Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10](=O)[CH3:11])=[N:6][CH:7]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH3:11])=[N:9][CH:8]=2)[CH:7]=1
Reactant: CC(=O)NCc1ccc(Br)cn1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ncc2ccc(Br)cn12
Yield: 70 %

Procedure:
To a solution of N-((5-bromopyridin-2-yl)methyl)acetamide (450 mg, 1.96 mmol) in toluene (15 mL) was added POCl3 (600 mg, 3.92 mmol) and the mixture stirred at refluxing temperature for 6 h. After cooling, the reaction mixture was quenched by adding water (1 mL) and concentrated to remove toluene. The residue was diluted with water (5 mL) and extracted with EtOAc (3×10 mL) with the organic layer concentrated to give a crude product which was used in next step without further purification (290 mg, Yield 70%). LCMS (m/z): 211.0 (M+1)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH:24]2[CH2:25][CH2:26][CH:20]1[CH2:21][C:22](=[O:27])[CH2:23]2)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH:24]2[CH2:25][CH2:26][CH:20]1[CH2:21][C:22]([OH:27])([C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=1)[CH2:23]2)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Brc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ccc3ccccc3c1)C2
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a −78° C. solution of 6.20 g (29.9 mmol) 2-bromonaphthalene and 125 mL THF is added 12 mL of 2.5 M n-BuLi/hexanes. After stirring at −78° C. for 30 mins a solution of 6.40 g (28.4 mmol) 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 14 mL THF is added dropwise. The reaction is allowed to proceed at −78° C. for 30 mins and then warmed to 23° C. over 6 h. After quenching with 100 mL 1N NaOH and extraction with 3×100 mL of EtOAc, the combined organics are washed with 1×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered, and the volatiles removed. Flash chromatography in SiO2 gel, eluting with hexanes/EtOAc (4/1 to 1/1) gives 7.00 g (19.8 mmol, a 66% yield) of the title compound as a white solid. MS (ES) m/z 354 (M++H, 100).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22]>CN(C=O)C>[Cl:19][CH2:20][C:21]([NH:12][C:10]1[S:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)=[O:22]
Reactant: Nc1nnc(-c2ccccc2)s1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1nnc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
To a mixture of 5-phenyl-1,3,4-thiadiazol-2-amine (C1, 1.06 g, 6 mmol) and K2CO3 (0.83 g, 6 mmol) in anhydrous DMF (20 mL), was added chloroacetyl chloride (C2, 0.48 mL, 6 mmol). The mixture was stirred at room temperature for 4 h. The reaction mixture was then poured into ice-water (100 mL), stirred, and then filtered. The resulting solid was washed with water, and then dried in the oven under vacuum to afford compound C3 (1.15 g, 76%) as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.[C:20]([Cu])#[N:21]>[Cl-].[NH4+]>[C:20]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)#[N:21]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2I)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: N#Cc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A solution of the iodide 77 (5.0 g, 13.66 mmol) and CuCN (1.65 g, 18.42 mmol) in 30 mL of anhydrous dimethiylsulfoxide was heated (180° C.) under an argon atmosphere. After 2 hr, the reaction mixture was added to a 0° solution of aqueous ammonium chloride (100 mL) and filtered through a Buchner funnel. The insoluble product was partitioned into methylene chloride and water. The separated or ganic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (1/1 Hexane/CH2Cl2 to 30%/69%/1% Hexane(CH2Cl2 /MeOH) to afford the nitrile 78 (3.3 g, 12.27 mmol, 90% from 77) as a light yellow solid. 1H NMR (DMSO-d6) δ8.69 (d, 1H, J=2.3), 8.56 (dd, 1H, J1 =8.6, J=2.3), 8.44-8.41 (m, 2H), 7.80-7.76 (m, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[S:34]>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:33](=[S:34])[NH:32][C:26]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=2[F:24])[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: O=C1c2ccccc2OCCC1(CO)CO
Reactant: Fc1ccc(N=C=S)c(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2OCCC1(CO)COC(=S)Nc1ccc(F)cc1F

