Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[CH2:13][S:14][C:15]([CH3:18])([CH3:17])[CH3:16].[CH3:20]N(C)N.C>CO>[CH2:1]([O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[CH2:13][S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:20]
Reactant: CN(C)N
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1CSC(C)(C)C
Agent: C
Solvent: CO
Product: CCOC(=O)c1ccc(N)cc1CSC(C)(C)C
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
2-tert-Butylsulfanylmethyl-4-nitro-benzoic acid methyl ester (5.68 g, 19.1 mmol), 1,1-dimethylhydrazine (11.6 mL, 192 mmol), and DARCO (2.0 g, 19.1 mmol) were combined in MeOH (200 mL). Ferric chloride (0.50 g, 3.1 mmol) was added, and the reaction was stirred at 70° C. for 3.5 hours. The mixture was stored in the freezer overnight, and then worked-up and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21](O)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:49][C@@H:50]1[CH2:55][CH2:54][CH2:53][N:52]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:51]1.S([O-])(O)(=O)=O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21]([NH:49][C@@H:50]3[CH2:55][CH2:54][CH2:53][N:52]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:51]3)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:24])([CH3:25])[C:8]1=[O:26]
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)O)cc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 764.7 %

Procedure:
4-(4-Methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (100 mg) was dissolved in dimethylformamide (2 ml), and thereto were added 1-hydroxybenzotriazole (61.1 mg), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (76.5 mg), triethylamine (55.6 μl) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (64.0 mg), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a 5% aqueous sodium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous sodium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (1136 mg) as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C@H:11]([NH:31]C(=O)OC(C)C)[CH2:10][C@@H:9]1[CH3:38])(=[O:7])[CH3:6].C(N(CC)CC)C.CCOC(C)=O>C(Cl)Cl.CO>[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C@H:11]([NH2:31])[CH2:10][C@@H:9]1[CH3:38])(=[O:7])[CH3:6]
Reactant: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.12 %

Procedure:
A suspension of aluminium chloride (1.053 g, 7.89 mmol) in DCM (10 mL) at room temperature under nitrogen was treated with 1-methylethyl {(2S,4R)-1-acetyl-2-methyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation see intermediate 67) (0.915 g, 1.974 mmol) as a solution in DCM (2.5 mL) and the resulting mixture was stirred at room temperature for 1 h then cooled using an ice bath and treated with triethylamine (3.30 ml, 23.68 mmol) in methanol (2 mL) producing a thick precipitate. AcOEt (25 mL) was added to the thick precipitate formed and the mixture was stirred for 30 min. The precipitate was filtered off and partitioned between a saturated NaHCO3 aqueous solution (50 mL) and AcOEt (50 mL). The resulting biphasic mixture was stirred at room temperature for 30 min and then the layers were separated. The aqueous layer was stirred with 1:1 DCM:AcOEt (50 mL) and the organic layer was collected using a hydrophobic frit. This was repeated twice. The first AcOEt phase was also eluted through the hydrophobic frit and the combined organics concentrated in vacuovacuo. Purification of the residue by flash chromatography on silica gel using a 100 G silica cartridge (gradient:1 to 10% (2N NH3 in MeOH) in DCM) gave (2S,4R)-1-acetyl-2-methyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinamine (150 mg, 0.358 mmol, 18.12% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[N:12]([C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)[N:13]=[C:14]([CH3:24])[C:15]=2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:6][CH:5]=1)=[O:3].[OH-].[Na+:31]>O>[Na+:31].[NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[N:12]([C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)[N:13]=[C:14]([CH3:24])[C:15]=2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O-:23])=[O:22])=[CH:6][CH:5]=1)=[O:3]
Reactant: CCc1ccc2c(-c3ccc(C(N)=O)cc3)c(CCCCCC(=O)O)c(C)nn12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc2c(-c3ccc(C(N)=O)cc3)c(CCCCCC(=O)[O-])c(C)nn12
Reaction time: 5 h
Yield: 98.2 %

