Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1OS(C(F)(F)F)(=O)=O.I[C:28]1[CH:36]=[C:35](C([O-])=O)[CH:34]=[CH:33][C:29]=1C([O-])=O>>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1[C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:29]=1
Reactant: COC(=O)c1ccc(OCc2cccnc2)cc1OS(=O)(=O)C(F)(F)F
Reactant: O=C([O-])c1ccc(C(=O)[O-])c(I)c1
Product: COC(=O)c1ccc(OCc2cccnc2)cc1-c1ccccc1

Procedure:
The desired compound was prepared according to the method of Example 158A, except substituting 4-(3-pyridylmethyloxy)-2-trifluoromethanesulfonyloxybenzoic acid methyl ester, prepared as in Example 240C for 2-iodoterephthalate.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[Li]CCCC.C[O:13][C:14](=O)[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Br:22])[CH:16]=1.Cl>C1COCC1.O>[Br:22][C:17]1[CH:16]=[C:15]([C:14]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[O:13])[CH:20]=[C:19]([Cl:21])[CH:18]=1
Reactant: COC(=O)c1cc(Cl)cc(Br)c1
Reactant: Cc1cncs1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(C(=O)c2cc(Cl)cc(Br)c2)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
To a stirring mixture of 5-methylthiazole (4.37 g, 44.1 mmol) in dry THF (30 L) under was added n-BuLi (44.1 mmol, 17.64 ml solution in hexanes) drop wise over 10 minutes at −78° C. under nitrogen atmosphere. The mixture was stirred between −78° C. and −60° C. for 30 minutes and then cooled to −78° C. A solution of 3-Bromo-5-chloro-benzoic acid methyl ester (11.0 g, 44.1 mmol) in THF (20 mL) was added drop wise over 10 minutes. The resulting mixture was stirred at −78° C. for 30 minutes and warmed to room temperature with stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL). The resulting mixture was adjusted to pH around 6 with HCl (1N) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc mixtures to afford (3-Bromo-5-chloro-phenyl)-(5-methyl-thiazol-2-yl)-methanone (14 g, yield=100%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.I[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: OCc1ccc(I)cc1
Reactant: Oc1ccc(Cl)cn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=c1ccc(Cl)cn1-c1ccc(CO)cc1

Procedure:
5-Chloro-2-pyridinol (0.61 g, 4.7 mmol), 4-iodobenzyl-alcohol (1.00 g, 4.27 mmol), Copper (0.27 g, 4.27 mmol) and K2CO3 (0.65 g, 4.70 mmol) were heated at 180° C. for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (2×) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc as eluent) to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(C[C:49]2[CH:50]=[C:51]([CH:55]=[CH:56][CH:57]=2)[C:52]([OH:54])=[O:53])N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:49]3[CH:50]=[C:51]([CH:55]=[CH:56][CH:57]=3)[C:52]([OH:54])=[O:53])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: Nc1ccn(Cc2cccc(C(=O)O)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)O)c3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 760 mg, 2.30 mmol) was dissolved in methylene chloride (10 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (1.15 mL, 2.30 mmol) was added and the reaction stirred at 25° C. for 15 min. The solution was chilled to 0° C. and 2,6-lutidine (0.536 mL, 4.6 mmol) was added dropwise. The reaction continued to stir at 0° C. for 15 min. The 3-(3-amino-pyrazol-1-ylmethyl)-benzoic acid (500 mg, 2.30 mmol) was added as a pre-dissolved reaction in methylene chloride (10 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (100 mL), washed with water (2×30 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Recrystallization from 17% ethyl acetate/methylene chloride afforded 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (684 mg, 56%) as a white powder: ESI-LRMS m/e calcd for C26H28ClN3O5S [M+] 529.14, found 530.26 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:11][O:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[N:7][CH:6]=1)=[O:10]
Reactant: O=C(O)c1cnc(Cl)nc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1cnc(Cl)nc1
Reaction time: 0.5 h

