Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH:13]=[O:14])[O:11][C:10]([CH3:16])([CH3:15])[N:9]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH:25]1[CH2:28][CH2:27][CH2:26]1.[Mg].[Cl-].[NH4+]>O1CCCC1>[CH:1]1([CH2:7][C@H:8]2[C@H:12]([C@H:13]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[OH:14])[O:11][C:10]([CH3:16])([CH3:15])[N:9]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: BrC1CCC1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](C=O)OC1(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)C2CCC2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.8 %

Procedure:
A solution of 7.23 g (22.2 mmol) of t-butyl (4S,5R)-4-(cyclohexylmethyl)-5-formyl-2,2-dimethyl-3-oxazolidinecarboxylate in 150 ml of tetrahydrofuran is added dropwise within 40 minutes at 30° to a solution of the Grignard compound prepared from 15 g (111 mmol) of bromocyclobutane and 2.7 g (111 mgram atom) of magnesium shavings in 150 ml of tetrahydrofuran and the reaction mixture is subsequently stirred at room temperature overnight. Thereafter, the reaction mixture is poured into 300 ml of a saturated ammonium chloride solution and extracted three times with 600 ml of ether each time. The ether extracts are washed with ammonium chloride solution, dried, filtered and evaporated. The crude product (9.34 g) is chromatographed on 500 g of silica gel with a 92.5:7.5 mixture of toluene and ethyl acetate as the eluting agent, whereby there are obtained 2.44 g of t-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(S)-cyclobutylhydroxymethyl]-2,2-dimethyl-3-oxazolidinecarboxylate as an oil, MS: 381 (M)+, and 2.9 g of the epimeric compound t-butyl (4S,5R)-4-(cyclohexYlmethyl)-5-[(R)-cyclobutylhydroxymethyl]-2,2-dimethyl-3-oxazolidinecarboxylate, likewise as an oil, MS: 381 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:3][CH:4]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C(CBr)c1ccccc1
Product: Cc1ccc(OCC(=O)c2ccccc2)cc1

Procedure:
Using the method of Example 17 and starting with 4-hydroxytoluene and α-bromoacetophenone one obtains α-(4-methylphenoxy)-acetophenone.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5]CN.N[C@H:12](C(O)=O)CS>>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:12]
Reactant: N[C@@H](CS)C(=O)O
Reactant: NCCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
1.3 (1), Lys:5.7 (6), Cys:-(2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26](=[O:39])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37]Br)=[CH:30][CH:29]=1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:39])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][N:13]2[CH2:12][CH2:11][CH:10]([C:8]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:9])[CH2:15][CH2:14]2)=[CH:30][CH:29]=1)[CH3:24]
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CCOC(=O)Nc1ccc(OCCCBr)cc1
Product: CCOC(=O)Nc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1

Procedure:
Following the procedure of Example 1, [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and [4-(3-bromopropoxy)phenyl]carbamic acid ethyl ester are reacted to give the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1.O>CN(C)C=O>[CH:13]1[C:14]2[N:15]([CH2:18][CH2:19][O:20][C:21]3[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=3)[C:16]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:8][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To a suspension of sodium hydride (60% mineral oil, 0.13 g, 3.24 mmol) in dimethyl formamide (3 ml) was added phenoxazine (0.5 g, 2.7 mmol) in dimethyl formamide (5 mL). The reaction mixture was stirred at 25° C. for 0.5 h and a solution of 4-(2-bromoethoxy)benzaldehyde (0.74 g, 3.24 mmol) in dimethyl formamide (3 mL) was added. The reaction mixture was stirred at 25° C. for 6 h. Water (25 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (50 ml), brine solution (50 ml) and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (3:7) as eluent to afford the title compound (0.52 g, 57%) as a syrupy liquid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[I:12][C:13]1[CH:18]=[CH:17][C:16](O)=[C:15]([CH3:20])[CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O>C1COCC1>[Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:5][C:16]1[CH:17]=[CH:18][C:13]([I:12])=[CH:14][C:15]=1[CH3:20]
Reactant: O[C@H](CCCl)c1ccccc1
Reactant: Cc1cc(I)ccc1O
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1O[C@@H](CCCl)c1ccccc1
Yield: 69.5 %

