Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9]2)=[CH:4][CH:3]=1.O=[C:24]([CH3:38])[CH2:25][CH2:26][N:27]1C(=O)C2C(=CC=CC=2)C1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:17]3[CH2:22][CH2:21][N:20]([CH:24]([CH3:38])[CH2:25][CH2:26][NH2:27])[CH2:19][CH2:18]3)[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: Clc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Product: CC(CCN)N1CCC(C2(c3ccc(Cl)cc3)Oc3ccccc3O2)CC1

Procedure:
Using general procedure B with the above amine (221 mg, 0.70 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (305 mg, 1.40 mmol) and then using general procedure D afforded 3-{4-[2-(4-chloro-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a colourless oil (185 mg, 68% over 2 steps).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH2:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>CN(C=O)C.O>[C:2]([CH:3]([CH:18]([CH2:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:1])[CH2:9][CH3:10]
Reactant: CCCC(Br)C(=O)OCC
Reactant: CCOC(=O)CC(=O)CC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)C(C(=O)CC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a solution of ethyl 3-oxopentanoate (7.21 mL; 50 mmol) in dry DMF (25 mL) under nitrogen atmosphere was added potassium carbonate (7.6 g; 55 mmol), which has been dried at 120° C. for 12 h before using. After stirring for 15 min at room temperature, ethyl 2-bromovalerate (8.53 mL; 50 mmol) was slowly added under nitrogen and the mixture was vigorously stirred at room temperature for 24 h. The reaction mixture was poured in water (240 mL) and neutralized by adding a solution of hydrochloric acid 6N. The product was extracted with diethyl ether (2×240 mL) and the combined organic layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by distillation under reduced pressure furnished 7.9 g (58%) of the title compound as a colorless liquid (bp. 130-135° C., 4 mbar, temperature of the oil bath 150° C.).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)C>[N:30]1([C:2]2[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=2)[C:5]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:10][CH:9]=2)=[O:6])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Solvent: CCO
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(N2CCOCC2)c1
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide (200 umol, 1 eq), morpholine (2 mmol, 10 eq.) and ethanol (2 ml) is heated at 100° C. for 3-4 days in a 2-dram vial with agitation. The mixture is cooled to room temperature and concentrated. The crude mixture is purified by flash column chromatography and re-crystallized from methanol to afford 2-morpholin-4-yl-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide. 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.31 (d, 1H), 8.21 (m, 1H), 7.85 (m, 1H), 7.58 (m, 2H), 2.42 (m, 2H), 7.23 (d, 1H), 7.08 (d, 1H), 4.38 (t, 2H), 3.78 (m, 4H), 3.60 (m, 8H), 2.88 (t, 2H) 2.58 (m, 4H). MS: 463.3 (M+1).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6](=[O:8])[CH3:7])(=[O:4])=[O:3].[Br:9]Br>CC(O)=O.ClCCl>[Br:9][CH:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6](=[O:8])[CH3:7]
Reactant: CC(=O)CS(C)(=O)=O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)C(Br)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.1 %

Procedure:
To a solution of methanesulphonylacetone (0.5 g, 3.67 mmol) in AcOH (7.34 mL) and dichloromethane (11.02 mL) in a round bottom flask was added bromine (0.189 mL, 3.67 mmol) dropwise. The reaction mixture was stirred at rt 90 min. Solvent was removed in vacuo. The residue was taken up in ether and washed with saturated aqueous sodium bicarbonate (2×). The organics were concentrated in vacuo. 1-Bromo-1-(methylsulfonyl)propan-2-one (0.332 g, 42% yield) was isolated as an oil.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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:28][C:29]1[C:34]([C:2]2[N:6]([S:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=2)=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: OB(O)c1cccnc1F
Reactant: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)c1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
tert-butyl ({5-bromo-1-[(3-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (459 mg), (2-fluoropyridin-3-yl)boronic acid (169 mg), sodium carbonate (254 mg), and tetrakis(triphenylphosphine)palladium (173 mg) were suspended in 1,2-dimethoxyethane (10 mL) and water (4 mL), and the mixture was stirred at 105° C. for 2 hr. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 303 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([N:18]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19]2)[CH2:14][CH2:13]1)=[O:10].[NH2:25][OH:26]>CCO.CCOC(C)=O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([N:18]2[CH:22]=[CH:21][C:20](/[CH:23]=[N:25]/[OH:26])=[CH:19]2)[CH2:14][CH2:13]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(n3ccc(C=O)c3)CC2)c(Cl)c1Cl
Reactant: NO
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1[nH]c(C(=O)NC2CCN(n3ccc(/C=N/O)c3)CC2)c(Cl)c1Cl

