Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].C(N(CC)CC)C.[Br:21][CH2:22][C:23](Br)=[O:24].Cl>C(Cl)Cl>[Br:21][CH2:22][C:23]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12])=[O:24]
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Reaction time: 3 h
Yield: 94 %

Procedure:
2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (500 mg, 2.55 mmol) and triethylamine (0.35 mL, 2.55 mmol) were stirred in DCM (10 mL). Bromoacetylbromide was added dropwise under a nitrogen atmosphere. Stirring was continued for 3 h. 2 M HCl (20 mL) was added and the reaction mixture extracted into DCM (3×50 mL). The combined DCM layers were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo to give the desired product as a cream solid (760 mg, 2.40 mmol, 94%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.4 %

Procedure:
tert-Butyl (3R)-6-cyclohexyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 44) (350 mg, 1.04 mmol) was treated with trifluoroacetic acid (3 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 45 minutes. The solvent was removed under reduced pressure and the residue azeotroped from toluene then dichloromethane to afford the title compound (185 mg).
Reaction SMILES: Br[CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:7]([O:6][CH:5]([O:9][CH2:10][CH3:11])/[C:4](/[CH3:12])=[CH:3]/[CH2:2][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1)[CH3:8]
Reactant: COc1cccc(O)c1
Reactant: CCOC(OCC)/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(OCC)/C(C)=C/COc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 43 h

Procedure:
A mixture of 12.65 g of crude (E)-4-bromo-1,1-diethoxy-2-methyl-2-butene, 6.4 ml of m-methoxyphenol, and 8.1 anhydrous potassium carbonate in 100 ml sieve dried dimethylformamide is stirred at room temperature under nitrogen for about 43 hours and the reaction mixture diluted to 500 ml with water and extracted with a 300 ml and two 100 ml portions of hexane. The combined hexane extracts are washed with two portions of brine and dried with sodium sulfate. Concentration of the hexane extracts yields 6.45 g (E)-1,1-diethoxy-(4-m-methoxyphenoxy)-2-methyl-2-butene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[Cl:9].[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: Clc1cccc(I)c1Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
1,2-Dichloro-3-iodobenzene (4.95 g, 18.1 mmol), trimethylsilylacetylene (2 g, 20 mmol), bis(triphenylphosphine)palladium(II)chloride (245 mg, 0.35 mmol), and copper(I)iodide (45 mg, 0.24 mmol) were combined in triethylamine (120 mL) and heated at reflux for 45 minutes. The mixture was allowed to cool to room temperature and was then partitioned between diethyl ether and saturated sodium chloride. The organic phase was dried with sodium sulfate, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was taken directly on to the next step.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.[F:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1>>[F:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=3)[CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1
Reactant: Fc1cccc(N2CCNCC2)n1
Reactant: CC(=O)N[C@H](C)c1ccc(CCl)cc1
Product: CC(=O)N[C@H](C)c1ccc(CN2CCN(c3cccc(F)n3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using (R)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead of phenylpiperazine, the title compound was obtained as a pale-yellow oil.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH:48]1[CH2:51][CH2:50][CH2:49]1>>[N:48]1([C:42](=[O:44])[CH2:41][N:38]2[CH2:39][CH2:40][N:35]([C:33]([N:13]3[C@@:14]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)([CH3:25])[C@@:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)([CH3:17])[N:16]=[C:12]3[C:9]3[CH:10]=[N:11][C:6]([C:2]([CH3:3])([CH3:5])[CH3:4])=[CH:7][C:8]=3[O:45][CH2:46][CH3:47])=[O:34])[CH2:36][CH2:37]2)[CH2:51][CH2:50][CH2:49]1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: C1CNC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCC2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with azetidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H47Cl2N6O3 [(M+H)+] 705.3081, observed 705.3081.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)=[C:27]([Cl:40])[CH:26]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[C:16]1[CH3:41])(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>CO>[Cl:40][C:27]1[CH:26]=[C:25]([NH:24][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[C:16]([CH3:41])=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: Cc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2n1CCOCCOC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2n1CCOCCO
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.6 %

