Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:20])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]2[CH2:18][NH:17][C:16](=[O:19])[CH2:15]2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)C>CO.C(Cl)(Cl)Cl>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([CH:14]2[CH2:18][NH:17][C:16](=[O:19])[CH2:15]2)=[CH:7][C:6]=1[O:5][CH2:4][CH2:3][CH:2]([CH3:20])[N:30]1[CH2:31][CH2:32][N:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:28][CH2:29]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OCCC(C)Br
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2CNC(=O)C2)cc1OCCC(C)N1CCN(c2ccccc2)CC1
Yield: 19.8 %

Procedure:
Analogously to Example 7, using 10 mmol of 4-[3-(3-bromobutoxy)-4-methoxyphenyl]-2-pyrrolidone and 11 mmol of 1-phenylpiperazine (95% strength), 4-{4-methoxy-3-[3-methyl-3-(4-phenylpiperazin-1-yl)propoxy]phenyl}-2-pyrrolidone is obtained in a 19.8% yield, m.p. 88°-90° (ethanol; after chromatography methanol/chloroform 1:9).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[Cl:26])=[CH:14][CH:15]=2)[C:10]([NH:27][C:28](=[O:55])[C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:31][C:30]=2[N:42]([CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)C(=O)C(F)(F)F)=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[Cl:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][N:9]=[C:10]2[NH:27][C:28](=[O:55])[C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]2)=[CH:31][C:30]=1[NH:42][CH:49]1[CH2:50][CH2:51][O:52][CH2:53][CH2:54]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4ccc(OCc5cc(F)ccc5Cl)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(OCc5cc(F)ccc5Cl)cc34)c(NC3CCOCC3)c2)CC1
Yield: 53.1 %

Procedure:
5-(2-Chloro-5-fluoro-benzyloxy)-3-{4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoylamino}-indazole-1-carboxylic acid tert-butyl ester (100 mg, 0.1269 mmol) in DCM (1.3 mL) was treated at room temperature with TFA (0.195 mL, 2.538 mmol). After 2 hours the volatiles were evaporated and the residue was treated with MeOH (3 mL) and TEA (0.357 mL, 2.538 mmol) and refluxed for three hours. After evaporation of the volatile components the crude was diluted with DCM (25 mL), washed with water, aqueous NaHCO3, water and finally brine, dried over sodium sulfate, evaporated and purified by flash chromatography over silica gel (eluent: DCM:7N NH3 in MeOH 93:7) to give 40 mg of title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=O)=[CH:7]2.Cl.CN(C)CCCN=C=NCC.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)=[O:13])=[CH:7]2
Reactant: Cc1cccc2cc(C(=O)O)[nH]c12
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc2cc(C(=O)N3CCN(C)CC3)[nH]c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
A mixture of 7-methylindole-2-carboxylic acid (1.79 g, 10 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 2.88 g, 15 mmol) in CH2Cl2 (100 mL) was treated with N-methylpiperazine (2.22 mL, 20 mmol). The reaction mixture was stirred at ambient temperature for 16 h and then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL), washed with water (25 mL×2) and then brine (25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. This product was purified via silica gel chromatography (5-10% methanol/dichloromethane) to give the title compound as a white solid (2.5 g, 97.3%). 1H NMR (400 MHz, CDCl3): δ 11.07 (br s, 1H), 7.43 (d, J=7.04 Hz, 1H), 7.00-6.92 (m, 2H), 6.71 (d, J=1.96 Hz, 1H), 3.86 (br s, 4H), 2.37 (s, 3H), 2.35-2.28 (m, 4H), 2.19 (s, 3H). MS (electrospray): exact mass calculated for C15H19N3O, 257.15; m/z found, 258.2 [M+H]+.
Reaction SMILES: Cl.C[N:3]1[C:12]2[C:7](=[CH:8][C:9](N=O)=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.CN1C2C(=CC=CC=2)CCC1>>[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CN1CCCc2cc(N=O)ccc21
Agent: CN1CCCc2ccccc21
Agent: Cl
Product: c1ccc2c(c1)CCCN2

Procedure:
1-methyl-6-nitroso-1,2,3.4-tetrahydroquinoline hydrochloride ##STR25## The title compound is prepared from 1-methyl1,2,3,4-tetrahydroquinoline (obtained from 1,2,3,4tetrahydroquinoline by heating with trimethylphosphate (according to Huisgen et al., Chem. Ber. 92, 203 (1959)). The crude product is produced in the usual manner analogous to Examples 10 and 11 and purified on silica gel 60 (Merck) with isopropanol/n-butylacetate/water=5:3:2. The title compound is obtained by dissolving this in acetone after addition of ethereal hydrochloric acid, m.p. 123°-124° C. (decomp.), TLC: silica gel 60, mobile phase: isopropanol/n-butylacetate/water=5:3:2, Rf =0.7.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](O)=O)=[N:14][CH:15]=1.[OH-].[Na+]>O>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:16]1[C:13]1[CH:12]=[CH:11][C:10]([CH3:9])=[CH:15][N:14]=1
Reactant: Cc1ccc(C(=O)O)nc1
Reactant: Nc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3s2)nc1
Yield: 88.4 %