Procedure:
To a suspension of 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid (590 mg) in water (3 mL) was added 1N sodium hydroxide (15 mL) at ambient temperature. After 5 hours, the mixure became clear solution. The solution was filtered through membrane filter, washed with water (0.4 mL×3), and was freezedried for 15 hours to give 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid sodium salt (612 mg, 98.2%) as a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[C:15]([C:20](O)=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:20](=[O:21])[C:15]3[C:14]([CH3:13])=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cc1cccnc1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccnc1C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H) in CH2Cl2 (10 mL) was treated with 3-methylpicolinic acid (143 mg, 1.04 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (332 mg, 1.30 mmol) and triethylamine (440 mg, 4.35 mmol). The reaction was stirred at room temperature for 1 hour. The mixture was filtered to remove the product, and the filtrate was concentrated in vacuo. The residue was stirred in anhydrous THF (10 mL), treated with 2M LiOH solution (3 mL) and stirred at room temperature for 1 hour. The organic solvent was removed in vacuo, and then water (10 mL) was added. The reaction stirred for 1 hour. The solid, which separated, was filtered and washed with water and CH2Cl2 (10 mL). The combined filtered cakes were dried to yield N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpicolinamide (197 mg, 65% yield). 1H NMR (400 MHz, (CD3)2SO) δ 12.13 (br s, 1H), 10.42 (s, 1H), 8.56 (d, 1H), 8.39 (d, 1H), 7.87 (d, 1H), 7.84 (d, 1H), 7.55 (dd, 1H) 2.67 (s, 3H); LCMS (APCI+) m/z 349.1, 351 (M+H)+, Retention time=3.42 minutes (Method 3).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)=[CH:5][C:4]([CH3:22])=[N:3]1.[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][N:2]1[C:6]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)=[CH:5][C:4]([CH3:22])=[N:3]1
Reactant: COC(=O)c1ccc2cnc(Nc3cc(C)nn3C)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2cc3cc(C(=O)O)ccc3cn2)n(C)n1