Procedure:
To a solution 2-chloropyrimidine-5-carboxylic acid (1.63 g, 10.28 mmol) in a mixture of methanol (20 ml) and benzene (50 ml) was added a solution of (trimethylsilyl)diazomethane in hexanes (2.0 M, 10 ml) at room temperature. The mixture was stirred for 30 min, and then was concentrated to give the title compound (1.77 g) as a yellow solid. Mass spectrum (ESI) 173.2 (M+1). 1H NMR (500 MHz, CDCl3) δ 9.18 (s, 2H), 4.02 (s, 3H).
Reaction SMILES: C([NH:4][C:5]1[CH:27]=[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:24][C:6]=1[O:7][CH2:8][CH2:9][N:10]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH3:11])(=O)C.[OH-].[Na+].[ClH:35]>>[ClH:35].[NH2:4][C:5]1[CH:27]=[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:24][C:6]=1[O:7][CH2:8][CH2:9][N:10]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH3:11]
Reactant: COc1ccc(CCN(C)CCOc2ccc(NS(C)(=O)=O)cc2NC(C)=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CCN(C)CCOc2ccc(NS(C)(=O)=O)cc2N)cc1OC

Procedure:
1-(2-Acetamido-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (1 g, 2.2 mmol) was heated in 3N HCl (10 ml) at the reflux temperature for 3 h. Thereafter, the reaction mixture was neutralized to a pH of 6-7 with a solution of 10% sodium hydroxide, followed by extraction with ethyl acetate; the organic extract was then dried with magnesium sulfate and the solvent was evaporated. The residue was subjected to column chromatography on silica gel using, as an eluent, chloroform containing methanol (5%-10%) to yield the titled compound 1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane hydrochloride (0.79 g).
Reaction SMILES: O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]([NH:35][NH:36][C:37](=[O:41])[C:38]([NH2:40])=[O:39])=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]1[O:41][C:37]([C:38]([NH2:40])=[O:39])=[N:36][N:35]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(=O)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
(CF3SO2)2O (0.58 g, 2.08 mmol) was slowly added to a −10° C. solution of 2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoacetamide (0.30 g, 0.83 mmol) and pyridine (0.6 mL) in dry DCM (5 mL). The reaction mixture was allowed to warm to rt. The reaction mixture was stirred at rt for 1 h then quenched with sat. NaHCO3 very slowly. The organic layer was separated and the aqueous layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 1:10 to 2:1 EtOAc/hexane followed by 10:1 to 2:1 petroleum ether/EtOAC) to give 5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazole-2-carboxamide (0.18 g, 47%) as a slight yellow solid. ESI-MS (EI+, m/z): 344.0 [M+H]+.
Reaction SMILES: [P:1](Cl)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[S:2].[OH:10][C:11]1[N:15]=[C:14]([N:16]([CH3:18])[CH3:17])[S:13][N:12]=1>>[CH2:4]([O:3][P:1]([O:10][C:11]1[N:15]=[C:14]([N:16]([CH3:18])[CH3:17])[S:13][N:12]=1)([O:6][CH2:7][CH3:8])=[S:2])[CH3:5]
Reactant: CN(C)c1nc(O)ns1
Reactant: CCOP(=S)(Cl)OCC
Product: CCOP(=S)(OCC)Oc1nsc(N(C)C)n1

Procedure:
Using the procedure of Example 6, diethyl chlorothiophosphate and 3 -hydroxy-5-dimethylamino-1,2,4-thiadiazole were reacted and after chromatography and elution with an 8-2benzene-ethylacetate mixture, there was obtained 3-(diethoxythiophosphoryloxy)-5-dimethylamino-1,2,4-thiadiazole with a melting point of 48° C and Rf=0.55.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][C:4]=2[N:3]=1.Br[C:20]1[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Br:26])[CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl.O1CCOCC1>[Br:26][C:24]1[CH:25]=[C:20]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][C:4]=3[N:3]=2)[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)ccc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(Br)cc(Nc2ccc3c(n2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Temperature: 100 °C

