Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[C:21]([N:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.6 %

Procedure:
Commercially available ethyl nipecotate (1.48 ml; 9.53 mmol) was dissolved in dichloromethane (20 ml), and diisopropylethylamine (1.82 ml; 10.45 mmol) was added. Benzoyl chloride (1.1 ml; 9.53 mmol) was then added slowly to control any rise in reaction temperature. After addition was complete the mixture was allowed to stir at ambient temperature for approximately 1-4 hours. The mixture was then diluted with fresh dichloromethane and washed with 1 N HCl. The dichloromethane solution was dried with anhydrous potassium carbonate and evaporated at ambient temperature under reduced pressure. The crude material was purified by high-vacuum distillation at approximately 200° C./0.1 torr giving ethyl 1-benzoyl-3-piperidinecarboxylate (2.38 g) as a colorless oil. (The temperatures given for distillations in these examples are oven temperatures and represent approximations. Similarly, the vacuum levels given for distillations are also approximates.) MS m/z (positive ion) 545 (dimer+; 25), 284 (M+Na+; 90), 262 (MH+; 100), 216 (25).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]Br)=[C:8]([Cl:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:16].[Ca+2].O1CCOCC1.O.Cl>O1CCOCC1>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][OH:16])=[C:8]([Cl:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(CBr)c1=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)n1ncc(Cl)c(CO)c1=O

Procedure:
2-tert-butyl-4-bromomethyl-5-chloro 3(2H)-pyridazinone (2 g, 7.19 mmol) and calcium carbonate (3.5 gm) are added to a 1:1 mixture of dioxane-water (40 ml). The mixture is refluxed for 6 hours after which 30 ml of 3N HCl solution is added to it. The solution is stirred for 10 minutes after which dioxane is removed under reduced pressure. The resulting solution is then extracted with dichloromethane and the dichloromethane layer is washed and dried. The crude obtained after concentration is purified by flash chromatography (ethyl acetate/hexanes: 1:2).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11]O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.C1(C)C=CC(S([Cl:29])(=O)=O)=CC=1>C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][Cl:29])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)N1CCN(CCO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(CCCl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
2-(4-Acetylpiperazin-1-yl)ethanol (500 mg, 2.90 mmol), (prepared as described for the starting material in this example hereinbefore), was dissolved in methylene chloride (10 ml) and triethylamine (445 μl, 3.19 mmol) and 4-toluenesulphonyl chloride (609 mg, 3.19 mmol) were added and the mixture was stirred at ambient temperature overnight. The mixture was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (98/2) to give 1-acetyl-4-(2-chloroethyl)piperazine (300 mg, 54%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([CH3:12])([CH3:11])[CH2:6][CH2:7][C:8](Cl)=[O:9])=[O:4].[CH2:13]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH3:16].CCN(C(C)C)C(C)C>C(OCC)(=O)C>[CH2:13]([N:17]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:21][CH:20]=1)[C:8](=[O:9])[CH2:7][CH2:6][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH3:12])[CH3:11])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCNCc1ccc(-c2ccccc2C#N)cc1
Reactant: COC(=O)C(C)(C)CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CCC(C)(C)C(=O)OC
Reaction time: 1 h

Procedure:
The starting material can be prepared, for example, as follows: A solution of 3.3 g (17 mmol) of 4-methoxycarbonyl-4-methyl-pentanoic acid chloride in 20 ml of ethyl acetate is added dropwise at from 0° to 5° to a solution of 3.0 g (11.3 mmol) of N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amine and 6.5 ml of Hunig base in 50 ml of ethyl acetate. The reaction mixture is stirred for 1 hour and then worked up analogously to Example 1 b) to yield 4-methoxycarbonyl-4-methyl-pentanoic acid N-butyl-N-(2'-cyano-biphenyl-4-ylmethyl)-amide in the form of an oil that has an Rf value of 0.27 [toluene/methanol (19:1)] and is further used in crude form.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1COCC1>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)c2ccc(F)cc2)CCN(C)C1
Reactant: Br[Mg]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(O)(c2ccccc2)c2ccc(F)cc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanone (168 mg, 0.5 mmol) was dissolved in 10 mL of anhydrous THF. Phenyl magnesium bromide (1.5 mL, 1.5 mmol) was added to it dropwise at RT under nitrogen atmosphere. The reaction mixture was stirred at RT for 1 h. Water (3 mL) was added and the product extracted with EtOAc. The combined organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:11]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:13]=2)[CH:10]=1.[Cl-].[NH4+]>C(O)C.O>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]3[N:9]([N:11]=[C:12]([NH:14][C:15]([CH:17]4[CH2:19][CH2:18]4)=[O:16])[N:13]=3)[CH:10]=2)=[C:2]([F:1])[CH:23]=1
Reactant: O=C(Nc1nc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cn2n1)C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c(F)c1
Yield: 34.1 %