Procedure:
2-{2-[4-({3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl benzoate (90.0 mg) was dissolved in methanol (1 mL), 1N aqueous sodium hydroxide solution (0.3 mL) was added, and the mixture was stirred at room temperature for 5 hrs. The reaction mixture was neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=33:67→0:100) to give the title compound (43.9 mg) as a pale-yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39](C=O)=[CH:38][CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:1][C:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:39]4[CH:42]=[CH:43][C:36]([C:35]([F:45])([F:44])[F:34])=[CH:37][CH:38]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCC3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(COc2ccc(N3CCN(Cc4ccc(C(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.9 %

Procedure:
Tert-butyl 4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]-piperazine-1-carboxylate prepared in Example 131 (88 mg, 0.19 mmol) was dissolved in trifluoroacetic acid (5 ml), and the solution was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and added methylene chloride (2 ml) and triethylamine (2 ml). The solution was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was dissolved in dichloroethane and added 4-trifluoromethylbenzaldehyde (40 μl, 0.29 mmol) and sodium triacetoxyborohydride (82 mg, 0.38 mmol) with cooling on ice-bath followed by stirring at room temperature overnight. To the solution, a saturated sodium hydrogencarbonate solution and methylene chloride were added. The mixture was extracted with methylene chloride, and the organic phase was dried over magnesium sulfate and filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and crystallized from methylene chloride-ethyl acetate to afford 2-methyl-6-nitro-2-{4-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (53 mg, yield 53%) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:27][C:28]([CH:31]5OCC[O:32]5)=[CH:29][CH:30]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[C:36]([F:39])([F:38])[F:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:27][C:28]([CH:31]=[O:32])=[CH:29][CH:30]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[C:36]([F:39])([F:37])[F:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(Nc2ncnc3ccc(-c4ccc(C5OCCO5)o4)cc23)ccc1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)c(C(F)(F)F)c4)c3c2)o1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Prepared according to Procedure C using (4-Benzyloxy-3-trifluoromethylphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine (470 mg, 0.88 mmol) solution in THF (5 ml) followed by the addition of 2N HCl (20 ml) at room temperature. The resulting mixture was stirred for 30 minutes. Water was added (15 ml) then filtered. The yellow solid was washed with water and small amount of ether and dried in vacuo (0.39 g, 84% yield). ESI-MS m/z 490 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]C#N)=[C:4]([C:12](=O)[C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:3]=1.[OH-].[NH4+:22]>CO>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[S:9][N:22]=[C:12]([C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cccnc1C(=O)c1cc(N)c(F)cc1SC#N
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccnc1-c1nsc2cc(F)c(N)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
A mixture of 4-amino-5-fluoro-2-(3-methylpicolinoyl)phenyl thiocyanate(3.06 g, 0.0112 mole), concentrated ammonium hydroxide (300 ml) and methanol (300 ml) is stirred overnight at room temperature. The methanol is removed in vacuo and the resultant mixture is filtered to afford the title compound as a green solid (1.93 g, 66.6%) which is identified by NMR spectral analysis.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:8]2([C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:19])[CH2:7][CH2:6][CH2:5][NH:4]1.[CH3:20]OC(OC)N(C)C>ClCCl>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]3([CH2:7][CH2:6][CH2:5][N:4]4[CH:20]=[N:1][CH2:2][CH:3]34)[C:9](=[O:19])[NH:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(c1)NC(=O)C21CCCNC1CN
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: COc1ccc2c(c1)NC(=O)C21CCCN2C=NCC21
Temperature: 25 °C

