Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br-].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[CH2:16][Zn+].Cl>C1COCC1.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>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[CH2:16][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Fc1cccc(F)c1C[Zn+]
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2c(F)cccc2F)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 58.5 %

Procedure:
Methyl 2-chloroisonicotinate (5.600 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved in THF (100 mL) under nitrogen and (2,6-difluorobenzyl)zinc(II) bromide (0.5 M in THF, 100 mL, 50.00 mmol) was added and the resulting solution was stirred at 60° C. for 4 h before it was cooled to room temperature and quenched with methanol (50.0 mL). The mixture was diluted with EtOAc and washed with satd NH4Cl. The organic phase was dried with MgSO4, filtered and evaporated. The crude product was dissolved in MTBE (200 mL), solids were filtered off, and HCl (4 M in dioxane, 8.16 mL, 32.64 mmol) was added dropwise. The mixture was stirred for 10 minutes before the precipitate was filtered off, washed with MTBE and dissolved in MTBE/satd NaHCO3. The organic layer was dried with MgSO4, filtered and evaporated to give methyl 2-(2,6-difluorobenzyl)isonicotinate (5.03 g, 58.6%) as a white solid. 1H NMR (400 MHz, cdcl3) δ 3.92 (s, 3H), 4.29 (s, 2H), 6.87-6.97 (m, 2H), 7.18-7.29 (m, 1H), 7.61-7.73 (m, 2H), 8.63-8.70 (m, 1H). MS m/z 264 (M+H)+
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=1.[OH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C1COCC1>>[CH:21]([C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][N:11]=[C:2]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1cccc(Nc2c(C#N)cnc3cnc(F)cc23)c1
Reactant: OCCN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)c1cccc(Nc2c(C#N)cnc3cnc(OCCN4CCOCC4)cc23)c1
Yield: 66 %

Procedure:
To 6-fluoro-4-[(3-isopropylphenyl)amino]-1,7-naphthyridine-3-carbonitrile (0.050 g, 0.16 mmol) was added a 1 M solution of freshly prepared alkoxide of N-(2-hydroxyethyl)morpholine in THF (1.88 mL, 1.88 mmol). The reaction was heated to reflux for 2 hours. The solvent was evaporated and water was added. Diethyl ehter and methylene chloride was added and crystals formed. The product was collected by filtration to give a yellow solid (0.044 g, 66%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (d, J=6.8 Hz, 6 H) 2.5 (m, 2 H) 2.7 (t, J=5.8 Hz, 2 H) 2.9 (m, 1 H) 3.3 (m, 2 H) 3.6 (m, 4 H) 4.5 (t, J=5.8 Hz, 2 H) 7.1 (m, 3 H) 7.3 (t, J=8.7 Hz, 1 H) 7.8 (s, 1 H) 8.4 (s, 1 H) 9.0 (s, 1 H) 9.9 (s, 1 H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[I:17])[C:10]([O:12][CH3:13])=[O:11].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:2]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[I:17])[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCI
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCOc1cc(C(=O)OC)ccc1I
Temperature: 60 °C
Yield: 49.5 %

Procedure:
14.7 ml (130 mmol) of iodobutane is added to a solution of 30 g (110 mmol) of methyl 3-hydroxy-4-iodobenzoate and 17.9 g (130 mmol) of potassium carbonate in 300 ml of 2-butanone. The reaction mixture is heated at 60° C. for 16 hours. After adding 100 ml of water and then extraction with ethyl acetate, the organic phases are combined, dried over sodium sulfate, and filtered. The solvents are evaporated and then the residue is taken up in heptane and filtered. 18.2 g of methyl 3-butoxy-4-iodobenzoate is obtained in the form of white crystals. The filtrate is concentrated and the residue is purified by silica column chromatography, eluted with a heptane/ethyl acetate mixture 8/2, obtaining 11.6 g of methyl 3-butoxy-4-iodobenzoate. 29.8 g (82%) of methyl 3-butoxy-4-iodobenzoate is thus obtained.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:12][CH2:11]1)(C)(C)C>O1CCOCC1.ClCCl>[NH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(NC(=O)c2cccc3ccccc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCC1CCC(NC(=O)c2cccc3ccccc23)CC1
Reaction time: 8 h