Procedure:
A solution of N-[6-(2-fluoro-4-nitrophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (400 mg, 1.12 mmol), reduced iron (312 mg, 5.59 mmol) and ammonium chloride (600 mg, 11.2 mmol) in ethanol (8 mL) and water (2 mL) was heated under reflux for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate was diluted with water and ethyl acetate and extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2→ethyl acetate/methanol=9/1) to give the title compound (125 mg, 34%) as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([O:36]C(=O)C3C=CC=C(Cl)C=3)=[CH:29][C:28]=2[CH:46]([CH3:48])[CH3:47])=[O:25])[C:6]1=[O:49])[CH2:2][CH2:3][CH3:4].C[O-].[Na+].O>CO>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([OH:36])=[CH:29][C:28]=2[CH:46]([CH3:48])[CH3:47])=[O:25])[C:6]1=[O:49])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(OC(=O)c3cccc(Cl)c3)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(O)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2,6-diisopropyl-4-(3-chlorobenzoyloxy)-phenyl]urea (1.0 g, 1.6 mmol) in methanol (30 ml) is added dropwise a 28% sodium methoxide (0.45 ml, 1.76 mmol) at room temperature, and the mixture is stirred at the same temperature for one hour. To the mixture is added water, and the mixture is extracted with ethyl acetate. The extract is washed with an aqueous ammonium chloride solution and a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (1% methanol/chloroform→2% methanol/chloroform) to give the title compound (0.79 g, 1.45 mmol) as amorphous.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1>CO>[CH3:1][O:2][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: C[O-]
Reactant: O=C(O)Cc1cccc(CBr)c1
Agent: [Na+]
Solvent: CO
Product: COCc1cccc(CC(=O)O)c1
Yield: 99.2 %

Procedure:
Under an atmosphere of argon gas, to sodium methoxide (160 g), methanol (800 ml) was added with stirring. Thereto, a solution of 3-bromomethylphenylacetic acid (226 g; prepared in Reference Example 18) in methanol (3200 ml) was added. The mixture was refluxed for 20 minutes. After the temperature of mixture became to room temperature, methanol was distilled off. The residue was poured into 2N HCl. Thereto, ethyl acetate was added. The organic layer was washed by an aqueous saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (176.3 g).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[O:36][CH:35]=[N:34][C:33]=2[C:37](O)=[O:38])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:37]([C:33]2[N:34]=[CH:35][O:36][C:32]=2[CH:29]2[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]2)=[O:38])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ocnc2C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ocnc2C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 0.30 g, 1.03 mmol), 5-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-oxazole-4-carboxylic acid (Reference Example 16, 0.33 g, 1.13 mmol), triethylamine (0.23 g, 2.26 mmol), EDCI (0.22 g, 1.13 mmol) and HOBt (0.17 g, 1.13 mmol) in acetonitrile (10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 10% sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 to 50:50) to give the title compound (0.47 g, 92%) as a white amorphous powder.
Reaction SMILES: S(=O)(=O)(O)O.CSC.CO.[C:11](O)(C)(C)C.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>>[C:17]1([C:16]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:23][CH2:11]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CSC
Product: c1ccc(C2(c3ccccc3)CO2)cc1
Reaction time: 2 h