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]oxepin-5-one (500 mg, 2.25 mmol) in 28 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.34 ml, 2.48 mmol) and 2,4-difluorophenyl isothiocyanate (734 μl, 5.63 mmol). The mixture was heated to reflux for 72 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 376 mg (43%).
Reaction SMILES: [P:1](Cl)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].[N+:11]([C:14]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]2[C:15]=1[CH2:16][CH2:17][C:18]2=[O:24])([O-:13])=[O:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:23][C:20]1[CH:21]=[CH:22][C:14]([N+:11]([O-:13])=[O:12])=[C:15]2[C:19]=1[C:18](=[O:24])[CH2:17][CH2:16]2)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C1CCc2c([N+](=O)[O-])ccc(O)c21
Reactant: CCCSP(=O)(Cl)OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCSP(=O)(OCC)Oc1ccc([N+](=O)[O-])c2c1C(=O)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Ethyl S-propyl chlorothiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 4-nitro-7-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product, O-ethyl S-propyl O-(4-nitroindan-1-on-7-yl) thiophosphate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][C@@H:16]1[CH2:20]OS(=O)(=O)[N:17]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([CH3:20])[NH:17][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C[C@@H]1COS(=O)(=O)N1c1ccccn1
Solvent: CC#N
Product: COc1ccccc1N1CCN(C[C@@H](C)Nc2ccccn2)CC1
Yield: 77.4 %

Procedure:
12.02 grams of 1-(2-methoxyphenyl)piperazine and 13.4 grams of (R)-4-methyl-3-pyridin-2-yl[1,2,3]oxathiazolidine-2,2-dioxide were stirred together in 50 millilitres of acetonitrile at room temperature overnight. The solvent was removed in vacuo. The residue was heated in 100 millilitres of dilute hydrochloric acid for 30 minutes. The mixture was cooled, washed with dichloromethane, basified by using dilute sodium hydroxide solution and extracted by means of dichloromethane. The organic phase was washed with water, dried and evaporated to dryness to give 15.8 g of the title compound as a slightly crude product. The product was 85 to 95% pure and contained 2 main impurities derived from the sulphone. The crude product was used directly, i.e. without purification, by acylation by means of cyclohexanecarbonyl chloride to yield (R)-N-[1-methyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:8]([CH3:28])[C:7]=2[CH:29]=1)#[N:2].Cl.[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37])[CH3:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:37][CH2:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:38])=[O:24])=[CH:21][CH:20]=3)[CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)=[C:8]([CH3:28])[C:7]=2[CH:29]=1)#[N:2]
Reactant: CCOC(=O)CCN
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(C#N)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(C#N)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a mixture of 4-{[(5-cyano-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}benzoic acid (250 mg) synthesized above, β-alanine ethyl ester hydrochloride (148 mg), 1-hydroxybenzotriazole monohydrate (148 mg), triethylamine (269 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (185 mg), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (195 mg, 62%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]#[C:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1>CO.[Pd]>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[NH:19][C:16]3=[N:17][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCN(CC)CC#Cc1cc2nc(CCc3cc(OC)cc(OC)c3)cnc2[nH]1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCCc1cc2nc(CCc3cc(OC)cc(OC)c3)cnc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.7 %