Procedure:
HCl in dioxane (10 mL, 4 N) was added to a solution of tert-butyl[4-(1-naphthoyl-amino)cyclohexyl]methylcarbamate (0.350 g) in dichloromethane (20 mL), stirred overnight, concentrated in vacuo, giving the desired product: 1H NMR δ 8.24 (dd, 1 H, J=1.2, 8.7 Hz), 7.85 (dt, 2 H, J=2.7, 9.7 Hz), 7.60-7.30 (m, 4 H), 5.98 (m, 1 H), 4.02 (m, 1 H), 3.80-3.40 (m, 4 H), 2.53 (d, 2 H, J=6.0 Hz), 2.02 (ABq, 4 H), 1.41-1.90 (m, 4 H).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:22])[NH:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][NH2:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.[C:30]([CH:38]=[C:39](Cl)[CH3:40])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][CH:32]=1.[Na].C(CC(=O)C)(=O)C1C=CC=NC=1.Cl.S(Cl)(Cl)=O.Cl.C(C(C)=CCl)(=O)C1C=CC=NC=1>C1(C)C=CC=CC=1>[C:30]([CH:38]=[C:39]([NH:18][CH2:17][CH:16]([OH:19])[CH2:15][O:14][C:13]1[CH:20]=[CH:21][C:10]([NH:9][C:8]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:22])=[CH:11][CH:12]=1)[CH3:40])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][CH:32]=1
Reactant: NCC(O)COc1ccc(NC(=O)NC2CCCCC2)cc1
Reactant: CC(Cl)=CC(=O)c1cccnc1
Agent: CC(=CCl)C(=O)c1cccnc1
Agent: CC(=O)CC(=O)c1cccnc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=CC(=O)c1cccnc1)NCC(O)COc1ccc(NC(=O)NC2CCCCC2)cc1
Reaction time: 36 h

Procedure:
6.1 g of 1-(p-cyclohexylureido-phenoxy)-3-amino-propan-2-ol ##STR49## are dissolved in 50 ml of anhydrous toluene and 5.7 g of anhydrous potassium carbonate are added. A mixture of 4.4 g of 2-nicotinoyl-1-methylvinyl chloride hydrochloride of the formula ##STR50## (prepared from the sodium salt of nicotinoyl-acetone, which is first converted by means of HCl gas into the hydrochloride of free nicotinoyl-acetone and then, using thionyl chloride, into nicotinoyl-methylvinyl chloride hydrochloride) in 50 ml of anhydrous toluene is added slowly, with cooling and stirring, to this mixture and stirring is subsequently continued for 36 hours at room temperature. The product is then filtered and the residue is dissolved in water and the solution is rendered alkaline by means of sodium carbonate and extracted three times with chloroform. The chloroform extracts are concentrated, together with the original toluene filtrate, in vacuo at approx. 14 to 20 mm Hg. 1-(2-Nicotinoyl-1-methylvinylamino)-3-(p-cylcohexylureidophenoxy)-propan-2-ol is thus obtained after repeated recrystallisation from aqueous ethanol. ##STR51## Melting point: 168° C Analysis: (C25H32N4O4)
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:32]=[C:31]([NH2:33])[NH:30][N:29]=2)=[CH:24][CH:23]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:32]=[C:31]([NH:33][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=3)[NH:30][N:29]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Reactant: Nc1cc(-c2ccc(Cl)cc2)n[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCNc2cc(-c3ccc(Cl)cc3)n[nH]2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid synthesized in Example 3 and 3-(4-chlorophenyl)-1H-pyrazole-5-amine as starting materials and by operations similar to those of Example 242-1 and Example 242-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (The objective compound was extracted in the saturated aqueous sodium hydrogen carbonate solution layer). Aqueous 10% citric acid solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]([CH:19]([C:33]3[CH:38]=[CH:37][C:36]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:35][CH:34]=3)[C:20](=[O:32])NCC(OC(OC)=O)(CC)C)[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1.CC(C)([O-])C.[K+]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:19]([C:33]4[CH:34]=[CH:35][C:36]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[CH:37][CH:38]=4)[C:20](=[O:32])[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]3=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)CC(=O)N(c1ccc2[nH]cnc2c1)C(C(=O)NCC(C)(CC)OC(=O)OC)c1ccc(N2CCOCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)C1C(=O)C(c2ccc(N3CCOCC3)cc2)N(c2ccc3[nH]cnc3c2)C1=O