Procedure:
A solution of 31 mmol of 2′-(aminomethyl)-6-methoxyspiro[indole-3,3′-piperidin]-2(1H)-one and 31 mmol of N,N-dimethyl formamide dimethylacetal in 50 ml of dichloromethane is heated to reflux for 6 hours. The reaction mixture is cooled to room temperature and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][CH:27]([NH2:30])[CH2:28][OH:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:30][CH:27]([CH3:26])[CH2:28][OH:29])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and DL-2-amino-1-propanol employing methods similar to those described in Example 2 and was obtained a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.73 (1H, br s), 10.73 (1H, br s), 10.02 (1H, br s), 8.18 (0.56H, s), 8.14 (0.44H, s), 7.34-7.22 (3H, m), 7.14-7.09 (2H, m), 4.78 (1H, t, J=5 Hz), 3.98 (2H, s), 3.48-3.41 (1H, m), 3.23-3.20 (2H, m), 1.14 (0.58H, d, J=6.6 Hz), 1.08 (0.42H, d, J=6.6 Hz); HRMS calcd for C19H18FN3O4+H+: 372.1360. Found 372.1370.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]2=[O:24])=[CH:2]1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[C:32]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[C:13](=[O:24])[CH:14]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)CC1NCCN(CCc2c[nH]c3ccccc23)C1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC1C(=O)N(CCc2c[nH]c3ccccc23)CCN1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
22.4 g of the product of Step C were dissolved in 225 ml of tetrahydrofuran and 14.3 ml of triethylamine and the mixture was cooled to 5° C. 7.9 ml of benzoyl chloride were slowly added and then stirring was maintained for 1 hour at ambient temperature. The insoluble part was separated and the filtrate was evaporated to dryness to obtain 28.4 g of the expected product melting at 144° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[C:15]([CH3:17])[C:8]2[N:9]=[C:10]([CH2:12][CH2:13][CH3:14])[NH:11][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].[C:20]([O:24][C:25]([C:27]1[C:28]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=2)=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[C:15]([CH3:17])[C:8]2[N:9]=[C:10]([CH2:12][CH2:13][CH3:14])[N:11]([CH2:39][C:36]3[CH:37]=[CH:38][C:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[CH:34][CH:35]=3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: CCCc1nc2c(C)cc(C(=O)OC)cc2[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(C(=O)OC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A solution of 7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid methyl ester (10.0 g, 43 mmol; prepared as described in Preparation 1) in DMF (300 mL) was cooled in an ice bath. Sodium hydride (4.5 g, 60 wt % in mineral oil) was slowly added over 5 minutes. 4′-Bromomethylbiphenyl-2-carboxylic acid t-butyl ester (15.7 g, 45.2 mmol; purchased from commercial source or prepared as described in Preparation 2) was then added. The mixture was gradually warmed to room temperature, then stirred at 75° C. overnight. The mixture was then cooled and concentrated in vacuo and the resultant residue was partitioned between saturated aqueous NaCl and EtOAc (1:1, 400 mL). The organic layer was collected, dried over MgSO4 and evaporated to dryness, yielding Intermediate (3a) as a pale yellow oil (16.0 g, 32.1 mmol). MS m/z: [M+H+] calcd for C31H34N2O4, 499.25. found 499.5.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13])([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1>O>[CH:20]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=2[C:12]#[N:13])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1cccc(C2NCCc3ccccc32)c1C#N
Temperature: 170 °C
Yield: 30 %

Procedure:
A mixture of 3-nitrophthalonitrile (2.04 g, 11.8 mmol), freshly dried potassium carbonate (6.0 g, 42 mmol) and 1,2,3,4-tetrahydroisoquinoline (16.5 mL) was heated at 170° C. for 4 h. The reaction mixture was poured into water (250 mL) and extracted with dichloromethane (2×200 mL); the combined organic layers were washed with hydrochloric acid (1 M, 2×200 mL), dried (Na2SO4) and the solvent removed. The product was purified by recrystallisation from methanol to give 9 as a beige powder (906 mg, 30%)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=O.[NH2:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14](C1C=CC=CC=1)=O.[OH-].[Na+]>C(O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[CH:1]=[CH:14][C:13]3[C:12](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:11]=2)=[CH:5][CH:6]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Brc1ccc(-c2ccc3ccccc3n2)cc1
Yield: 78.3 %