Procedure:
The compound [S]-(-)-1-chloro-3-phenyl-3-(4-iodo-2-methylphenoxy)propane (Compound 12) was prepared in the same manner as Compound 2 in Example 1 but using [R]-3-chloro-1-phenylpropanol (1.0 g, 5.88 mmol), 4-iodo-2-methylphenol (1.38 g, 5.88 mmol), triphenylphosphine (1.54 g, 5.88 mmol) and ethyl azodicarboxylate (0.93 mL, 1.04 g, 5.88 mmol) in THF (15 mL) at room temperature for 15 hours. Workup and purification gave 1.58 g (69%) of Compound 12 as a thick pale yellow liquid: [α]25D +14.97 (c 10.73, CHCl3); 1H NMR (CDCl3, 250 MHz) δ 7.42-7.20 (m, 7H), 6.39 (d, J=8.8 Hz, 1H), 5.34 (dd, J=4.6, 8.8 Hz, 1H), 3.83-3.73 (m, 1H), 3.65-3.55 (m, 1H), 2.55-2.40 (m, 1H), 2.29-2.13 (m, 1H), 2.25 (s, 3H), FTIR (neat) 3050, 3015, 2950, 2900, 1600, 1480 (s), 1460, 1395, 1350, 1300, 1250(s), 1200, 1135 cm-1. Anal C17H20INO; C, H.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[CH:12]=2)[CH2:3][CH2:2]1.Br[C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:35]1[CH2:40][CH2:39][N:38]([S:41]([CH2:44][CH3:45])(=[O:43])=[O:42])[CH2:37][CH2:36]1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[CH:12]=[C:11]([C:23]3[CH:24]=[C:25]4[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=3)[NH:28][CH:27]=[C:26]4[CH:35]3[CH2:36][CH2:37][N:38]([S:41]([CH2:44][CH3:45])(=[O:42])=[O:43])[CH2:39][CH2:40]3)[CH:10]=[N:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cncc(CNCC3CC3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Temperature: 150 °C
Reaction time: 0.13 h

Procedure:
To a CEM microwave tube containing (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine (21 mg, 0.0725 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), dioxane (0.75 mL), a solution of potassium carbonate (60 mg, 0.434 mmol) in H2O (0.25 mL), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with H2O (3 mL), MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40° C. and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 65° C. to give impure title compound, which was repurified on the Agilent MDAP as shown above to give 25 mg of the title compound (70%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH:15]=[C:14]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=1)[CH:13]=[CH:12]2)(=[O:3])[CH3:2].CO.O.[OH-].[Na+]>C1COCC1>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH:15]=[C:14]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=1)[CH:13]=[CH:12]2)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc(OCCOc3ccc4cccc(CCNC(C)=O)c4c3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCCc1cccc2ccc(OCCOc3ccc(-c4ccc(C(=O)O)cc4)cc3)cc12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
In a 100 ml round-bottomed flask, 19 mmol of the compound obtained in Example 1 are suspended in 25 ml of THF, and then 15 ml of methanol, 15 ml of water and 38 mmol of sodium hydroxide are added. The reaction mixture is maintained at ambient temperature with stirring for 10 hours. The solution is subsequently concentrated, poured into water and then acidified with 12M HCl. The precipitate obtained is filtered off, washed with water and recrystallised to yield the title product.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([OH:22])(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O>>[OH:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([OH:22])=[C:1]([CH3:8])[CH:2]=2)=[CH:2][C:1]=1[CH3:8].[OH:7][C:6]1[CH:5]=[CH:4][C:3]([C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([CH3:8])[CH:2]=2)=[O:22])=[CH:2][C:1]=1[CH3:8]
Reactant: Cc1ccccc1O
Reactant: O=C(O)CCCCCCCCC(=O)O
Product: Cc1cc(C(=O)CCCCCCCCC(=O)c2ccc(O)c(C)c2)ccc1O
Product: Cc1cc(CCCCCCCCCCc2ccc(O)c(C)c2)ccc1O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
This was prepared by the method reported by Schlack and Koller in Aromatic aliphatic diketones. P Schlack and W Koller. Ger. 1,086,711 Aug. 11, 1960. The title compound was prepare by treatment of orthocresol (2.2 moles) with sebacic acid (1 mole) in the presence of polyphosphoric acid (3 moles). The mixture was stirred for 4 hrs at 80° C. and poured to ice-water after cooling. The precipitant was filtered, dissolved in ethyl acetate and washed with water three times. The solvent was evaporated to yield a crude 1,10-bis(4-hydroxy-3-methylphenyl)decane-1,10-dione which was then subjected to Clemmensen reduction to give the title compound.
Reaction SMILES: [Cl-].ClC1N(C)CC[NH+]1C.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[N:15][CH:16]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[C:40]([O:47][C:48](=[O:50])[CH3:49])[CH:39]=2)[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:18][O:17][C:14]1[N:15]=[CH:16][C:11]([NH:10][C:42](=[O:43])[C:41]2[CH:45]=[CH:46][C:38]([CH2:37][C:31]3[C:32](=[O:36])[C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[C:29](=[O:52])[C:30]=3[CH3:51])=[CH:39][C:40]=2[O:47][C:48](=[O:50])[CH3:49])=[CH:12][CH:13]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OC(C)=O)c2)=C(C)C1=O
Reactant: COc1ccc(N)cn1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccc(OC)nc3)c(OC(C)=O)c2)=C(C)C1=O
Yield: 17.8 %