Procedure:
22.5 g (0.18 mol) of o-aminothiophenol, 25 g (0.18 mol) of 5-methylpicolic acid and 100 g of polyphosphoric acid were admixed and stirred in nitrogen gas streams at 170°-200° C. and the mixture was poured in 1 l of water. The mixture was adjusted to pH 5 with an aqueous solution of sodium hydroxide and the resulting crystals were recovered by filtration, whereupon 40 g of 2-(benzothiazol-2-yl)-5methylpyridine was obtained as crude crystals. This crude product was recrystallized from ligroine. By the above procedure was obtained 36 g of the same compound as colorless flakes melting at 169.5°-170.0° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7](O)=[O:8].[CH2:11]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH3:14].CCN(C(C)C)C(C)C.O>C(OCC)(=O)C>[CH2:11]([N:15]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])=[CH:19][CH:18]=1)[C:7](=[O:8])[CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:10])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCNCc1ccc(-c2ccccc2C#N)cc1
Reactant: COC(=O)CCC(=O)O
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CCC(=O)OC
Reaction time: 1 h

Procedure:
A solution of 5.1 g (34 mmol) of succinic acid monomethyl ester monochloride in 20 ml of ethyl acetate is added dropwise, while cooling with ice, to a solution of 6.0 g (22.7 mmol) of N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amine and 13 ml of Hunig base in 100 ml of ethyl acetate. The reaction mixture is stirred at from 0° to 5° for 1 hour and then 30 ml of water are added. The organic phase is washed in succession with 30 ml of 2N hydrochloric acid, water and saturated potassium hydrogen carbonate solution and is dried. Evaporation of the solvent yields crude 3-methoxycarbonylpropanoic acid N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amide in the form of an oil that has an Rf value of 0.32 [toluene/methanol (19:1)].
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:16][N:15]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[CH3:20][C:18]1[C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:16][N:15]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[CH:19]=1
Reactant: O=COc1ccccc1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)(F)F
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ncc1OCC(F)(F)F
Yield: 63 %

Procedure:
The title compound is prepared in 63% yield (120 mg, yellow oil) from 4-chloro-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.40 mmol, Intermediate-66, single enantiomer) and phenyl formate (95 mg, 0.78 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [CH2:1]([C:5]1[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:7]([C:15]#[N:16])=[C:8]([C:10]([OH:14])([CH3:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C>[CH2:1]([C:5]1[NH:6][C:7]([C:15]#[N:16])=[C:8]([C:10]([OH:14])([CH3:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(C)(O)CC)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: CCCCc1nc(C(C)(O)CC)c(C#N)[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A mixture of 1.21 g of 2-butyl -5-cyano-4-(1-hydroxy-1-methyl propyl)-1-tritylimidazole (prepared as described in Preparation 17) and 20 ml of 75% v/v aqueous acetic acid was stirred at 50° C. for 1 hour, after which the mixture was cooled, and the deposited crystals of trityl alcohol were removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and the remaining water and acetic acid were distilled off as a toluene azeotrope under reduced pressure. The residue was purified by column chromatography through silica gel, using a 9:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.47 g of the title compound as a crystalline powder, melting at 139°-142° C.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1.C([O:16][C:17](=[O:21])C([O-])=O)C.[K+].[OH-].[Na+]>CN1C(=O)CCC1.O.C(O)(C(F)(F)F)=O.C(O)(C(F)(F)F)=O.[Pd]>[CH3:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[C:11]([CH3:12])[C:2]([C:17]([OH:21])=[O:16])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CCOC(=O)C(=O)[O-]
Reactant: Cc1ccc2ccc(Br)c(C)c2n1
Agent: [Pd]
Agent: [K+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2ccc(C(=O)O)c(C)c2n1
Temperature: 150 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
A 250 mL round-bottomed flask was charged with 7-bromo-2,8-dimethylquinoline (2.0 g, 8.47 mmol), potassium 2-ethoxy-2-oxoacetate (1.98 g, 12.7 mmol) and dcpp-2HBF4 (0.311 g, 0.508 mmol) in anhydrous NMP (28 mL) and nitrogen was bubbled into the mixture for 10 minutes, followed by the addition of Pd(TFA)2 (0.085 g, 0.254 mmol). The mixture was heated at 150° C. in an oil bath under a nitrogen atmosphere for 18 hours. The reaction mixture was cooled to ambient temperature and treated with a 2N NaOH solution (20 mL), and the mixture stirred at ambient temperature for 18 hours. The mixture was diluted with water (100 mL) and washed with ethyl acetate (180 mL). The aqueous layer was adjusted to pH 3 with 6N HCl and extracted with a 10% IPA-ethyl acetate solution. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Biotage SP4, 40M, C-18; 0-40% MeCN—H2O) to afford 2,8-dimethylquinoline-7-carboxylic acid (0.921 g, 54% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[C:9](O)=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=O)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)COCCO>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[C:8]3[C:9](=[CH:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[CH:17]=3)[NH:23][N:22]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cc2ccccc2cc1O
Reactant: NN
Solvent: OCCOCCO
Solvent: O
Product: Clc1ccc(-c2n[nH]c3cc4ccccc4cc23)cc1