Procedure:
To a round-bottomed flask equipped with a stirring bar, 158b (851 mg, 3.41 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.37 g, 5.12 mmol), Pd2(dba)3 (312.5 mg, 0.341 mmol), XantPhos (316 mg, 0.546 mmol), Cs2CO3 (3.67 g, 11.3 mmol) and dioxane (17 mL) were added. The reaction mixture was heated at 100° C. overnight. DCM (200 mL) was added to the resulting mixture was washed with water (30 mL×3). DCM (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. DCM/ether (1:2, 5 mL) was added followed by sonication, the precipitation was filtered as 158c, green solids, 865 mg (58%).
Reaction SMILES: [CH:1]1([N:7]([CH3:18])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.[Na].O>CO.[Ni](Br)Br>[CH:1]1([N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(Cc1ccc([N+](=O)[O-])cc1)C1CCCCC1
Agent: Br[Ni]Br
Agent: B
Agent: [Na]
Solvent: O
Solvent: CO
Product: CN(Cc1ccc(N)cc1)C1CCCCC1
Yield: 36.5 %

Procedure:
To a solution of N-cyclohexyl-N-methyl-N-(4-nitrobenzyl)amine (12.4 g, 50.0 mmol) in methanol(250 ml) were added nickel bromide (1.09 g, 5.0 mmol) and then sodium boron hydride (7.57 g, 200 mmol) at 0° C., and the mixture was stirred at room temperature for 30 minutes. To the mixture were added nickel bromide (0.55 g, 2.5 mmol) and then sodium boron hydride (3.78 g, 100 mmol) at 0° C., and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water (100 ml), and the mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and insoluble material was filtered off with Celite. The filtrate was washed with ethyl acetate, and the ethyl acetate layer was dried with MgSO4 and concentrated under reduced pressure. The residue was washed with hexane to give 4-(N-cyclohexyl-N-methylaminomethyl)aniline (3.99 g, 37%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1(B(O)O)[C:22]2[C:23]3=[C:24]4[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[C:15]4[CH:14]=[CH:13][C:12]3=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[C:15]3[C:24]4=[C:23]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][CH:9]=[C:22]5[CH:21]=[CH:20][C:19]4=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc3ccc4cccc5ccc2c3c45)cc1
Yield: 80.3 %

Procedure:
Under an atmosphere of argon, 4-bromoiodobenzene (7.0 g, 25 mmole), 1-pyreneboronic acid (5.7 g, 23 mmole) and tetrakis(triphenyl-phosphine)palladium(0) (0.5 g, 0.43 mmole, 1.7% Pd) were dissolved into toluene (50 ml). To the obtained solution, an aqueous solution of sodium carbonate (7.3 g, 69 mmole, 3 eq/35 ml) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+10% dichloromethane, successively) and white needle crystals (6.6 g, 80%) were obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:35])[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([NH:16][C:17]([C:19]1[C:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-].Cl>C1COCC1.CO.O>[Cl:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:16][C:17]([C:19]3[C:20]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=4)=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:18])[CH:12]=2)[N:7]([CH3:35])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(C(=O)O)c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of step (d) may be hydrolyzed as follows: the compound (5.51 g) was dissolved in THF (120 mL) and methanol (40 mL). Under stirring conditions was added LiOH (1.32 g) in water (40 mL). The reaction mixture was stirred at room temperature overnight. To the reaction mixture was then added 1 N HCl solution (60 mL), and the aqueous layer was extracted with EtOAc (250 mL). The organic layer was washed with brine (200 mL), and dried (MgSO4). The solvent was evaporated in vacuo to give the crude product which was purified by recrystallization from 1:1 EtOAc/ether to afford 4.4 g of the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:31])[C@:4]1([OH:30])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][C:27]([CH3:29])=[CH2:28].ClC1C=CC=C(C(OO)=[O:40])C=1>ClCCl>[Cl:1][CH2:2][C:3](=[O:31])[C@:4]1([OH:30])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][C:27]1([CH3:29])[CH2:28][O:40]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl
Solvent: ClCCl
Product: CC1(CO[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@@]2(O)C(=O)CCl)CO1