Procedure:
A solution of 3,4-dichloro-N-[1-(3-formyl-1H-pyrrol-1-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 259, 151 mg, 0.41 mmol) and 50% aqueous hydroxylamine (55 μl, 0.83 mmol) in 5 ml EtOH was heated at 80° C. for 30 min. The mixture was diluted with EtOAc and washed with brine. Drying (MgSO4) and removal of solvent gave a solid that was purified by reverse phase HPLC (30-55% gradient CH3CN in water with 0.1% TFA) to give product as a mixture of geometrical isomers.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:35][S:36]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)(=[O:38])=[O:37]>C(#N)C.O.Cl>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:43][C:42]3[CH:41]=[CH:40][C:39]([S:36]([CH3:35])(=[O:38])=[O:37])=[CH:46][CH:45]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2ccn(Cc3ccc(S(C)(=O)=O)cc3)c2c(=O)n1C
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
A suspension of methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (17 mg, 0.044 mmol) in Acetonitrile (0.4 mL) was treated with Cs2CO3 (57.9 mg, 0.178 mmol), 4-methylsulfonylbenzyl bromide (44.3 mg, 0.089 mmol), and stirred at 70° C. for 1.5 hours. The reaction was cooled to rt, diluted with water and 1N HCl, extracted with EtOAc, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) gave methyl 2-(tert-butoxy)-2-(6-methyl-1-(4-(methylsulfonyl)benzyl)-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (22 mg, 0.040 mmol, 90% yield) as yellow oil. The ester intermediate was dissolved in Methanol (0.5 mL) and Tetrahydrofuran (THF) (0.5 mL), treated with 2M LiOH (0.120 mL, 0.24 mmol), and stirred at 60° C. for 2 hours. The reaction was concentrated and purified with reverse phase HPLC (20-100% MeCN/H2O-0.1% TFA) to give title compound (9.3 mg, 0.017 mmol, 37.6 yield) as off white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.00 (s, 9H), 2.44 (s, 3H), 3.02 (s, 3H), 3.64 (s, 3H), 5.47 (s, 1H), 5.81 (d, J=15.7 Hz, 1H), 6.02 (d, J=15.6 Hz, 1H), 6.10 (d, J=2.8 Hz, 1H), 7.05 (d, J=2.9 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.32-7.43 (m, 3H), 7.47-7.58 (m, 1H), 7.89 (d, J=8.4 Hz, 2H). LCMS (m/z) ES+=537 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[N:34][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:30]1[CH:35]=[N:34][C:33]([Cl:36])=[CH:32][CH:31]=1
Reactant: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Clc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2ccc(Cl)nc2)c1
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-N-(2-methoxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (60 mg, 0.15 mmol), 5-bromo-2-chloro-pyridine (29 mg, 0.15 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), K2CO3 (41 mg, 0.3 mmol) in dioxane (1 mL), was heated at 100° C. for 12 hrs. The mixture was filtered and purified by prep. LCMS to yield 4-chloro-3-(6-chloro-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide 2-1.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:1][C@H:2]2[CH2:5][C@H:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)[C@H]1C[C@@H](O)C1
Reactant: COc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1C[C@H](Oc2ccc(OC)cc2)C1
Temperature: 80 °C

Procedure:
To a stirred solution of ethyl cis-3-hydroxycyclobutanecarboxylate (1.32 g, 9.20 mmol), 4-methoxyphenol (3.43 g, 27.6 mmol) and triphenylphosphine (3.12 g, 11.9 mmol) in dry THF (25 ml) was added dropwise diethyl azodicarboxylate (2.07 g, 11.9 mmol) in dry THF (5 ml) under argon atmosphere at room temperature. After completion of addition, the mixture was heated to 80° C., maintained at the same temperature for 1 h, and then volatiles removed under reduced pressure. Chromatographic purification of the residue {SiO2, 150 g; hexane/ethyl acetate (20/1)} provided 1.96 g (85%) of ethyl trans-3-(4-methoxyphenoxy)cyclobutanecarboxylate as a colorless oil. 1H NMR δ56.85-6.69 (m, 4H), 4.90-4.80 (m, 1H), 4.18 (q, J=7.0 Hz. 2H), 3.76 (s, 3H), 3.20-3.09 (m, 1H), 2.78-2.62 (m, 2H), 2.5-2.35 (m, 2H), 1.29 (t, J=7.0 Hz, 3H).
Reaction SMILES: O.Cl.[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].N[C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)[C:19]=1[C:31]#[N:32].O>C(O)(=O)C>[NH2:32][C:31]1[N:11]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[C:18]2[NH:22][N:21]=[C:20]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=3)[C:19]=12
Reactant: N#Cc1c(Nc2ccc(Br)cc2)n[nH]c1N
Reactant: N=C(N)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-c2ccccc2)nc2[nH]nc(Nc3ccc(Br)cc3)c12
Reaction time: 4 h

