Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]3[CH:28]=[C:29]([Cl:33])[C:30](I)=[CH:31][C:18]=3[N:17]=2)[CH:12]=[CH:11][C:10]=1[CH3:34])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH:35]1([C:41]2[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][P:4]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]3[CH:28]=[C:29]([Cl:33])[C:30]([C:38]4[CH:37]=[CH:36][C:35]([CH:41]5[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]5)=[CH:40][CH:39]=4)=[CH:31][C:18]=3[N:17]=2)[CH:12]=[CH:11][C:10]=1[CH3:34])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Reactant: CCOP(=O)(OCC)c1cc(Oc2nc3cc(I)c(Cl)cc3n2Cc2ccccc2)ccc1C
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: Cc1ccccc1
Solvent: O
Product: CCOP(=O)(OCC)c1cc(Oc2nc3cc(-c4ccc(C5CCCCC5)cc4)c(Cl)cc3n2Cc2ccccc2)ccc1C
Temperature: 130 °C

Procedure:
To a solution of [5-(1-Benzyl-6-chloro-5-iodo-1H-benzoimidazol-2-yloxy)-2-methyl-phenyl]-phosphonic acid diethyl ester (5.2 g, 8.5 mmol) in toluene (30 ml) was added 4-cyclohexylbenzeneboronic acid (3.5 g, 17 mmol), tetrakis(triphenylphosphine)palladium(0) (983 mg, 0.9 mmol), and then potassium carbonate (4.7 g, 34 mmol) in a solution of H2O (15 ml). The resulting mixture was heated in a microwave reactor at 130° C. for 15 minutes, and then quenched with saturated ammonium chloride solution. The mixture was then partitioned between EtOAc and H2O. The organic layer was washed with H2O, brine, and then dried with MgSO4. The crude mixture was then purified by flash chromatography (SiO2, 80 g). The title compound was eluted with 60% EtOAc in Hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:18])[C:14]=1[S:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:19][C:20]1[N:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].Cl.CN(C)CCCN=C=NCC.O>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:18][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[N:28][C:20]=3[CH3:19])[C:14]=1[S:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: CCSc1c(Cl)cc2c([nH]c3cnccc32)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: CCSc1c(Cl)cc2c([nH]c3cnccc32)c1NC(=O)c1cccnc1C
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 40.7 %

Procedure:
A 25 ml round-bottom flask with magnetic stirrer was charged with 6-chloro-7-ethylsulfanyl-9H-β-carbolin-8-ylamine (37.2 mg, 0.13 mmol) and 2-methylnicotinic acid (36.2 mg, 0.26 mmol) in 3 ml anhydrous pyridine. To the resulting light-orange mixture at RT was added solid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73.2 mg, 0.38 mmol) and the resulting reaction mixture was heated to 80° C. for 5 days. Next, the reaction mixture was cooled to RT and concentrated to afford a brown, viscous syrup. The syrup was dissolved in a minimal amount of MeOH (−2 ml), slowly added to a 5:1 mixture of H2O/saturated sodium bicarbonate (20 ml), and stirred at RT for 2.5 hr. The resulting precipitated solid was collected via suction filtration, washed with 1:1 hexanes/diethyl ether (2×20 ml), and air-dried to afford 21.0 mg of N-(6-chloro-7-ethylsulfanyl-9H-β-carbolin-8-yl)-2-methyl-nicotinamide as a tan solid (˜38%). LCMS (ammonium acetate standard method) retention time=2.33 min. (M+=397; M−=395). 1H-NMR (300 MHz, CD3OD, ppm) δ 8.89 (1H, s) 8.63-8.58 (1H, m) 8.44-8.38 (2H, m) 8.36 (1H, d) 8.15 (1H, d) 7.52-7.44 (1H, m) 2.98 (2H, q) 2.84 (3H, s) 1.20 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=4)[CH2:16][CH2:15][C:14]3=[O:26])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)[CH2:16][CH2:15][C:14]3=[O:26])=[N:11][CH:12]=2)=[CH:27][CH:28]=1
Reactant: COc1cccc([C@H]2CCC(=O)N2c2cnc(Oc3ccc(Cl)cc3)cn2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CC[C@H](c2cccc(O)c2)N1c1cnc(Oc2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
A mixture of (R)-1-[5-(4-chlorophenoxy)pyrazin-2-yl]-5-(3-methoxyphenyl)pyrrolidin-2-one (286 mg, 0.72 mmol), DCM (10 mL) and BBr3 (1M in DCM, 4 mL) is stirred at room temperature for 1 h. The reaction mixture is then diluted with DCM (120 mL), washed with saturated NaHCO3 (20 mL) and brine (20 mL) and dried over Na2SO4. After concentrating, the residue is purified on silica gel (0-33% ethyl acetate in hexane) to give (R)-1-[5-(4-chlorophenoxy)pyrazin-2-yl]-5-(3-hydroxyphenyl)pyrrolidin-2-one (276 mg, 100%) as a white solid. HPLC-MS calculated for C20H16ClN3O3 (M+H+) 382.09, found 382.10.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12](COCC[Si](C)(C)C)[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.N>>[OH:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(Sc2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Agent: BrB(Br)Br
Agent: N
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(Sc5cccc(O)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 68.7 %