Procedure:
Dissolving 5.0 g (25 mmol) of 4-bromoacetophenone and 5.0 g (25 mmol) of 2-aminobenzophenon into 50 milliliter of ethanol, adding 3.1 g of sodium hydroxide, the resultant suspension was refluxed under heating for 7 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and ethanol, thereby obtaining 5.56 g of 2-(4-bromo-phenyl)-quinoline (yield: 61%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH3:13])[N:6]([CH3:14])[C:5]2=[O:15].[Br:16]Br.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([Br:16])[CH3:13])[N:6]([CH3:14])[C:5]2=[O:15]
Reactant: BrBr
Reactant: CCc1nc2ccc(Br)cc2c(=O)n1C
Solvent: CC(=O)O
Solvent: O
Product: CC(Br)c1nc2ccc(Br)cc2c(=O)n1C
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of 6-bromo-2-ethyl-3-methyl-3H-quinazolin-4-one (2.6 g, 9.73 mmol) in glacial acetic acid (2 ml) cooled in an ice bath was added dropwise a solution of bromine (3.1 g, 19.46 mmol) in glacial acetic acid (5 ml). After addition was complete, the reaction was heated to reflux for 18 hours. At which time it was allowed to cool to room temperature. Water was then added to the solution and the mixture was extracted with dichloromethane. The organic layer was then washed with 10% sodium bisulfite solution, and then washed with saturated brine (2×30 ml). The combined organic phase was collected and dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a brown crude product. The resulting residue was purified by silica gel chromatography with 50% dichloromethane in hexane. The product was collected and was dried under reduced pressure to give 6-Bromo-2-(1-bromo-ethyl)-3-methyl-3H-quinazolin-4-one (Yield 2.78 g, 82.5%). 1H NMR (400 MHz, CDCl3): δ 2.23 (d, 3H, J=6.82 Hz), 3.80 (s, 3H), 5.11 (q, 1H, J=13.14, 6.82 Hz), 7.64 (d, 1H, J=8.84 Hz), 7.87 (dd, 1H, J=8.59, 2.26 Hz), 8.46 (d, 1H, J=2.26 Hz). MS m/z calc. 345.9, found (ESI); 347.0 (M+1)+. Retention time 3.43 minutes.
Reaction SMILES: Br.C(O[C:5](=O)[CH2:6][N:7]1[CH:12]=[C:11]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)[CH:10]=[CH:9][C:8]1=[NH:22])C.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:5]1[N:22]=[C:8]2[CH:9]=[CH:10][C:11]([B:13]3[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]3)=[CH:12][N:7]2[CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=N
Agent: Br
Product: CC1(C)OB(c2ccc3nc(Cl)cn3c2)OC1(C)C
Temperature: 105 °C

Procedure:
8.78 g of ethyl[2-imino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-1-yl]acetate hydrobromide in 20 ml of POCl3 are placed in a round-bottomed flask. The reaction mixture is heated at 105° C. for 16 h, cooled to ambient temperature and concentrated under reduced pressure. The residue is taken up between dichloromethane and water at 0° C., and a 30% aqueous solution of NH4OH is added until a basic pH is obtained. The organic phase is separated, dried over magnesium sulphate and concentrated under reduced pressure. 4.3 g of compound are obtained.
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[O:1]([CH2:8][C:9]([O:11][CH2:17][CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 30 g. of phenoxyacetic acid, 100 ml. of ethanol and 10 ml. of sulfuric acid is refluxed for 22 hours, cooled, poured into ice water and extracted with methylene chloride. The organic extract is washed with water to neutrality, dried over sodium sulfate and evaporated to dryness under vacuum, to yield ethyl phenoxyacetate, b.p. 123°/17 mm.Hg.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([C:12]([O:14]CC)=[O:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:3]1[C:11]([C:12]([OH:14])=[O:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1c(CC)nn2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nn2ccccc2c1C(=O)O
Temperature: 60 °C
Yield: 93.7 %

Procedure:
Ethyl 2-ethylpyrazolo[1,5-a]pyridine-3-carboxylate (5.0 g, 23 mmol) was stirred in methanol (200 mL) and a solution of sodium hydroxide in water (100 mL, 3 N) was added. The mixture was heated at 60° C. for 16 h. Evaporation gave a thick suspension which was treated with aqueous hydrogen chloride (100 mL, 3 N). The solids briefly dissolved and a new precipitate formed. The solid was filtered and washed with water to give the desired compound (4.1 g, 96%). LCMS for C10H11N2O2 (M+H)+: m/z=191.1. 1H NMR (300 MHz, DMSO-d6): δ 8.52 (m, 1H), 8.15 (m, 1H), 7.23 (m, 1H), 6.81 (m, 1H), 3.05 (m, 2H), 1.22 (m, 3H).