Procedure:
To a stirred solution of 3-{2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazin-6-yl}-N,N-diethylprop-2-yn-1-amine (from Example 27, 5 mg, 12.7 μmol) in methanol (2 mL), Pd/C (10% w/w, 5.0 mg, 4.7 μmol) was added. The resulted mixture was stirred under H2 at ambient temperature. After 1.5 hours, the palladium catalyst was filtered and the crude mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (2.4 mg, 50%) as its TFA salt. LCMS calculated for C23H33N4O2 (M+H)+: m/z=397.3. Found: 397.3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:33][CH:32]([OH:34])[CH2:31][CH2:30][C:29]=5[C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=5)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15]C)=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.C(OCC)(=O)C>O1CCCC1.CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:33][CH:32]([OH:34])[CH2:31][CH2:30][C:29]=5[C:35]5[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=5)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([OH:15])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(O)C3)CC2)cc1Oc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(O)C3)CC2)cc1Oc1ccc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 224C (1.78 g) in tetrahydrofuran (30 mL), methanol (10 mL) and water (10 mL) was added LiOHH2O (0.262 g). The mixture was stirred overnight. The mixture was then neutralized with 5% aqueous HCl and exacted with ethyl acetate (3×) and the combined organic layers were washed with brine and dried over Na2SO4. Evaporation of solvent gave the title compound.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([CH2:27][C:28]([OH:30])=O)=[O:26])=[CH:21][CH:22]=2)[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([CH3:31])[CH2:16][C:15]1([CH3:39])[CH3:38])(=[O:13])[CH3:12].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>O1CCCC1>[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([CH2:27][C:28]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:30])=[O:26])=[CH:21][CH:22]=2)[C:17]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([CH3:31])[CH2:16][C:15]1([CH3:38])[CH3:39])(=[O:13])[CH3:12]
Reactant: CC(=O)N1c2ccc(NC(=O)CC(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CCNCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccc1)C(=O)CC(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Condensation of N-ethylbenzylamine (5.2 mg) with 1-acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), under the agency of HATU (19 mg) and N,N-diisopropylethylamine (16 μl) in tetrahydrofuran (2 ml) was performed according to the method described in example 11.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:15])[NH:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9](=[O:15])[NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NCCCNC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNCCCNC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of (3-aminopropyl)carbamic acid phenylmethyl ester (7.08 g, 34 mmol) and N,N-diisopropylethylamine (4.5 mL, 26 mmol) in anhydrous dimethylformamide (100 mL) under nitrogen was cooled to 10° C. and treated with t-butyl bromoacetate (2.80 mL, 17 mmol) over 5 minutes. After one hour the bath was removed and the reaction mixture was stirred overnight, poured into water (500 mL), and made basic (pH 12) with 2.5N sodium hydroxide solution. The aqueous layer was extracted with dichloromethane (2×250 mL), which was dried over sodium sulfate and concentrated in vacuo with heat to remove dimethylformamide. The residue was purified by flash chromatography (9 cm diameter, gradient elution with 2.5-3.5% methanol in dichloromethane) to yield [3-[[(1,1-dimethylethyloxycarbonyl)-methyl]amino]propyl]carbamic acid phenylmethyl ester as a pale yellow oil (4.50 g 82%); 1H NMR (CDCl3 200 MHz): δ 7.35 (m, 5H), 5.43 (br s, NH), 5.09 (s, 2H), 3.35-3.24 (m, 4H), 2.68 (t, J=6.5 Hz, 2H), 1.68 (p, J=6.5 Hz, 2H), 1.46 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.Cl.[C:11]([O:15][C:16](=[O:20])[CH2:17][CH2:18][NH2:19])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CS(C)=O.CCOCC>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:19][CH2:18][CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:20])[CH:7]=1)#[N:9]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCNc1cc(C#N)ccn1

Procedure:
A solution of 2-chloro-4-cyanopyridine (2.00 g, 14.4 mmol), beta-alanine tert-butyl ester hydrochloride (3.14 g, 17.3 mmol) and DIEA (9.88 mL, 57.7 mmol) in anhydrous DMSO (30 mL) was heated at 150° C. for 3 days. The reaction mixture was diluted with Et2O (100 mL) and washed with water (3×60 mL) and brine (60 mL). The organic layer was dried (MgSO4) and the solvents were removed under reduced pressure. Purification by flash chromatography (silica, EtOAc/cHex) gave the title compound as a brown oil. HPLC (Method A), Rt: 2.8 min (purity: 92.2%). UPLC/MS, M+(ESI): 248.1, M−(ESI): 246.2. 1H NMR (DMSO-d6, 300 MHz) δ 8.16 (dd, J=5.2, 0.7 Hz, 1H), 7.16 (t, J=5.7 Hz, 1H), 6.83 (m, 1H), 6.79 (dd, J=5.2, 1.4 Hz, 1H), 3.46 (td, J=6.8, 5.7 Hz, 2H), 2.46 (t, J=6.8 Hz, 2H), 1.38 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[O:24])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]2C(C)(C)[NH:19][C:20](=[O:21])[CH:14]2[CH2:13]1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:19][C:20]([CH:14]1[NH:15][CH2:16][CH2:17][N:12]([CH2:11][C:10]([NH:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[O:24])[CH2:13]1)=[O:21]
Reactant: CC1(C)NC(=O)C2CN(CC(=O)Nc3c(Cl)cccc3Cl)CCN21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: NC(=O)C1CN(CC(=O)Nc2c(Cl)cccc2Cl)CCN1
Yield: 64 %

Procedure:
A mixture of 23.8 parts of N-(2,6-dichlorophenyl)hexahydro-3,3-dimethyl-1-oxoimidazo[1,5-a]pyrazine-7(8H)-acetamide and 256 parts of a hydrochloric acid solution 0.5N was stirred and refluxed for 2 hours. The reaction mixture was cooled overnight to room temperature, alkalized and salted out with sodium carbonate. The product was extracted with trichloromethane. The extract was filtered and the filtrate was dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 13.6 parts (64%) of 3-(aminocarbonyl)-N-(2,6-dichlorophenyl)-1-piperazineacetamide; mp. 180.4°-182.8° C. (intermediate 125).
Reaction SMILES: C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCCCC)(=O)C1C=CC=CC=1.[C:26]([C:34]1[C:42]([N+:43]([O-])=O)=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:43][C:42]1[C:34]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:35]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:36]=[C:37]([CH:41]=1)[C:38]([OH:40])=[O:39]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Agent: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: Nc1cc(C(=O)O)cc(OCc2ccccc2)c1C(=O)c1ccccc1