Procedure:
Sulphuric acid (23.7 g at 98%, 0.237 moles) was added dropwise, with stirring, to dimethylsulphide (20.0 g at 98%, 0.316 moles) over 60 minutes, maintaining the temperature below 26° C. Methanol (5.0 g, 0.156 mole) was added slowly to the stirred mixture maintaining the temperature below 31° C. The reaction mixture was stirred for 41/2 hours and head overnight unagitated at room temperature. Tertiary butanol (3.6 g, 0.048 mole) and benzophenone (27.4 g, 0.15 mole) were added to the reaction mixture. Potassium hydroxide flake (43.4 g, 0.73 mole) was added in 10 equal aliquots over 3 hours while maintaining the temperature below 40° C. The reaction was monitored by GC and then stirred overnight at room temperature.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(Br)ccc1N
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-methylaniline (3.55 g) in pyridine (95 mL) was added benzoyl chloride (2.66 mL). The mixture was stirred at room temperature for 1 hr and the solvent was evaporated under reduced pressure. To the residue was added 2N hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (4.35 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N:16]1([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)c1cccc(OCCBr)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cccc(OCCN2CCOCC2)c1
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-[(2-bromoethyl)oxy]benzoate D46 (100 mg), morpholine (44.7 mg, 0.513 mmol) in Acetonitrile (2 mL) stirred under nitrogen at 25° C. was added K2CO3 (106 mg, 0.769 mmol). The reaction mixture was stirred at 60° overnight. The mixture was filtered and the filtrate was concentrated in vacuo to give 98 mg of the crude product D47 without more purification. LCMS Retention time=1.57 mins, [M+H]+280 (5 min run)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[C:24](C(F)(F)F)[C:22]=5[N:23]=4)[C:15]([NH2:18])=[N:16][CH:17]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.ClC1SC2C=C([O:42][C:43]([F:46])([F:45])[F:44])C=CC=2N=1>>[NH:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:42][C:43]([F:46])([F:45])[F:44])[CH:25]=[CH:24][C:22]=5[N:23]=4)[C:15]([NH2:18])=[N:16][CH:17]=3)[CH:9]=[N:8]2)[CH2:5][CH2:6]1
Reactant: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)cccc2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(OC(F)(F)F)cc2s1