Procedure:
1.87 g (10.7 mmol) benzamidin hydrochloride hydrate and 0.89 g (10.7 mmol) sodium acetate are added to 1.0 g (3.6 mmol) 5-amino-4-cyano-3-(4-bromophenyl)aminopyrazol in 20 ml ethanoic acid by stirring. The reaction mixture is boiled for a period of 4 h, treated with 50 ml water, filtered and washed with 20 ml of cold methanol and 20 ml of cold ester. The raw product is purified by means of crystallization from ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[F:8].S(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([Cl:16])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1ccc(F)c(Br)c1
Product: O=C(Cl)C=Cc1ccc(F)c(Br)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
3-(3-Bromo-4-fluoro-phenyl)-acrylic acid (3.3 g, 13.3 mmol) prepared in Step 1 was added to thionyl chloride (10.0 mL). The reaction mixture was stirred at 100° C. for 2 hours, concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 3.5 g of the titled compound as an unpurified dark brown liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[NH2:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1>C1COCC1.C1(C)C=CC=CC=1>[C:2]1([C:16]2[CH:17]=[CH:18][N:19]=[C:14]([NH2:13])[N:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncccn1
Reactant: Brc1ccccc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1nccc(-c2ccccc2)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 9.7 %

Procedure:
To a solution of bromobenzene (4.43 mL, 42.06 mmol) in dry THF (100 mL) at −78° C. was added BuLi (394 mL, 63.08 mmol) and the mixture left to stir at −78° C. for 2 h. To this was added 2-aminopyrimidine (2.0 g, 21.03 mmol) in hot toluene (80 mL) over a 15 minutes period. The mixture was refluxed for 16 h and allowed to cool to room temperature and carefully quenched with aqueous NaHCO3. The mixture was filtered and the filtrate concentrated under vacuum. The residue was then dissolved in DCM and washed with aqueous NaHCO3, brine and dried (MgSO4). The solvent was removed to afford 350 mg of 47 (10%) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J=4.8 Hz, 1H), 7.97 (m, 2H), 7.45 (m, 3H), 7.02 (J=4.8 Hz, 1H). 5.27 (br s, 2H); MS (+)-ES [M+H]+ 172.2 m/z.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1>>[CH3:40][S:37]([CH2:36][C:33]1[CH:34]=[CH:35][C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)=[CH:31][CH:32]=1)(=[O:38])=[O:39]
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cc1ccc(Br)cc1
Product: COc1ccc(-c2ccc(CS(C)(=O)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (200 mg, 0.51 mmol) is coupled to aryl bromide 197 (127 mg, 0.51 mmol) using Method A. On filtration of the cooled reaction mixture through celite and removal of the solvents in vacuo, the crude residue obtained is used in the next synthetic step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C@@H:9]([CH2:12][C:13]3[NH:14][CH:15]=[CH:16][N:17]=3)[C@@H:10]([OH:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20][S:21][CH2:22]Cl.CCOCC>CN(C)C=O>[Cl:1][C:2]1[C:7]2[S:8][C@@H:9]([CH2:12][C:13]3[NH:17][CH:16]=[CH:15][N:14]=3)[C@@H:10]([O:11][CH2:20][S:21][CH3:22])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CSCCl
Reactant: O[C@H]1c2cccc(Cl)c2S[C@H]1Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CSCO[C@H]1c2cccc(Cl)c2S[C@H]1Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of cis-7-chloro-3-hydroxy-2,3-dihydro-2-(1'-imidazolylmethyl)benzo(b)thiophene (2.67 gms., 10 mmols) in dry dimethylformamide (30 ml.) at 0°-5° C., add sodium hydride (50% oil dispersion) (0.53 gms., 11 mmols) and stir for one hour at room temperature. Add chloromethyl methyl sulfide (1.06 gms., 11 mmols) and stir again for one hour at room temperature. Pour the reaction mixture into ether (500 ml.) and extract with three portions (500 ml. each) of water. Dry the ether solution over anhydrous magnesium sulfate and evaporate in vacuo. Chromatograph the resultant residue by high pressure liquid chromatography using two silica gel cartridges and eluting with ethyl acetate. Combine the like eluates as determined by thin layer chromatography and evaporate the combined residues to give cis-7-chloro-3-(methylthiomethoxy)-2,3-dihydro-2-(1'-imidazolylmethyl)benzo(b)-thiophene.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[CH3:8][O:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:8][O:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:6][CH2:5][CH2:4][CH2:3][C:2]#[CH:1]
Reactant: C#CCCCCO
Reactant: COC(=O)CCc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CCCCCOc1ccccc1CCC(=O)OC
Temperature: 25 °C
Reaction time: 100 h
Yield: 76.8 %