Procedure:
A solution of 21-chloro-11β,17-dihydroxy-16α-(2-methyl-2-propenyloxy)pregna-1.4-diene-3,20-dione (16 mmoles) in 300 ml of dichloromethane is stirred with 3.2 g of m-chloroperbenzoic acid for 3 hours. The solution is washed with a mixture of 5% sodium bicarbonate solution and 5% sodium sulfite solution, dried, and evaporated to give the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[CH:17]=[CH:16][N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH:14]=1)=[O:12].O1CCOCC1.[OH-].[Na+].CCOCC>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[CH:17]=[CH:16][NH:15][CH:14]=1)=[O:12]
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)c3ccc4ccccc4c3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(c1cc[nH]c1)c1ccc2ccccc2c1
Yield: 50.8 %

Procedure:
Into a flask was placed 46 g (0.12 mole) of 3-(2-naphthalenoyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole, 250 mL of 1,4-dioxane and 59.8 mL (0.18 mole) of 3 N NaOH. The reaction mixture was stirred overnight after which Et2O and water were added. The organics were separated off, washed with water, brine and dried (Na2SO4). Evaporation of the solvent in vacuo and crystallization from toluene gave 13.5 g of (51%) 3-(2-naphthalenoyl)-1H-pyrrole. mp134-136° C. CIMS m/z 223 (MH+). 1H NMR (300 MHz, CDCl3) δ 8.35 (Ar, 1H); 7.9 (Ar, 4H); 7.7 (Ar, 1H); 7.5 (Ar, 2H); 7.4 (Ar, 1H); 6.85 (Ar, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[C:8]2[C:13]([C:14]=1[C:15](=[O:19])C(O)=O)=[CH:12][C:11]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:10][CH:9]=2)(=[O:3])C.[OH-].[K+].Cl>>[CH2:21]([O:20][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1)[C:6]1[CH2:5][O:4][C:1](=[O:3])[C:15](=[O:19])[C:14]2=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)OCc1c(C(=O)C(=O)O)c2cc(OCc3ccccc3)ccc2n1Cc1ccc(C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(Cn2c3c(c4cc(OCc5ccccc5)ccc42)C(=O)C(=O)OC3)cc1

Procedure:
The title compound was prepared from [2-[(acetyloxy)methyl]-5-(benzyloxy)-1-(4-methylbenzyl)-1H-indol-3-yl](oxo)acetic acid and aqueous potassium hydroxide according to the procedure described in step 6 of Example 1, followed by the treatment with aqueous HCl in substantially the same manner, as described in step 7 of Example 1. The product was obtained as an off-white solid; mp: 206-207° C. Mass spectrum (ESI, [M+H]+) m/z 412. 1H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 1H), 7.54 (d, 1H, J=9.01 Hz), 7.47 (d, 2H, J=7.33 Hz), 7.38 (t, 2H, J=8.63 Hz), 7.31 (t, 1H, J=7.18 Hz), 7.15-7.11 (m, 4H,), 7.05 (dd, 2H, J=9.44 and 2.44 Hz), 5.86 (s, 2H), 5.41 (s, 2H), 5.16 (s, 2H), 2.25 ppm (s, 3H).
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([O:22][CH3:23])=[N:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][N:17]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.[F:33][CH:34]([F:53])[CH2:35][N:36]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([NH:47][CH2:48][CH2:49][C:50]#[N:51])[N:42]=2)[C:38](I)=[N:37]1.[F-].[Cs+].[I-]>C(COC)OC>[NH2:8][C:16]1[N:17]=[CH:18][C:19]([C:38]2[C:39]([C:41]3[CH:46]=[CH:45][N:44]=[C:43]([NH:47][CH2:48][CH2:49][C:50]#[N:51])[N:42]=3)=[CH:40][N:36]([CH2:35][CH:34]([F:53])[F:33])[N:37]=2)=[N:20][C:21]=1[O:22][CH3:23]
Reactant: N#CCCNc1nccc(-c2cn(CC(F)F)nc2I)n1
Reactant: COc1nc(B2OC(C)(C)C(C)(C)O2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Cs+]
Agent: [F-]
Agent: [I-]
Solvent: COCCOC
Product: COc1nc(-c2nn(CC(F)F)cc2-c2ccnc(NCCC#N)n2)cnc1N
Temperature: 80 °C