Procedure:
A solution of 37 g. of the 3-(p-chlorobenzoyl)-2-naphthol of Step 2, above, in a mixture of 300 ml. of diethylene glycol and 75 ml. of hydrazine hydrate is refluxed for 4 hours. It is then cooled and poured on ice-water to yield a precipitate which is collected by filtration. This solid is crystallized from a mixture of methylene chloride (dichloromethane) and ether (1:3) to yield the title product, m.p. 192°.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([N:25]([C:27]([CH3:32])([CH2:29][CH2:30]Cl)[CH3:28])[CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:18]([N:25]([C:27]([CH3:28])([CH3:32])[CH2:29][CH2:30][C:9]([C:10]#[N:11])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(Cc1ccccc1)C(C)(C)CCCl
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(Cc1ccccc1)C(C)(C)CCC(C#N)(c1ccccc1)c1ccccc1

Procedure:
Sodium hydride (4.4 g of a 60% dispersion in mineral oil) was added in portions to a solution of diphenylacetonitrile (19.3 g) in anhydrous toluene (100 ml). The mixture was heated under reflux for 1.5 hours then allowed to cool to 50° whereupon a solution of 2-(N-benzyl-N-methylamino)-4-chloro-2-methylbutane (11.3 g-see Preparation 11) in anhydrous toluene (20 ml) was added and the mixture heated under reflux for 3 hours. The mixture was partitioned between toluene (200 ml) and 10% aqueous sodium hydroxide (100 ml), the layers separated and the toluene layer washed with water (100 ml). The toluene solution was dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing toluene (50% up to 100%) and then with toluene containing ethyl acetate (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a straw coloured oil, yield 14.5 g.
Reaction SMILES: I.[NH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[C:13]3=[N:20][O:21][C:22]([CH3:23])=[C:12]3[C:11]2=[O:24])[CH2:5]1.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:23][C:22]1[O:21][N:20]=[C:13]2[C:14]3[C:19](=[N:18][CH:17]=[CH:16][CH:15]=3)[N:10]([CH:6]3[CH2:7][CH2:8][CH2:9][CH:4]([CH2:3][NH:2][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:5]3)[C:11](=[O:24])[C:12]=12
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CN)C1)c1ncccc21
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1ncccc21
Yield: 75.2 %

Procedure:
Combine 5-(3-aminomethyl-cyclohexyl)-3-methyl-5H-2-oxa-1,5,6-triaza-cyclopenta[a]naphthalen-4-one hydroiodide (100 mg, 0.23 mmol) with benzoic acid (28 mg, 0.23 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol), 1-hydroxy-7-azabenzo-triazole (31 mg, 0.23 mmol), and N,N-diisopropylethyl amine (0.12 mL, 0.69 mmol), in N,N-dimethylformamide (4 mL) and stir over a weekend at ambient temperature. Concentrate in vacuo and take up in water and extract with ethyl acetate. Dry over sodium sulfate and concentrate in vacuo. Eluted over silica gel using methanol/dichloromethane to give 72 mg (75%) of the desired amide as an off white solid. MS(ES): (M+1)+ 417.2, 418.2 m/z.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:19][C:16]2[CH:15]=[CH:14][C:13]([S:10]([CH3:9])(=[O:12])=[O:11])=[CH:18][CH:17]=2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)cn2)cc1
Temperature: 170 °C