Procedure:
(S)-2-(1-((5-((3-Methoxyphenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (36.4 mg, 0.06 mmol) was treated with boron tribromide (1M in dichloromethane, 1 mL, 1 mmol) and a solution of ammonia (7N in methanol, 3 mL, 21 mmol) according to the method described in Example 41 to give 21 mg (75% yield) of the title compound. Purity 88%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]1[O:14][N:13]=[C:12]([CH3:15])[N:11]=1)[NH2:6].[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:6]([C:5]1[CH:7]=[CH:8][C:9]([C:10]2[O:14][N:13]=[C:12]([CH3:15])[N:11]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:16]=[S:17]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc(N)ccc1-c1nc(C)no1
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-c1nc(C)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.5 %

Procedure:
Step I (1): Dichloromethane (50 mL) was added to a flask charged with 3-methoxy-4-(3-methyl-1,2,4-oxadiazol-5-yl)aniline (1.2 g, 5.85 mmol, N. Smith et. al PCT Publication WO 2003/077918) and 1,1′-thiocarbonyldipyridin-2(1H)-one (1.36 g, 5.85 mmol). The resulting mixture was stirred for 24 h at rt. The crude reaction mixture was concentrated and the crude products were purified using silica gel chromatography (20-50% EtOAc/hexane) linear gradient to afford 5-(4-isothiocyanato-2-methoxyphenyl)-3-methyl-1,2,4-oxadiazole (1.28 g, 5.18 mmol, 89% yield). LC-MS (M+H)+ 248.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[S:32]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1)(=[O:35])(=[O:34])[NH2:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:41][CH2:40][C:39]3[CH:38]=[CH:37][C:36]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:43][CH:42]=3)=[O:23])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(CNC(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)cc1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-sulfamoylbenzylamine as in General Procedure 10 to give the title compound. LCMS: In/z=615.9 (M+H+); retention time=0.77 minutes.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH:11]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(CO)c1ccccc1
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
reacting 2-hydroxyacetophenone appropriately substituted with A, B and C with benzaldehyde appropriately substituted with D and E to obtain chalcone;
Reaction SMILES: [CH:1]([C:3]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=[CH2:2].[H-].[Na+].S(OC)(O[CH3:16])(=O)=O.[NH4+].[Cl-]>O1CCCC1>[CH3:16][O:9][C:3]1([CH:1]=[CH2:2])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COS(=O)(=O)OC
Reactant: C=CC1(O)CCOCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC1(OC)CCOCC1
Temperature: 25 °C

Procedure:
To a solution of EXAMPLE 234A (9.4 g) in tetrahydrofuran (150 mL) was added 60% sodium hydride (5.28 g) at 0° C. portionwise. After the addition was complete, the solution was heated under reflux for three hours. After cooling, to this suspension was added dimethyl sulfate (8.41 mL) slowly. The solution was heated under reflux overnight, cooled to room temperature, and hydrolyzed with cool saturated aqueous NH4Cl. After extraction with diethyl ether several times, the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatograph on silica gel using 1-10% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH2:14][CH:15]1[CH2:17][CH2:16]1.[C:18]([CH:20]1[CH2:22][CH2:21]1)#[CH:19]>C1(C)C=CC=CC=1.C(N(CC)CC)C.CO.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]1([C:18]#[C:19][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:22][CH2:21]1
Reactant: C#CC1CC1
Reactant: CCOC(=O)c1ccc(Br)c(OCC2CC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C#CC2CC2)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61 %

Procedure:
Ethyl 4-bromo-3-(cyclopropylmethoxy)benzoate (0.77 g, 2.57 mmol), ethynylcyclopropane (0.45 mL of a 70% w/v solution in toluene, 3.86 mmol), copper(I) iodide (49 mg, 0.26 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.36 g, 0.51 mmol) were placed in 50 mL triethylamine and stirred in a sealed tube at room temperature for 20 h. The reaction was diluted with MeOH and filtered through Celite®., then the filtrate was concentrated to an oil. Purification by column chromatography on silica gel using 25% EtOAc/hexane gave the product (0.47 g, 61%) as a brown oil.
Reaction SMILES: [CH3:1][O-].[Na+].[I:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([CH3:12])[C:6]=1[CH3:13].C=O.[BH4-].[Na+].[OH-].[Na+]>CO>[I:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][CH3:1])=[C:7]([CH3:12])[C:6]=1[CH3:13]
Reactant: Cc1c(N)ccc(I)c1C
Reactant: C[O-]
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc(I)c(C)c1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 88 %