Procedure:
A slurry of 84 (350 mg, 1.181 mmol) and LiOH (62.2 mg, 2.60 mmol) in THF (5.75 mL) and water (0.85 mL) was stirred at RT for 24 h. The THF was removed on a rotary evaporator. The reaction mixture was suspended in water (6 mL) and treated with 10M HCl in water (0.71 mL, 7.1 mmol). A yellow-brown colored precipitate formed and was collected by filtration to afford 3-(1,3-dimethyl-1H-pyrazol-5-ylamino)isoquinoline-6-carboxylic acid (86) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C@@H:2]1[C:14]2=[CH:15][C:16]([CH:18]=[CH:19][C@:13]2([CH3:20])[C@@H:12]2[C@H:4]([C@H:5]3[C@:9]([CH3:22])([CH2:10][C@@H:11]2[OH:21])[C@@:8]([OH:27])([C:23]([CH2:25][OH:26])=[O:24])[CH2:7][CH2:6]3)[CH2:3]1)=[O:17].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:45](OC)(OC)([O:47]C)[CH3:46].C([O-])(O)=O.[Na+]>ClCCl>[C:45]([O:27][C@:8]1([C@:9]2([CH3:22])[C@H:5]([C@H:4]3[C@H:12]([C@@H:11]([OH:21])[CH2:10]2)[C@:13]2([CH3:20])[C:14](=[CH:15][C:16](=[O:17])[CH:18]=[CH:19]2)[C@@H:2]([CH3:1])[CH2:3]3)[CH2:6][CH2:7]1)[C:23](=[O:24])[CH2:25][OH:26])(=[O:47])[CH3:46]
Reactant: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)C=CC(=O)C=C12
Reactant: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
To a solution (60 ml) of 6α-methylpredonisolone (6α-methyl-11β,17α,21-trihydroxy-1,4-pregnadiene-3,20-dione) (12) (2.13 g ) in dichloromethane were added pyridinium p-toluenesulfonate (28.0 mg) and trimethyl orthoacetate (1.01 ml). The mixture was stirred at room temperature (20°-25° C.) for 5 hours. When the reaction was completed, the reaction mixture was concentrated, and the residue was dissolved in acetone. (30 ml). While cooling the mixture on ice, an aqueous solution (30 ml) of p-toluenesulfonic acid.H2O (1.19 g) was added thereto. The mixture was stirred for 30 minutes on ice. Upon completion of reaction, a saturated aqueous NaHCO3 solution was added and extraction was performed using ethyl acetate. After steps of washing with brine, drying over Na2SO4, evaporation of the solvent, and silica gel column chromatography (silica gel, 40 g) using 50% ethyl acetate/hexane as eluant, 17α-acetoxy-11β,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione (13) (2.11 g, 89%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:20])=[O:19].[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](OCC)=O)=[CH:24][CH:23]=1.CC[O-].[Na+].CC(O)=O>CCO>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]2[N:1]=[C:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=3)[NH:20][C:18](=[O:19])[C:3]=2[C:4]([CH:15]([CH3:16])[CH3:17])=[N:5]1
Reactant: CC(C)c1nn(-c2c(Cl)cccc2Cl)c(N)c1C(N)=O
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1nn(-c2c(Cl)cccc2Cl)c2nc(Cc3ccc(O)cc3)[nH]c(=O)c12
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To a suspension of 5-amino-1-(2,6-dichlorophenyl)-3-isopropyl-1H-pyrazole-4-carboxylic acid amide (5.0 g, 16 mmol) in EtOH (20 mL) was added ethyl 4-hydroxyphenylacetate (8.6 g, 48 mmol) followed by NaOEt (2.66M in EtOH, 36 mL, 96 mmol). The reaction was then heated to reflux for 3 h. The reaction was then cooled to room temp and poured onto 10% aq. HOAc (100 mL). The resulting suspension was then cooled to 0° C. and filtered. The precipitate was then washed with 1:1 MeOH/H2O (100 mL) and 1:1 Et2O/hexane (75 mL). The solid was then dried under vacuum to yield the desired product (5.2 g, 76%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[Br:16][CH2:17][CH2:18]Br>CN(C=O)C.O>[Br:16][CH2:17][CH2:18][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OCCBr)cc1
Temperature: 57.5 °C
Reaction time: 8 h

Procedure:
Anhydrous potassium carbonate (233 g, 1.68 mol) was added to a solution of 4-hydroxybezonitrile (100 g, 0.84 mol) in DMF (700 mL), and the resultant mixture was stirred for 1 h under a N2 atmosphere. 1,2-Dibromo-ethane (362 mL, 4.2 mol) was added slowly to the reaction mixture, which was then stirred at 55-60° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (3×750 mL). The combined organic layer was washed with water and then concentrated. The crude product was purified by column chromatography (silica gel: 60-120 mesh, eluent: petroleum ether-ethyl acetate, 90:10). Yield: 60 g (32%).
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:9][C:10](=[O:34])[C@@H:11]([NH:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]=[CH2:22])=[CH:15][CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[OH-].[Na+].CO>C1COCC1.O>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C@H:11]([NH:23][S:24]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)(=[O:25])=[O:26])[C:10]([NH:9][C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:35])=[O:2])=[O:34])=[CH:14][CH:15]=1)[CH:21]=[CH2:22]
Reactant: C=CCOc1ccc(C[C@H](NS(=O)(=O)c2ccc(F)cc2)C(=O)N[C@@H](CC(C)C)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CCOc1ccc(C[C@H](NS(=O)(=O)c2ccc(F)cc2)C(=O)N[C@@H](CC(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl ester 11 (2.70 g, 5.33 mmol) was dissolved in THF (30 mL). Sodium hydroxide (0.853 g, 21.3 mmol) pre-dissolved in water (10 mL) was added. Methanol (15 mL) was added to obtain a homogenous solution and this was stirred at rt for 18 h before being concentrated in vacuo. The residue was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted twice more with EtOAc and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield a white foam, 2.50 g, 95%.
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.Br[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:29][O:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:25][CH3:26])[C:4]([OH:3])=[O:27])=[CH:12][CH:11]=3)=[CH:23][CH:22]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(O)cc2)cc1)OC
Reactant: BrCC1CCCCC1
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(OCC3CCCCC3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-{4-[3-(4-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 263, Step B) and (bromomethyl)cyclohexane following the procedure described for Example 264.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([F:26])[CH:3]=1.IC.[C:29](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:29])[CH:17]=2)=[O:11])=[C:4]([F:26])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1F
Agent: [K+]
Solvent: CI
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1F