Procedure:
The compound was synthesized starting from ethyl 2-[(1H-benzo[d]imidazol-5-yl)({[4-(morpholin-4-yl)phenyl]({2-[(methoxycarbonyl)oxy]-2-ethylpropyl}carbamoyl)methyl})-carbamoyl]acetate (which may be prepared in accordance with the procedure described for Intermediate 4; 0.38 g, 0.638 mmol) and potassium tert.-butoxide solution (1M, 1.276 ml, 1.276 mmol) according to the method described in Step 2.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH2:26])[C:21]1[O:25][CH:24]=[CH:23][CH:22]=1>>[O:25]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:20][NH:26][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Reactant: NCc1ccco1
Product: O=C(Nc1nc2cccc(NCc3ccco3)n2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and furfurylamine (1.0 mL) as a beige powder (31 mg, 51%). HPLC, Rt: 2.20 min. (purity 94.1%). LC/MS, M+(ESI): 334.1, M−(ESI): 332.1.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[OH:9].[OH-].[Na+].Cl[CH2:13]Cl.O>CS(C)=O.C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]2[O:9][CH2:13][O:5][C:4]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(O)c1O
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: Cc1cccc2c1OCO2
Temperature: 120 °C

Procedure:
To a stirred solution of 11.00 g of 3-methylcatechol and 7.09 g of sodium hydroxide in 10 mL of dry dimethylsulfoxide is added 6.34 mL of dichloromethane. A reflux condenser is attached and the mixture heated in an oil bath to 120° C. for 30 minutes. The mixture is allowed to cool to room temperature and then is distributed between 50 mL of water and 200 mL of chloroform. The chloroform layer is dried over magnesium sulfate and concentrated under reduced pressure to yield a red liquid, which is purified by chromatography on silica gel to afford 3.0 g of 4-methyl-1,3-benzodioxole as a light yellow liquid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3([CH2:15][OH:16])[CH2:14][CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3([CH2:15][O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:14][CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: OCC1(Nc2ccc3[nH]ncc3c2)CCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(Nc2ccc3[nH]ncc3c2)CCC1
Yield: 139.5 %

Procedure:
To a stirred suspension of [1-(1H-indazol-5-ylamino)-cyclobutyl]-methanol (0.690 g, 3.18 mmol) in DCM (100 mL) at ambient temperature and under nitrogen was added Et3N (2.66 mL, 19.1 mmol) followed by methanesulfonyl chloride (0.74 mL, 9.54 mmol). After 5 minutes the mixture was washed with saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered and concentrated in vacuo to give methanesulfonic acid 1-(1H-indazol-5-ylamino)-cyclobutylmethyl ester (1.31 g) as a gum that was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[NH:4][C:5]([CH3:10])=[C:6]([CH2:8][CH3:9])[CH:7]=1.Cl[CH2:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.C(N(CC)CC)C>C(O)C>[S:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[CH2:13][NH:1][C:2]1[C:3](=[O:11])[NH:4][C:5]([CH3:10])=[C:6]([CH2:8][CH3:9])[CH:7]=1
Reactant: CCc1cc(N)c(=O)[nH]c1C
Reactant: ClCc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1cc(NCc2nc3ccccc3s2)c(=O)[nH]c1C
Yield: 77.8 %

Procedure:
A solution of 3-amino-5-ethyl-6-methyl-2-(1H)-pyridinone (152 mg, 1.0 mmol), 2-chloromethyl-1,3-benzthiazole (184 mg, 1.0 mmol) and triethylamine (0.14 mL, 1.0 mmol) in absolute ethanol (5 mL) was stirred at reflux for 24 hours. After filtering and concentrating under reduced pressure, the residue was flash chromatographed over silica gel. Elution with 4% MeOH- 96% CHCl3 gave 233 mg of product. Recrystallization from EtOH-water gave 77 mg of analytically pure product, mp 209°-210° C. Anal. Calcd for C16H17N3OS: C, 67.83; H, 6.05; N, 14.83. Found: C, 67.71; H, 6.03; N, 14.70.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:31][CH2:32]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: O=C(CCCCCl)c1ccccc1Cl
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccccc1Cl