Procedure:
By replacing in Example 1, step C, 4-benzoyl-3-n-butoxy-5-nitrobenzoic acid with 4-benzoyl-3-benzyloxy-5-nitrobenzoic acid, and following the procedure described, 5-amino-4-benzoyl-3-benzyloxybenzoic acid is obtained with a melting point of 216.5°-217.5° C.
Reaction SMILES: [I:1][CH2:2][CH2:3][OH:4].CN(C1C=CC=CN=1)C.C(N(C(C)C)CC)(C)C.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[C:26]([Si:23]([O:4][CH2:3][CH2:2][I:1])([CH3:25])[CH3:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCI
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCI
Reaction time: 8 h

Procedure:
To 2-iodoethanol (20 gm, 116 mmol) suspended in methylene chloride (500 mL) was added dimethylaminopyridine (100 mg) followed by diisopropylethylamine (30 mL, 174 mmol) and tert-butyldimethylsilyl chloride (19 gm, 128 mmol). The reaction was stirred overnight and the solvent was removed in vacuo and the residue was passed through a short column of silica gel and eluted with 95:5 methylene chloride: methanol. The desired fractions were combined and the solvent was removed in vacuo to give the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.BrC1C=CC(OC)=C([N+]([O-])=O)C=1.[CH3:21][O:22][C:23]1[C:28]2[N:29]=[C:30]([NH:32][C:33]([C:35]3[S:36][C:37]([CH3:40])=[CH:38][CH:39]=3)=[O:34])[S:31][C:27]=2[C:26](N2CCOCC2)=[CH:25][CH:24]=1>>[CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][N:5]([C:26]2[C:27]3[S:31][C:30]([NH:32][C:33]([C:35]4[S:36][C:37]([CH3:40])=[CH:38][CH:39]=4)=[O:34])=[N:29][C:28]=3[C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:4]1
Reactant: CN(C)C1CCNC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Agent: COc1ccc(Br)cc1[N+](=O)[O-]
Product: COc1ccc(N2CCC(N(C)C)C2)c2sc(NC(=O)c3ccc(C)s3)nc12

Procedure:
The title compound is synthesized starting from 3-(dimethylamino)pyrrolidine and 4-bromo-2-nitroanisole as described for 5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide and was obtained as yellow solid in 10% overall yield, MS: m/e=417 (M+H+).
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.O=S(Cl)Cl.[CH3:19]O>>[CH3:19][O:9][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:12]([I:14])=[CH:13][C:5]=1[NH2:4]
Reactant: CC(=O)Nc1cc(I)ccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(I)cc1N
Temperature: 65 °C

Procedure:
To 2-acetylamino-4-iodo-benzoic acid (13.8 g, 45.3 mmol) in 200 mL of dry methanol was added SOCl2 (32.7 mL, 453 mmol) dropwise at 0° C. The reaction mixture was then heated at 65° C. for 2 h. The reaction was then cooled to 0° C., an additional portion of SOCl2 (10 mL, 137 mmol) was added, and the reaction was heated at 65° C. for 2 h. The reaction was then cooled to 0° C., a final portion of SOCl2 (10 mL, 137 mmol) was added, and the reaction was heated at 65° C. for 48 h. The reaction was then cooled to 22° C. and concentrated in vacuo The resulting residue was diluted with H2O and extracted with 3×150 mL CH2Cl2. The combined organic fractions were washed with brine and dried over Na2SO4 to give i-b (11.7 g, 93%): MS m/z═278 (M+H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.O>CN(C)C=O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([O:6][CH2:5][C:4]([NH2:3])([CH3:8])[CH3:7])=[CH:11][CH:12]=1)#[N:15]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CC(C)(N)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(N)COc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
4.0 g of 60% sodium hydride was added to a solution containing 8.9 g of 2-amino-2-methyl-1-propanol dissolved in 100 ml of N,N-dimethylformamide in an ice bath. After the reaction mixture was stirred for 30 minutes at room temperature, 13.7 g of 4-chlorobenzonitrile was added to the reaction mixture and the reaction mixture was stirred for 15 hours at room temperature. The reaction mixture was poured into water. The organic layer of the reaction mixture was extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure. The fraction possessing a low boiling point was removed from the residue, thus obtaining 15 g of the desired product (yield: 79%).