Procedure:
2,5-dichloropyridine (1.48 g; 10 mmol), 4-methylsulfonylphenol (1.89 g; 11 mmol) and Cs2CO3 (4.24 g; 13 mmol) was slurried in 75 mL of NMP. The slurry was heated to approx 170° C. over night. After cooling the Cs2CO3 was filtered off and the solvent was extracted between H2O and EtOAc. The organic phase was dried over Na2SO4 and evaporated. Heptane:EtOAc 2:1 was added to the residue and the crystals was filtered off. 1.42 g (50%).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21](Cl)=[O:22].Cl>O.CC(C)=O>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)=[O:22]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O)c1c(Cl)cccc1Cl
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To 13 mL of acetone, there were added 10.04 g of p-nitro-L-phenylalanine and 28 mL of water to thus form a suspension and the latter was cooled in an ice-bath. To this suspension, there were alternatively dropwise added 18.4 mL of a 6M sodium hydroxide solution and 10.05 g of 2,6-dichlorobenzoyl chloride in such a manner that the pH value of the suspension was maintained at a level of not less than 13 at a temperature of not more than 15° C. After the completion of the dropwise addition, the suspension was further stirred for 2 hours with cooling in an ice-bath, then the progress of the reaction was confirmed by HPLC and 36 mL of a 2M hydrochloric acid solution was dropwise added while taking care to prevent any excess generation of heat. The suspension containing separated solid matter was stirred at 10° C. overnight, the precipitates were isolated through filtration and then dried under reduced pressure at 60° C. to thus obtain 17.32 g of the title compound as a white crystalline solid (yield: 95%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(Cl)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 10.0 g (42.9 mmol)) 4-chloro-6-nitro-3-quinolinecarbonitrile, 260 ml ethanol, and 5.40 ml 3-chloroaniline was heated to reflux under N2. Removed heat at 4 hours, cooled to 25° C. and added saturated sodium bicarbonate until the pH was basic. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solid, and air dried. Washed solids with water and dried in vacuo. Dissolved in boiling ethyl acetate, stirred with Darco, and filtered. Stripped solvent and dried residue in vacuo, giving 6.5 g of yellow solid: mass spectrum (electrospray m/e): M+H=325.0, 327.0.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]CC)=O)[N:6]=1.Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH:32][C:10]([C:7]1[N:6]=[C:5]([CH2:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[CH3:1])[O:9][N:8]=1)=[O:12]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1noc(Cc2ccccc2C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccccc1Cc1nc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)no1
Yield: 35.1 %

Procedure:
This compound was prepared according to method F with ethyl 5-(2-methylbenzyl)-1,2,4-oxadiazole-3-carboxylate (0.106 g; 0.433 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.186 mL; 1.08 mmol), in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.060 g (35%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[CH2:36](O)[CH2:37][CH2:38][OH:39]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[O:39]1[C:32]2([CH2:31][CH2:30][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[O:35][CH2:36][CH2:37][CH2:38]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCCO3)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.5 g), propane-1,3-diol (0.12 g), p-toluenesulfonic acid monohydrate (0.01 g) and toluene (15 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 16 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.56 g, 100%).
Reaction SMILES: [OH:1][C:2]1[C:3]([F:17])=[C:4]([C:13]([NH:15][CH3:16])=[O:14])[C:5](=[C:9]([F:12])[C:10]=1[F:11])[C:6](O)=[O:7].OC1C(F)=C(C=C(F)C=1F)C(N)=O>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([F:17])=[C:4]2[C:13](=[O:14])[N:15]([CH3:16])[C:6](=[O:7])[C:5]2=[C:9]([F:12])[C:10]=1[F:11]
Reactant: CNC(=O)c1c(F)c(O)c(F)c(F)c1C(=O)O
Agent: NC(=O)c1cc(F)c(F)c(O)c1F
Solvent: Cc1ccccc1
Product: CN1C(=O)c2c(F)c(O)c(F)c(F)c2C1=O

Procedure:
Mixed together were 48 g of a mixture of 4-hydroxy-3,5,6-trifluoro-N-methylphthalamic acid and 3-hydroxy-2,4,5-trifluorobenzamide (preparation given in Example 1 of U.S. Pat. No. 5,233,082) and 200 mL of toluene. The mixture was heated to reflux and water was collected in a Barret trap. After all the water had been collected, the mixture was cooled and the toluene evaporated under vacuum. A total of 40.88 g of solids were collected. This material was assayed as 75% 4-hydroxy-3,5,6-trifluoro-N-methylphthalimide and 11% 3-hydroxy-2,4,5-trifluoro-N-methylbenzamide. For the N-methylphthalimide: 19F nuclear magnetic resonance (NMR) (ppm acetone d6): -136.9 (m) , -141.5 (m) , -147.8 (m) .