Procedure:
A 28% solution of sodium methoxide in methanol (0.694 ml, 6.07 mmol) was added to a solution of 4-iodo-2,3-dimethyl-aniline (500 mg, 2.02 mmol) and paraformaldehyde (121 mg, 4.05 mmol) in methanol (8.0 ml), and the mixture was stirred at room temperature for 17 hours. Sodium borohydride (153 mg, 4.05 mmol) was further added, and the mixture was stirred at room temperature for four hours. A 1 N aqueous NaOH solution was added to the reaction mixture, followed by extraction with dichloromethane. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-iodo-N,2,3-trimethyl-aniline (146 mg, 88%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[C:18](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH3:18])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(OC)c(O)c1
Reaction time: 8 h

Procedure:
A mixture of 3-hydroxy-4-methoxybenzoic acid (Aldrich, 10 g, 59.5 mmol), methanol (250 ml) and concentrated sulfuric acid (1 ml) was stirred overnight and the product was poured into a mixture of sodium bicarbonate and ice. The aqueous mixture was then extracted three times with ethyl acetate. The resulting organic layers were combined, washed with water and brine, and dried over anhydrous magnesium sulfate. Rotary evaporation of the solution gave 9.5 g of the desired product as a colorless oil. NMR (δ):3.89 (s, 3H), 3.95 (s, 3H).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]O)=[CH:12][CH:11]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[O:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.CC(C)=O>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][N:21]3[C:22](=[O:24])[CH2:23][O:19][C:20]3=[O:25])=[CH:14][CH:15]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: OCCc1ccc(-n2ccc3cccnc32)cc1
Reactant: O=C1COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C1COC(=O)N1CCc1ccc(-n2ccc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.6 %

Procedure:
A solution of 1.0 g (4.20 mmol) of 2-[4-(1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl]ethanol, prepared in step 13.1., 0.51 g (5.04 mmol) of 1,3-oxazolidine-2,4-dione and 1.21 g (4.62 mmol) of triphenylphosphine in 16 ml of tetrahydrofuran, cooled by a bath of acetone and ice, is admixed dropwise with 0.84 g (4.2 mmol) of diisopropyl azodicarboxylate in solution in 2 ml of tetrahydrofuran. The mixture is subsequently heated to ambient temperature again and stirred overnight. 4 g of silica are added and the mixture is evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 70/30 then 60/40 then 50/50 and 40/60 mixture of cyclohexane and ethyl acetate, to give 1.52 g of product in the form of a sticky solid, which is used as it is in the following step.
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([CH:9]2[CH2:12][CH2:11][CH:10]2[C:13]([OH:15])=[O:14])=[O:8])=[CH:5][CH:4]=1.Br.[C:19](O)(=O)[CH3:20]>O>[CH2:19]([O:15][C:13]([CH:10]1[CH2:11][CH2:12][CH:9]1[C:7](=[O:8])[C:6]1[CH:16]=[CH:17][C:3]([OH:2])=[CH:4][CH:5]=1)=[O:14])[CH3:20]
Reactant: COc1ccc(C(=O)C2CCC2C(=O)O)cc1
Reactant: CC(=O)O
Agent: Br
Solvent: O
Product: CCOC(=O)C1CCC1C(=O)c1ccc(O)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 2-(4-methoxy-benzoyl)-cyclobutanecarboxylic acid (10.28 g, 43.88 mmol) was added 48% hydrogen bromide in water (50 mL) and acetic acid (50 mL). After overnight stirring at 120° C., the reaction was concentrated, stirred with ethanol a few times, and the product was purified using a Single Step column (7:3 hexanes:ethyl acetate) to obtain 7.70 g (71%); MS m/z 247 (M−H)
Reaction SMILES: [C:1]([CH:4]1[N:9]([CH3:10])[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)(=O)[NH2:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[C:1]([CH:4]1[N:9]([CH3:10])[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)(=[S:27])[NH2:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1C(N)=O
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)OC(C)(C)C)CC1C(N)=S
Yield: 79.9 %