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-2-fluoro-phenyl)-3-o-tolyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=428.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)[C:16](=[O:28])[N:15]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH2:41][C:42]([F:45])([F:44])[F:43])=[CH:25][CH:26]=4)[C:16](=[O:28])[N:15]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)ncn1Cc1ccc(O)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)ncn1Cc1ccc(OCC(F)(F)F)cc1
Yield: 20.3 %

Procedure:
To an N,N-dimethylformamide solution of 4-[4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl]-1-(4-hydroxybenzyl)-1,3,5-triazin-2(1H)-one (10.0 mg, 0.0260 mmol) synthesized in Synthesis Example 483a, cesium carbonate (10.3 mg, 0.0320 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.57 μL, 0.0320 mmol) were added and the resultant mixture was stirred at 70° C. for 2 and a half hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (chloroform/ethyl acetate=1/1) to obtain the title compound (2.43 mg, yield: 14%).
Reaction SMILES: [CH3:1][N:2]([C:4]([C:6]1[O:10][C:9]2[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:8]=2[C:7]=1O)=[NH:5])[NH2:3].[OH-].[Na+]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:8]2[C:7]3[C:6]([O:10][C:9]=2[CH:11]=1)=[C:4]([NH2:5])[N:2]([CH3:1])[N:3]=3
Reactant: CN(N)C(=N)c1oc2cc(Cl)ccc2c1O
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc2c(oc3cc(Cl)ccc32)c1N
Temperature: 0 °C
Reaction time: 4 h