Procedure:
2-Chloro-1,3-dimethylimidazolinium chloride (93 mg, 0.555 mmol), 5-amino-2-methoxypyridine (55 mg, 0.440 mmol) and triethylamine (44 mg, 0.440 mmol) were added to a methylene chloride solution (5 ml) of 4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (137 mg, 0.366 mmol) in a nitrogen atmosphere and the resulting solution was stirred all the night through. The reaction solution was diluted with chloroform, then washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (hexand:ethyl acetate=3:1) to obtain the titled compound (31 mg, 0.065 mmol, 18%).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:9][CH:8]=1)[C:4]#N.[OH-:24].[Na+].Cl.[CH3:27][OH:28]>>[CH3:1][O:2][CH:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:9][CH:8]=1)[C:4]([O:28][CH3:27])=[O:24]
Reactant: CO
Reactant: [OH-]
Reactant: COC(C#N)Cc1ccc(OCCN(C)c2ccccn2)cc1
Agent: Cl
Agent: [Na+]
Product: COC(=O)C(Cc1ccc(OCCN(C)c2ccccn2)cc1)OC
Reaction time: 168 h

Procedure:
A mixture of 2-methoxy-3-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]-phenyl]propanonitrile (1.15 g), sodium hydroxide solution (10% w/v; 10 mL) and methanol (20 mL) was heated at reflux for 2.5 hrs, cooled and neutralised to pH7 with dilute HCl. The mixture was evaporated in vacuo and the residue redissolved in methanol presaturated with hydrogen chloride gas. The mixture was allowed to stand at room temperature for 7 days, then evaporated. Saturated sodium bicarbonate solution (100 mL) was added and the suspension extracted with ethyl acetate (3×200 mL). The combined ethyl acetate solutions were washed with water (2×500 mL) and brine (500 mL), dried (MgSO4) and evaporated. The resulting gum was chromatographed on silica gel with 1% methanol in dichloromethane to afford the title compound, a gum.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:8][C:9](=S)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2F)[CH:5]=[CH:6][CH:7]=1.[NH2:19][NH2:20]>CS(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:8][C:9]2[C:10]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NC(=S)c1ccccc1F
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(Br)cccc1Nc1n[nH]c2ccccc12
Temperature: 150 °C