Procedure:
To a solution of the crude di-tert-butyl[3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl]imidodicarbonate B-79-3 (0.6 mmol) in dimethoxyethane (2.5 mL) was added 3-{4-[1-(2,2-Difluoro-ethyl)-3-iodo-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-propionitrile B-33-3 (150 mg, 0.37 mmol) and Cesium Fluoride (1.1 mL of a 1M aqueous solution, 1.1 mmol). The resulting mixture was deoxygenated with a nitrogen bubbler for 5 min and then 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (15 mg, 0.019 mmol) was added. The mixture was then heated in an 80° C. oil bath for 20 hours. LCMS indicated the iodide had been completely consumed. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organics were dried over magnesium sulfate and reduced to minimum volume. The residue was taken up in dimethoxyethane (3 mL) and then heated at 170° C. in the microwave for 25 minutes to thermolyze the tert-butoxycarbonyl groups. The resulting dark mixture was filtered through a 0.45μ filter and the filtrate reduced to minimum volume. The residue was purified by HPLC to give 59 mg (37%) of B-79 as a fluffy white solid after lyophilization of the desired fractions. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.17 (s, 1H), 8.15 (d, J=5.05 Hz, 1H), 7.83 (s, 1H), 6.72 (d, J=5.31 Hz, 1H), 6.27 (tt, J=54.98, 3.76 Hz, 1H), 5.91 (br.t, J=5.18 Hz, 1H), 5.34 (br. s., 2H), 4.59 (td, J=14.65, 3.79 Hz, 2H), 3.76 (s, 3H), 3.55 (q, J=6.23 Hz, 2H), 2.64 (t, J=6.44 Hz, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[CH3:9][C:10]1([CH2:16][NH2:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(N(CC)CC)C>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([NH:17][CH2:16][C:10]2([CH3:9])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(CN)CCOCC1
Reactant: Fc1cccc(Br)n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1(CNc2cccc(Br)n2)CCOCC1
Temperature: 110 °C

Procedure:
To a solution of 2-bromo-6-fluoropyridine (619 mg, 3.52 mmol) in DMSO (3 mL) was added (4-methyltetrahydro-2H-pyran-4-yl)methanamine (500 mg, 3.87 mmol) and triethylamine (498 mg, 4.93 mmol). The mixture was heated at 110° C. for 18 hr. The mixture was allowed to cool to ambient temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 solution (1×), water (1×), brine (1×), dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 24 g, EtOAc/heptane= 0/100 2 min, 0/100 to 40/60 2-25 min] providing 6-bromo-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as a white solid. Yield: 750 mg. LCMS (m/z): 285.0/287.0 [M+H]+; Retention time=0.88 min.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:13]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[O:18]=[C:17]1[CH:16]=[CH:15][N:14]([CH:19]2[CH2:24][CH2:23][N:22]([C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[CH2:21][CH2:20]2)[N:13]=[C:12]1[C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9][CH:10]=1
Reactant: O=c1ccn(C2CCNCC2)nc1-c1ccnn1-c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)N1CCC(n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(1-phenyl-1H-pyrazol-5-yl)-1-piperidin-4-ylpyridazin-4(1H)-one (0.10 g) in THF (10 mL) was added phenyl isocyanate (0.041 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was recrystallized from 2-propanol/n-heptane to give the title compound (0.13 g).