Procedure:
The crude 6-chloro-3-hydroxybenzo[b]furan-2-carboximidic acid, 1-methylhydrazide, (25 g, described in Example 5) was combined with polyphosphoric acid (250 g) and the mixture was stirred at 70°-80° C. for 4 hr. The hot mixture was poured into ice-water and the solution was made alkaline with 50% aqueous sodium hydroxide. The product was extracted several times with methylene chloride and the combined extracts were dried and evaporated. The crude product was triturated with diethyl ether to give the title compound (13 g): mp 210°-211° C.; IR (mineral oil) 3370, 3240 and 3120 cm-1 ; UV max (MeOH) 227 nm (ε=15400), 253 (22100), shoulder 209 nm; NMR (DMSO-d6) δ3.7 (3H, s), 5.4 (2H, s), and 7.5 (3H, m); and Anal. Calcd for C10H8ClN3O: C, 54.19% H, 3.64%, N, 18.96% and Found: C, 53.91% H, 3.60% N, 18.90%.
Reaction SMILES: [NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:11]=[C:9]([I:10])[C:8]([O:12][C:13]2[CH:20]=[C:18]([I:19])[C:17]([OH:21])=[C:15]([I:16])[CH:14]=2)=[C:6]([I:7])[CH:5]=1.[F:25][C:26]([F:31])([F:30])[C:27](O)=[O:28].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl-].[Na+]>C(OCC)(=O)C.O>[F:25][C:26]([F:31])([F:30])[C:27]([NH:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:5]=[C:6]([I:7])[C:8]([O:12][C:13]2[CH:14]=[C:15]([I:16])[C:17]([OH:21])=[C:18]([I:19])[CH:20]=2)=[C:9]([I:10])[CH:11]=1)=[O:28]
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Reactant: O=C(O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 20 g [25.6 millimoles (mmol)] of L-thyroxine (Sigma Chemical Co., St. Louis, Mo. USA) in 240 ml of dry ethyl acetate containing 46 ml of trifluoroacetic acid and 7.6 ml of trifluoroacetic anhydride was stirred at 0° C. for one hour. Upon warming to room temperature and adding 200 ml of H2O, a suspension formed which was then saturated with sodium chloride. The organic phase of the mixture was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to give 21.3 g of the N-protected thyroxine derivative (6). A sample was recrystallized from ether-pentane to give fine crystals, m.p. 233°-235° C. (decomposed).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([P:9]([CH3:14])(=[O:13])[O:10][CH2:11][CH3:12])=[CH:5][CH:4]=1)=O.Cl.[NH2:16][OH:17].C([O-])(O)=O.[Na+]>C(O)C>[OH:17]/[N:16]=[CH:1]/[C:3]1[CH:8]=[CH:7][C:6]([P:9]([CH3:14])(=[O:13])[O:10][CH2:11][CH3:12])=[CH:5][CH:4]=1
Reactant: NO
Reactant: CCOP(C)(=O)c1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOP(C)(=O)c1ccc(/C=N/O)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of compound 38-c (530 mg, 2.5 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (230 mg, 3.2 mmol) and NaHCO3 (360 g, 3.60 mmol). The reaction mixture was then stirred for 10 h at room temperature. The resulting mixture was concentrated under reduce pressure to afford crude compound 38-d (570 mg). LC-MS 228 [M+H]+
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:11]([N:29]=2)=[N:12][C:13]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])[CH2:17]2)=[CH:14][CH:15]=3)[CH:5]=[CH:4][CH:3]=1.[CH:30]1([C:33]#[N:34])[CH2:32][CH2:31]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1.C1COCC1>[N:24]1([C:22]([C@@H:18]2[CH2:19][CH2:20][CH2:21][N:16]([C:13]3[N:12]=[C:11]4[N:29]=[C:8]([C:6]5[N:7]=[C:2]([C:30]6([C:33]#[N:34])[CH2:32][CH2:31]6)[CH:3]=[CH:4][CH:5]=5)[NH:9][C:10]4=[CH:15][CH:14]=3)[CH2:17]2)=[O:23])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C([C@@H]1CCCN(c2ccc3[nH]c(-c4cccc(Br)n4)nc3n2)C1)N1CCCC1
Reactant: N#CC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#CC1(c2cccc(-c3nc4nc(N5CCC[C@@H](C(=O)N6CCCC6)C5)ccc4[nH]3)n2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 7 %

Procedure:
To a stirred solution of (R)-(1-(2-(6-bromopyridin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (300 mg, 0.658 mmol) in toluene was added cyclopropane carbonitrile. The mixture was cooled to 0° C. then a 1M solution of sodium bis(trimethylsilyl)amide in THF was added dropwise. The reaction mixture was stirred for 16 h at room temperature. The mixture was quenched with water and then was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and was concentrated under reduced pressure. The residue was purified via preparative TLC (twice) to afford (R)-1-(6-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)cyclopropanecarbonitrile (20 mg, 7%) MS (ES+APCI) (M+H) 442.2; LCMS retention time 2.969 min (Method C1); 1H NMR (400 MHz, CDCl3) δ 1.24-1.31 (m, 4H), 1.65-1.71 (m, 2H), 1.78-2.04 (m, 6H), 2.69 (m, 1H), 3.01 (t, 1H), 3.07-3.18 (m, 1H), 3.43-3.56 (m, 3H), 3.60-3.72 (m, 1H), 4.35 (br s, 1H), 4.54 (d, 1H), 6.72 (d, 1H), 7.48 (d, 1H), 7.79-7.95 (m, 2H), 8.58 (d, 1H), 10.28 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(Cl)cc4Cl)cc3c2C1
Yield: 69.2 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 9.5 μL (0.051 mMol) 2,4-dichlorobenzoyl chloride, 12.8 mg (72%) of the title compound were recovered as a light beige solid.