Procedure:
Step 3 A yellow solution of N-(3-bromo-2-methylphenyl)-2-fluorobenzothioamide (500 mg, 1.542 mmol) in DMSO (5 mL) was treated with anhydrous hydrazine (0.484 mL, 15.42 mmol) and heated at 150° C. After 2 h 20 min the solution was cooled to rt, diluted with NaHCO3 (aq) and extracted twice with EtOAc. The combined organic phases were washed twice with water and once with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 85:15 to 50:50 hexane-EtOAc) to provide N-(3-bromo-2-methylphenyl)-1H-indazol-3-amine as a tan waxy solid (162 mg, 35%). 1H NMR (400 MHz, chloroform-d) δ 9.38 (1 H, br. s.), 7.49 (1 H, d, J=8.1 Hz), 7.45 (1 H, d, J=7.9 Hz), 7.40 (2 H, d, J=3.5 Hz), 7.19 (1 H, dd, J=7.9, 0.9 Hz), 7.10 (1 H, dt, J=8.1, 4.0 Hz), 6.98 (1 H, t, J=8.1 Hz), 6.10 (1 H, s), 2.49 (3 H, s). Mass spectrum m/z 302, 304 (M+H)+.
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=3)=[O:27])[CH:21]=2)=[CH:15][CH:14]=1.O.[ClH:39].CCCCO>CCO.[Fe]>[Cl-:39].[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26]([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[NH:19][C:16]2[CH:15]=[CH:14][N+:13]([CH3:12])=[CH:18][CH:17]=2)=[O:27])=[CH:30][CH:31]=1
Reactant: C[n+]1ccc(Nc2cccc(C(=O)Nc3ccc([N+](=O)[O-])cc3)c2)cc1
Reactant: Cl
Agent: [Fe]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Solvent: CCCCO
Solvent: CCO
Product: C[n+]1ccc(Nc2cccc(C(=O)Nc3ccc(N)cc3)c2)cc1
Product: [Cl-]
Reaction time: 1 h
Yield: 80 %