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(2-chlorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 439.1 (M+H)+.
Reaction SMILES: NCCN[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH2:26]>>[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH:26][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6]
Reactant: COC(=O)CN
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Product: COC(=O)CNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using amino-acetic acid methyl ester instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 331 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (1H, br. s.) 10.22 (1H, s) 8.54 (1H, t, J=5.76 Hz) 8.04 (1H, d, J=5.42 Hz) 7.83 (1H, d, J=5.42 Hz) 7.51 (1H, d, J=5.47 Hz) 7.32 (1H, dd, J=3.49, 2.37 Hz) 6.86 (1H, d, J=5.47 Hz) 6.41 (1H, dd, J=3.54, 1.83 Hz) 4.00 (2H, d, J=5.81 Hz) 3.66 (3H, d, J=0.10 Hz)
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](=[O:27])[C:18]([CH3:26])([CH3:25])[C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][C:10]=1[O:28][CH3:29])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](=[O:27])[C:18]([CH3:26])([CH3:25])[C:19](=[O:24])[C:20]([CH3:23])([CH3:21])[CH3:22])=[CH:11][C:10]=1[O:28][CH3:29]
Reactant: COc1cc(/C=C/C(=O)C(C)(C)C(=O)C(C)(C)C)ccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(/C=C/C(=O)C(C)(C)C(=O)C(C)(C)C)ccc1O
Temperature: 25 °C
Yield: 91.6 %

Procedure:
(E)-1-(4-tert-butyldimethylsilyloxy-3-methoxyphenyl)-4,4,6,6-tetramethylhept-1-ene-3,5-dione (266 mg, 0.635 mmol) was dissolved in anhydrous THF (10 ml) and stirred at room temperature under a nitrogen atmosphere. TBAF (0.22 ml, 0.76 mmol) was added (yellow/green solution goes deep red colour) and the mixture was stirred overnight at room temperature. After this time the solvents were removed under vacuum to leave a residue which was purified by column chromatography on silica using dichloromethane/diethyl ether (1:0 to 10:1) to give (E)-1-(4-hydroxy-3-methoxyphenyl)-4,4,6,6-tetramethylhept-1-ene-3,5-dione (177 mg, 92%) as a dark yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.19 (9H, s, C(CH3)3), 1.42 (6H, s, 2×C(CH3)), 3.93 (3H, s, OCH3), 6.03 (1H, brs, phenol OH), 6.54 (1H, d, J=15.6 Hz, vinyl CH), 6.92 (1H, d, J=8.0 Hz, ArH), 6.99 (1H, d, J=2.0 Hz, ArH), 7.12 (1H, dd, J=8.0, 2.0 Hz, ArH), 7.66 (1H, d, J=15.6 Hz, vinyl CH) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:24]1[C:29]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:28][C:27]([NH2:41])=[C:26]([N+:42]([O-:44])=[O:43])[CH:25]=1>C(COC)OC>[NH2:41][C:27]1[C:26]([N+:42]([O-:44])=[O:43])=[CH:25][C:24]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=2)=[C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=2)[CH:28]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CS(=O)(=O)c1ccc(Oc2cc(N)c([N+](=O)[O-])cc2Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1cc([N+](=O)[O-])c(N)cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
7.9 g of 1-(t-butoxycarbonyl)pyrrole-2-boronic acid, 1.8 g of dichlorobistriphenylphosphine palladium, 50 ml of aqueous saturated sodium carbonate solution and 50 ml of water were added in order to a dimethoxyethane (100 ml) solution of 10.3 g of 4-bromo-5-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine, and the reaction liquid was stirred in a nitrogen atmosphere at 80° C. for 1 hour. After cooled, the reaction liquid was filtered through Celite, the filtrate was diluted with ethyl acetate, washed with water and saturated saline in order, and then dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound as a brown oily substance.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH:14]=2)[NH2:11])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=2)[N:26]=[CH:25][CH:24]=1.Cl>C(O)C>[N:1]1([C:6]([C:8]2[CH:9]=[C:10]([NH:11][C:23]3[C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[N:26]=[CH:25][CH:24]=3)[CH:12]=[C:13]([C:15]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)=[O:16])[CH:14]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cc(C(=O)N2CCCC2)cc(C(=O)N2CCCC2)c1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CCO
Product: O=C(c1cc(Nc2ccnc3cc(Cl)ccc23)cc(C(=O)N2CCCC2)c1)N1CCCC1
Yield: 646.1 %