Procedure:
Following the procedure for 5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-3-(4-trifluoromethylbenzothiazol-2-yl)-pyridin-2-ylamine, but using 2-chloro-6-trifluoromethoxy-1,3-benzothiazole, the title compound was obtained as yellow solid. MS (ES+): m/z=461.08 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>C(#N)C.O>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 80 °C
Yield: 118.2 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (10 g, 0.05 mol) in acetonitrile (150 mL) were added K2CO3(23 g, 0.16 mol) and 2-(chloromethyl) quinoline (14.2 g, 0.06 mol) under an inert atmosphere. The reaction mixture was then heated at 80° C. for 16 h, diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (19 g, 95%) as an oil.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH:19]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=2[CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[CH2:21][CH2:20][N:19]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Oc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(O)cccc21
Yield: 57.6 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 270 mg of 2,3-dihydro-1H-indol-4-ol, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of N,N-dimethylformamide. 205 mg of 2-[2-(4-hydroxy-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink solid, the characteristics of which are the following:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C:23]#[N:24])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C:23]#[N:24])[CH2:17][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: N#CCC[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#CCC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.087 g, 0.41 mmol), 3-(trans-4-aminocyclohexyl)propanenitrile (0.080 g, 0.52 mmol) TFA salt and N,N-diisopropylethylamine (0.35 mL, 2.0 mmol) in isopropyl alcohol (0.89 mL) was heated at 90° C. for 2 h. The resulting mixture was concentrated and purified on silica gel (eluting with 0 to 20% EtOAc in dichloromethane) to give the desired product (63 mg, 47%). LCMS calculated for C16H19N4O2S (M+H)+: m/z=331.1. Found: 331.0.
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:6][C:7]1[C:8](=[O:20])[O:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-])=O)=[CH:12][CH:11]=2)(=[O:5])[CH3:4]>O.CO.[Pd]>[C:3]([NH:6][C:7]1[C:8](=[O:20])[O:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([NH2:17])=[CH:12][CH:11]=2)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1cc2cc([N+](=O)[O-])ccc2oc1=O
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1cc2cc(N)ccc2oc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
Palladium 10 wt % on activated carbon (0.322 g, 1/10th the mass of 1) was placed in a 1-L round-bottom flask and the flask was purged with nitrogen. A solution of sodium borohydride (1.21 g, 32.9 mmol) in 22.6 mL water was added drop-wise. A suspension of compound 1 (3.20 g, 12.9 mmol) in methanol (775 mL) was then added over a two hour period and allowed to stir at room temperature an additional 30 min, when the reaction mixture was filtered through Celite and the solvent was removed by rotary evaporation. Water (750 mL) was added to the residue and the solution was cooled to 4° C. for 20 h. The resulting precipitate was filtered and rinsed with cold distilled water. The solid was recrystallized from ethanol to give 2 as a yellow solid (1.59 g, 7.3 mmol) in 57% yield. mp 250-252° C. (lit 252-253° C.). FTIR (KBr) (cm−1): 3410, 3310, 1700, 1650, 1630. 1H-NMR (DMSO-d6): δ (ppm) 9.65 (s, 1H), 8.40 (s, 1H), 7.10 (dd, J=9.1 Hz, J=2.7 Hz, 1H), 6.73 (d, J=9.1 Hz, 1H), 6.68 (d, J=2.7 Hz, 1H), 5.19 (bs, 2H), 2.14 (s, 3H). 13C-NMR (DMSO-d6): δ (ppm) 171.12, 158.78, 146.92, 142.52, 125.26, 124.98, 120.82, 117.54, 117.15, 110.66, 24.93. HRMS expected, 219.07770; found, 219.07697. Elemental analysis for C11H10N2O3: expected: C, 60.55; H, 4.62; N, 12.84; found: C, 60.15; H, 4.50; N, 12.62.
Reaction SMILES: [Cl-].[CH2:2]([N+:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C.O>[CH2:2]([N:9]1[CH2:10][CH:11]=[C:12]([CH3:15])[CH2:13][CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc[n+](Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
To a stirred solution of the product from Method A (38 grams/0.171 mol) dissolved in 140 mL of 10:1 ethanol/water at 0° C. was added 16 grams (0.427 mol) of sodium borohydride portion-wise over 25 minutes. The resulting mixture stirred for 18 hours at room temperature, at which time, the reaction was quenched upon addition of 100 mL of water. The reaction mixture was filtered, the filter cake washed with water and ethylacetate, and the combined filtrates concentrated under reduced pressure to remove the organics. The residue was diluted with water (100 mL) and extracted 3 times with 150 mL with ethylacetate. The combined ethylacetate extracts were dried over Na2SO4 and concentrated to dryness in vacuo affording 32 grams (100%) of the title compound as a yellow oil. LRMS: 188 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:34])[CH2:17][CH2:18][NH:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:23][CH:22]=2)[CH2:11][CH2:10]1.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(N(CC)CC)C>C(Cl)Cl>[C:35]([O:34][CH:16]([CH2:17][CH2:18][NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[CH2:14][CH2:13]1)(=[O:37])[CH3:36]
Reactant: O=C(NCCC(O)CN1CCN(c2cccc(Cl)c2Cl)CC1)c1ccc(-c2ccccn2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(CCNC(=O)c1ccc(-c2ccccn2)cc1)CN1CCN(c2cccc(Cl)c2Cl)CC1
Reaction time: 16 h

Procedure:
A solution of 16 (0.25 g, 0.5 mmol) in 10 mL of CH2Cl2 was treated with 70 μL (0.75 mmol) acetic anhydride followed by 140 μL (1.0 mmol) triethylamine. After stirring for 16 h, the mixture was washed with sodium bicarbonate solution, dried with sodium sulphate and purified by flash chromatography. Yield: 0.22 g (82%). Mp. (oxalate): foam. 1H NMR (CDCl3): δ 1.84 (m, 1H), 2.05 (m, 1H), 2.12 (s, 3H), 2.52 (dd, J 13.2, 5.2, 1H), 2.65 (m, 5H), 2.99 (s, 4H), 3.25 (dq, J 9.7, 5.00, 1H), 3.81 (dt, J 12.3, 5.7, 1H), 5.19 (m, 1H), 6.89 (dd, J 7.7, 1.8, 1H), 7.06-7.17 (m, 3H), 7.26 (ddd, J 6.1, 4.8, 2.44, 1H), 7.73-7.76 (m, 2H), 7.93 (d, J 8.6, 2H), 8.07 (d, J 8.6, 2H), 8.70 (td, J 4.83, 1.50, 1.50, 1H). 13C NMR (CDCl3): δ 21.0, 32.4, 36.1, 51.3, 53.7, 61.5, 69.6, 118.6, 120.8, 122.7, 124.5, 127.0, 127.4, 127.5, 133.9, 134.7, 136.9, 142.1, 149.8, 151.1, 156.2, 167.1, 171.5, Anal. (C26H30Cl2N4O3.1.5(COOH)2.H2O) C, H, N.