Procedure:
tert-Butyl 3-carbamoyl-4-methylpiperazine-1-carboxylate (400 mg, 1.64 mmol) was dissolved in toluene (20 mL) and Lawesson reagent (332 mg, 0.82 mmol) was added. The reaction mixture was heated to reflux for 5 h. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10-15% MeOH in CHCl3) to afford tert-butyl 3-carbamothioyl-4-methylpiperazine-1-carboxylate (0.17 g, yield 40%) as pale yellow liquid. 1H NMR (300 MHz, CDCl3) δ 8.16 (br s, 1H), 7.47 (br s, 1H), 4.28-4.21 (m, 1H), 4.06-3.99 (m, 1H), 3.62 (m, 1H), 3.18-3.13 (dd, J=10.2 Hz, 4.1 Hz, 1H), 2.89-2.82 (m, 2H), 2.52-2.47 (dd, J=11.5 Hz, 3.4 Hz, 1H), 2.26 (s, 3H), 1.47 (s, 9H). MS (ESI) m/z: Calculated for C11H21N3O2S: 259.14. found: 260.2 (M+H)+
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[N:15]12[CH2:23][CH2:22][CH2:21][C@@H:20]1[CH2:19][NH:18][CH2:17][CH2:16]2.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:18]2[CH2:17][CH2:16][N:15]3[CH2:23][CH2:22][CH2:21][C@@H:20]3[CH2:19]2)=[CH:3][C:4]=1[O:11][CH:12]([CH3:14])[CH3:13])([O-:10])=[O:9]
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1cc(N2CCN3CCC[C@@H]3C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 21 h
Yield: 93.9 %

Procedure:
A mixture of 1.0 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 634 mg of (R)-1,4-diazabicyclo[4,3,0]nonane and 1.04 g of potassium carbonate in 7 ml of DMSO is stirred at ambient temperature for 21 hours. The reaction medium is run into 15 ml of water and the mixture is then extracted three times with 30 ml of ethyl acetate. The organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum, so as to obtain 1.44 g of (8aR)-2-[4-nitro-3-(propan-2-yloxy)phenyl]octahydropyrrolo[1,2-a]pyrazine in the form of an orangey-coloured oily residue.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([OH:16])[N:10]=1)[CH2:2]2.Cl.[CH:18]12[O:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][NH:20][CH2:19]2.CCN(C(C)C)C(C)C>CO>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:14]=[C:13]([N:20]3[CH2:19][CH:18]4[O:25][CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[N:12]=[C:11]([OH:16])[N:10]=1)[CH2:2]2
Reactant: Oc1nc(Cl)cc(N2CC3CCC(C2)O3)n1
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Oc1nc(N2CC3CCC(C2)O3)cc(N2CC3CCC(C2)O3)n1
Temperature: 140 °C
Yield: 41.6 %

Procedure:
In a 2-5 mL microwave vial was placed 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloropyrimidin-2-ol (26, 50 mg, 0.207 mmol) in MeOH (2.5 ml) to give a colorless solution. 8-Oxa-3-azabicyclo[3.2.1]octane, HCl (2, 61.9 mg, 0.414 mmol) and DIPEA (0.217 ml, 1.241 mmol) were added. The reaction was heated under microwave irradiation at 140° C. for 30 min. Silica gel was added and the solvents were removed under reduced pressure. The mixture was purified by HPLC, using NH4OH buffers (Waters semi-prep LCMS) to give the title compound (27.4 mg, 42%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.S(Cl)(Cl)=O.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34].[OH-].[Na+]>C(Cl)Cl.O.CN(C)C=O>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:5][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)=[O:9]
Reactant: CN(C)CCN
Reactant: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1C(=O)NCCN(C)C
Reaction time: 2.5 h
Yield: 36.7 %

Procedure:
To a mixture of 2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylic acid (1.98 g), methylene chloride (20 ml) and N,N-dimethylformamide (4 ml) was added a solution of thionyl chloride (0.47 ml) in methylene chloride (2 ml) at 7° C. under ice cooling. After stirring for 2.5 hours at the same condition, a solution of 2-dimethylaminoethylamine (1.3 g), in methylene chloride (20 ml) was added thereto and stirred for 2 hours at the same temperature. After adding water (150 ml) and methylene chloride (150 ml) thereto, the mixture was adjusted to pH 9.0 with 10% aqueous sodium hydroxide. The organic layer was separated, washed successively with water and saturated brine, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a column chromatography on alumina (70 g) and eluted with chloroform. The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 3-(2-dimethylaminoethylcarbamoyl)-2-methyl-4-(3-nitrophenyl)-6-phenylpyridine (0.88 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].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>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH:31][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([O:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1ccc(Oc2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Oc2cccc(F)c2)cc1
Yield: 20.5 %

Procedure:
A solution of 4-(3-fluorophenoxy)benzoic acid (0.180 g, 0.775 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.180 g; 0.775 mmol), HATU (0.324 g; 0.852 mmol) and N,N-diisopropylethylamine (0.334 mL; 1.94 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 20% ethyl acetate in dichloromethane and 20 to 100% ethyl acetate in heptane) to yield 0.065 g (20%) of the title compound as a white solid.