Procedure:
Compound C5 (1.59 g, 3.06 mmol) was dissolved in ˜6:1 EtOH:H2O (46 mL), Fe dust (885 mg) was added, and the resulting suspension brought to reflux. Two drops of c.HCl were added, and refluxing was continued for 1 h. (until TLC with the top phase of 5:4:1 mixture of n-BuOH:H2O:CH3CO2H showed complete consumption of starting material). The reaction mixture was diluted with EtOH (100 mL) and brought to reflux. The hot reaction mixture was filtered through a pad of Celite, and the top layer of the Celite pad was boiled with more EtOH and filtered (this procedure was repeated three times to ensure complete extraction of product from iron residues). The combined EtOH extracts were evaporated to dryness, and the residue was extracted with hot water, and filtered through a pad of Celite. The filtrate was concentrated to a smaller volume, and then stirred in pre-washed ion-exchange resin (55g). The resulting slurry was loaded onto a column packed with pre-washed ion-exchange resin and eluted with water. Fractions containing product were combined and evaporated to dryness, and the residue was azeotroped several times with EtOH. The residue was dissolved in a small volume of MeOH, methanolic HCl (1.25 M ,1 mL) was added, and the solution stirred for 10 min. The solution was diluted with EtOAc, and the resulting precipitate filtered and then crystallized from MeOH/EtOAc to give C6 (873 mg, 80%); mp (MeOH/EtOAc)>300° C.; 1H NMR [(CD3)2SO] δ10.77 (br s, 1 H, NH), 9.95 (s, 1 H, NH), 8.41 (br d, J=5.5 Hz, 2 H, Py H-2,6), 7.87-7.84 (m, 2 H, H-2,4), 7.61 (t, J=7.8 Hz, 1 H, H-5), 7.49 (br d, J=7.8 Hz, 1 H, H-6), 7.37 (d, J=8.7 Hz, 2 H, H-2′,6′), 7.21 (br d, J=4.6 Hz, 2 H py H-3,5), 6.55 (d, J=8.8 Hz, 2 H, H-3′,5′), 4.93 (s, 2 H, NH2), 3.97 (s, 3 H, N+CH3).
Reaction SMILES: ClC([O:4][CH2:5][CH3:6])=O.[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]2(CC(O)=O)[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[NH:15]2)[CH:9]=1.C(N(CC)CC)C.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]2[N:22]([CH2:6][C:5]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[O:4])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:9]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)Cl
Reactant: O=C(O)CC1(c2cc(Cl)ccn2)Nc2cccnc2N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)Cn2c(-c3cc(Cl)ccn3)nc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
A solution of ethyl chloroformate (0.66 g, 0.0061 mole) in 20 ml of methylene chloride was added slowly to a solution of 2-(4-chloro-2-pyridinyl)-3H-imidazo[4,5-b]pyridine acetic acid (1.75 g, 0.006 mole) and triethylamine (0.68 g, 0.0067 mole) in 75 ml of methylene chloride. After the solution was allowed to stir at room temperature for 2 hrs, a solution of N-methylpiperazine (0.61 g, 0.0061 mole) in metylene chloride was added slowly at room temperature and allowed to stir overnight. The recaction mixture was filtered and the filtrate was evaporated to dryness. The residue was partitioned between dilute hydrochloric acid and diethyl ether. The aqueous layer was separated and extracted with diethyl ether (2x) and methylene chloride (3x). The aqueous layer was neutralized (pH 7) and refrigerated. The small amount of precipitate was removed by filtration. The aqueous filtrate was basified and extracted with methylene chloride (3x). The methylene chloride extracts were combined and evaporated to a gum. The gummy residue was purified by alumina column chromatography (Brockman activity 1, 80-200 mesh, 40 g) by elution with 20% acetone/80% benzene. The appropriate fractions (TLC) were combined and evaporated. The residue was crystallized from acetone/petroleum ether (bp 50°-110° C.). The crystalline solid was collected, washed with petroleum ether and isopropyl ether, and dried under high vacuum at room temperature to give 0.54 g (24%) of title compound, mp 174°-75° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26]([OH:28])=O)[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C[N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[Br:62][C:63]1[CH:64]=[C:65]([CH2:70]N)[CH:66]=[CH:67][C:68]=1[CH3:69]>C(Cl)Cl>[Br:62][C:63]1[CH:64]=[C:65]([CH2:70][N:20]([CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:29][CH3:30])[C:21]([C:23]2([C:26]([NH2:32])=[O:28])[CH2:25][CH2:24]2)=[O:22])[CH:66]=[CH:67][C:68]=1[CH3:69]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)O)CC1
Reactant: Cc1ccc(CN)cc1Br
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(Br)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
A mixture of 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylic acid (600 mg, 1.444 mmol), HBTU (657 mg, 1.733 mmol), Et3N (1006 μL, 7.22 mmol) and 1-(3-bromo-4-methylphenyl)methanamine (318 mg, 1.589 mmol) in DCM was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give the crude residue. It was then purified with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-[(3-bromo-4-methylphenyl)methyl]-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (70 mg, 8.11%). LC-MS m/z 597 M+, 0.88 min (ret time).
Reaction SMILES: O1[C:5]2[CH:6]=[CH:7][C:8]([C:10](OC)=O)=C[C:4]=2[CH:3]=[CH:2]1.[C:14]([O-:17])(O)=O.[Na+].[Br:19]Br.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:10][C:8]1[O:17][C:14]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[C:7]=1[Br:19]
Reactant: BrBr
Reactant: COC(=O)c1ccc2occc2c1
Reactant: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1oc2ccccc2c1Br
Reaction time: 1 h
Yield: 75 %

Procedure:
Methyl benzofuran-5-carboxylate (1.74 g, 9.9 mmol) is dissolved in CH2Cl2 (50 mL), layered with saturated NaHCO3 (75 mL) using very slow magnetic stirring so that the two layers are not mixed and treated with Br2 (3.1 mL, 59.1 mmol). The bi-phasic mixture is stirred slowly for 2 h, then vigorously for 1 h. The layers are separated and the aqueous layer is extracted with CH2Cl2 (2×50 mL). The organics are dried (Na2SO4) and concentrated under reduced pressure without heat. The residue is dissolved in MeOH (100 mL), treated with K2CO3 (8.17 g, 59.1 mmol) and stirred at RT for 18 h. The mixture is concentrated to dryness, partitioned between 50% saturated NaHCO3 (75 mL) and EtOAc (2×75 mL) and the organics are dried (Na2SO4) and concentrated in vacuo. The crude material (2.21 g) is adsorbed onto silica gel (4.5 g) chromatographed over 90 g slurry-packed silica gel, eluting with 8% EtOAc/hexane then 15% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 1.88 g (75%) of methyl 3-bromo-1-benzofuran as a white solid. 1H NMR (300 MHz, CDCl3): δ 3.99, 7.55, 7.74, 8.11, 8.31 ppm.