Procedure:
3,5-Bis[(pyrrolidin-1-yl)carbonyl]aniline (287 mg, 1.0 mmol) and 4,7-dichloroquinoline (198 mg, 1 eq) were refluxed in 20 mL of ethanol and 2 mL of HCl 1M for 12 h. The reaction mixture was then evaporated. The residue was purified by flash chromatography (DCM/MeOH//9/1) to yield expected compound as a yellow powder (2.90 g, 78% yield). m/z (ESI) 449.1 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][CH2:8][C:9]1[N:13](CC2C=CC(OC)=CC=2)[C:12]([SH:23])=[N:11][N:10]=1)=[O:5])C.C(OC(COCC(NN)=O)=O)C.[OH-].[Na+]>>[C:4]([CH2:6][O:7][CH2:8][C:9]1[N:13]=[C:12]([SH:23])[NH:11][N:10]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)COCc1nnc(S)n1Cc1ccc(OC)cc1
Agent: CCOC(=O)COCC(=O)NN
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)COCc1n[nH]c(S)n1

Procedure:
By employing a procedure similar to that described in Example XVI, Part A, 3-(ethoxycarbonylmethoxymethyl)-4(p-methoxybenzyl)-1,2,4-triazole-5-thiol was prepared from ethoxycarbonylmethoxyacetohydrazide. The ethoxycarbonyl group was then hydrolyzed to the free acid using aqueous 2N sodium hydroxide, and the p-methoxybenzyl blocking group was thereafter removed by using trifluoroacetic acid in a manner similar to that earlier described in Example XVI, Part B to finally give pure 3-(carboxymethoxymethyl)-1,2,4-triazole-5-thiol, m.p. 180°-182° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])=[N:5][CH:4]=[C:3]1[C:18]([O:20]CC)=[O:19].Cl.C(O)C>[OH-].[Na+]>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])=[N:5][CH:4]=[C:3]1[C:18]([OH:20])=[O:19]
Reactant: CCCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1ccccc1-c1ncc(C(=O)O)c(=O)[nH]1
Yield: 97.3 %

Procedure:
A solution of ethyl 1,6-dihydro-6-oxo-2-(2-n-propoxyphenyl)pyrimidine-5-carboxylate (3.02 g., 0.01 mole) in 1N sodium hydroxide (22 ml.) was heated on a steam bath for 20 minutes. The cooled solution was treated with 1N hydrochloric acid (23 ml.). The precipitated 1,6-dihydro-6-oxo-2-(2-n-propoxyphenyl)pyrimidine-5-carboxylic acid (2.67 g., 97.4% yield), m.p. 203°-206°, was recrystallized from ethanol to give product with m.p. 205.5°-207.5°.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:12])[CH2:9][CH2:10][S:11][C:6]=2[C:5]([CH3:13])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br.Cl>C(Cl)Cl.O>[Br:18][C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[S:11][CH2:10][CH2:9][C:8](=[O:12])[C:7]=2[C:2]=1[CH3:1]
Reactant: Cc1ccc(C)c2c1SCCC2=O
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Br)c(C)c2c1SCCC2=O
Reaction time: 0.25 h
Yield: 46 %

Procedure:
A solution of 4.07 g (0.021 mol) of the title compound of Step B in 25 mL of methylene chloride was added dropwise to a mixture of 7.07 g (0.053 mol) of aluminum chloride (purchased from Aldrich Chemical Company) and 25 mL of methylene chloride. The suspension was stirred for approximately 15 minutes, 1.14 mL (0.022 mol) of bromine (purchased from Janssen) was added dropwise and the mixture was refluxed for 10 minutes. The hot mixture was poured into 10 mL of concentrated hydrochloric acid containing 75 g of ice, stirred for 10 minutes, diluted with 50 mL of water, and extracted with diethyl ether (2×200 mL). The organic layer was washed with water (2×200 mL), dried (Na2SO4), filtered and evaporated to dryness. The crude product was chromatographed over silica gel eluting with ethyl acetate:hexane (5% 95%) to yield 2.62 g of the title compound of Step C as a solid melting at 87-88° C. 1H NMR (CDCl3): δ2.3 (s,3H), 2.6 (s,3H), 3.0 (m,2H), 3.2 (m,2H), 7.45 (s,1H).