Procedure:
A mixture of 0.98 g (10 mmol) of 5-hexyn-1-ol, 1.98 g (11 mmol) of 2-hydroxybenzenepropanoic acid methyl ester, 2.88 g (11 mmol) of triphenylphosphine, 1.91 g (11 mmol) of diethyl azodicarboxylate, and 220 mL of dry tetrahydrofuran was stirred at room temperature for 100 hr and then concentrated under reduced pressure. The residue was triturated with 9:1 hexane-ether. The solid was filtered with suction and washed with the same solvent mixture. The filtrate and washes were combined and concentrated in vacuo. Flash chromatography of the residue on silica gel, eluting with 9:1 hexane-ether gave 2 g (77%) of 2[(5-hexynyl)oxy]benzenepropanoic acid methyl ester as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][C@@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cn2)C1

Procedure:
2-Chloro-5-nitropyridine was treated with tert-butyl (R)-(+)-pyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 278.36 (C14H22N4O2); MS (ESI): 279 (M+H+).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:14]=[C:15]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:16][O:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:25]=1)[C:23]#[N:24]>C(#N)C>[C:23]([C:22]1[CH:21]=[N+:20]([O-:9])[CH:19]=[C:18]([O:17][CH2:16][C:15]2[CH:26]=[C:27]([F:29])[CH:28]=[C:13]([F:12])[CH:14]=2)[CH:25]=1)#[N:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1cncc(OCc2cc(F)cc(F)c2)c1
Solvent: CC#N
Product: N#Cc1cc(OCc2cc(F)cc(F)c2)c[n+]([O-])c1
Reaction time: 20 h
Yield: 75.1 %

Procedure:
224 mg of m-CPBA is added at 0° c. to a solution in acetonitrile of 250 mg of 5-(3,5-difluorobenzyloxy)nicotinonitrile. The reaction medium is stirred for 20 hours while a precipitate is formed progressively. this solid is then filtered and washed to yield 200 mg (75%) of 3-cyano-5-(3,5-difluorobenzyloxyl)pyridine 1-oxide in the form of a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].[OH-].[K+].Cl>CS(C)=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][C:5]=1[CH2:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Reactant: O=S(=O)(CCl)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1CS(=O)(=O)c1ccccc1
Reaction time: 0.75 h
Yield: 41 %

Procedure:
Adapting the procedure of Makosza, et al, Liebigs Ann. Chem., 1984, 8-14, a stirred mixture of 4-nitro-pyridine-N-oxide (1.40 g, 10.0 mmol) and chloromethylphenylsulfone (1.92 g, 10.0 mmol) in DMSO (25 mL) in a cold water bath is treated with a solution of KOH (4.0 g, 71 mmol) in DMSO, stirred for 45 min, poured into 1.0 M hydrochloric acid and water and extracted with CH2Cl2. The aqueous phase is filtered and the filtercake is dried in vacuo to afford the title compound, 1.20 g (41% yield). The organic extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant wet solid is heated in boiling ethanol:water (4:1) and filtered. The filtrate is cooled, concentrated and filtered. This filtercake is dried in vacuo to afford an additional portion of the title compound, 0.967 g (74% total yield), mp 219-220° C., identified by mass spectral and HNMR analyses.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][C:18]([O:20]CC)=[O:19])[CH:13]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23]I.[OH-].[K+].Cl>O.CC(C)=O>[CH3:23][N:8]1[C:9]2[C:14](=[CH:13][C:12]([CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)[CH2:15][CH2:16][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)CCC(c1ccccc1)N2
Reactant: CI
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CN1c2ccc(CC(=O)O)cc2CCC1c1ccccc1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
The compound (3 g) of Example 2 was dissolved into acetone and, after methyl iodide (0.8 ml) and potassium hydroxide (3.7 g) were added, the mixture was stirred at 40° C. for 20 hours under heat. After water was added and the reaction mixture was acidified with hydrochloric acid, it was extracted with methylene chloride. The residue obtained by drying methylene chloride layer over anhydrous sodium sulfate and then concentrating under reduced pressure was recrystallized from ethanol-hexane to obtain aimed product (1.25 g) as pale yellow powdery crystals. Melting point: 110°-111° C.