture was refluxed for 5 minutes and cooled to ambient temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solids were slurry-washed with 30 mL of refluxing ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and vacuum dried to give 6.2 g (80% yield) of 3-[2-(5-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as an orange solid.
Reaction SMILES: [F:1][CH:2]([P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[F:3].[Li+].CC([N-]C(C)C)C.[NH2:20][C:21]1[C:30]2[N:29]=[CH:28][C:27]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[CH3:41])=[CH:26][C:25]=2[C:24]2[CH:42]=[CH:43][C:44]([CH:46]=[O:47])=[CH:45][C:23]=2[N:22]=1>C1COCC1>[NH2:20][C:21]1[C:30]2[N:29]=[CH:28][C:27]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[CH3:41])=[CH:26][C:25]=2[C:24]2[CH:42]=[CH:43][C:44]([CH:46]([OH:47])[C:2]([P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])([F:3])[F:1])=[CH:45][C:23]=2[N:22]=1
Reactant: COc1ccc(CCc2cnc3c(N)nc4cc(C=O)ccc4c3c2)c(C)c1
Reactant: CCOP(=O)(OCC)C(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(F)(F)C(O)c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
To a solution of diethyl difluoromethylphosphonate (3.0 equiv.) in THF (0.3 M) at −78° C. under nitrogen atmosphere was added dropwise 2M LDA (3.0 equiv., commercial grade). The reaction was stirred at −78° C. for 25 min, and a solution of 5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbaldehyde (2-2) (1.0 equiv.) in THF (0.1 M) was added slowly. The reaction was stirred at −78° C. for 1 hour, 0° C. for 1 hour, and then warmed to room temperature over 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using a gradient of 0-5% MeOH/DCM to provide diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-hydroxyethylphosphonate (2-3) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[NH3:15]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:15])(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: N
Solvent: CO
Product: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 0.5 h

Procedure:
2-Chloro-5-nitrobenzenesulphonyl chloride (5.12 g, 20 mmole) was added in portions to liquid ammonia with stirring at -78° C. (methanol/dry-cold). The mixture was stirred for 0.5 h. and the excess ammonia then allowed to evaporate. The residue was crystallised from aqueous ethanol (1:1) to afford lustrous prisms of 2-chloro-5-nitrobenzenesulphonamide, 4.42 g, 93%, (m.p. 180°-187° C.). TLC analysis (CH2Cl2) showed one spot (Rf =0.2). Spectroscopic data was consistent with the product.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13]1.Cl>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1
Reactant: Brc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
Anhydrous aluminum trichloride (29.1 g, 218 mmol) was suspended in dichloromethane (120 mL) and cooled to 0° C. Bromobenzene (35.1 g, 224 mmol) was added carefully. When the addition was complete, succinic anhydride (10.0 g, 100 mmol) was added in ten portions carefully. Then the mixture was warmed to room temperature and stirred for 4 h. TLC showed the reaction was complete, 6N HCl (50 mL) was added dropwise. The solid was filtered, washed with distilled water (10 mL×2) and dried in vacuo to afford A-1 as a white solid (22 g, yield 82%).