Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=[O:31])C>S(=O)(=O)(O)O>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23](=[O:31])[NH2:24])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Temperature: 0 °C
Yield: 77 %

Procedure:
A solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanoindoline (1.0 g) in conc. sulfuric acid (1 l) was heated at 50° C. for 2 hr. After diluting with ice water, the reaction solution was basified with a conc. aqueous solution of sodium hydroxide. Then ethyl acetate was added thereto and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.81 g) as a white powder (yield: 77%).
Reaction SMILES: CC([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([S:22][CH3:23])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([O:28][CH3:29])=[C:11]([O:26][CH3:27])[C:12]=2[O:24][CH3:25])[CH2:7][CH2:6]1)=O.S(=O)(=O)(O)O>>[CH3:29][O:28][C:10]1[CH:9]=[C:8]2[CH2:7][CH2:6][C@H:5]([NH2:4])[C:21]3[C:14](=[CH:15][CH:16]=[C:17]([S:22][CH3:23])[C:18]([CH:20]=3)=[O:19])[C:13]2=[C:12]([O:24][CH3:25])[C:11]=1[O:26][CH3:27]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(SC)c(=O)cc1[C@@H](NC(C)=O)CC2
Agent: O=S(=O)(O)O
Product: COc1cc2c(c(OC)c1OC)-c1ccc(SC)c(=O)cc1[C@@H](N)CC2

Procedure:
In the case of thiocolchicine, the hydrolysis with hydrohalogen acids or, more preferably, with sulfuric acid (20% H2SO4 --120 h) allows one to obtain N-deacetylthiocolchicine and 3-demethyl-N-deacetylthiocolchicine in essentially quantitative yields.
Reaction SMILES: [CH2:1]([N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[C:6](=[O:9])[CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[O:14]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]1[C:16]([O:18][CH3:19])=[O:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:14][CH:15]([C:20]([O:8][CH2:7][C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Reactant: CCCCN(CCCC)C(=O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)COC(c1ccccc1)(c1ccccc1)C(O)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.7 %

Procedure:
1.3 g of N,N-di-n-butyl-2-hydroxyacetamide and 1.8 g of methyl 2,3-epoxy-3,3-diphenylpropionate were dissolved in 30 ml of methylene chloride and, while cooling in ice, a catalytic amount of p-toluenesulfonic acid was added. The mixture was stirred at room temperature for 24 hours and then added to sodium bicarbonate solution, the organic phase was separated off and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by chromatography, and 1.4 g of an oil were isolated and were immediately reacted further.
Reaction SMILES: [NH2:1][C:2](=S)[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:15]2[N:16]=[C:17]([CH2:20][N:21]3[CH:25]=[C:24]([C:26]([O:28]CC)=[O:27])[CH:23]=[N:22]3)[S:18][CH:19]=2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.IC.[C:34]([NH:37][NH2:38])(=O)[CH3:35].[OH-].[Na+]>CC(C)=O.C(O)C.O.C(O)C.O1CCCC1>[CH3:35][C:34]1[NH:1][C:2]([CH2:3][CH2:4][C:5]2[CH:6]=[C:7]([C:15]3[N:16]=[C:17]([CH2:20][N:21]4[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[N:22]4)[S:18][CH:19]=3)[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=2)=[N:38][N:37]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cc(CCC(N)=S)cc(C(F)(F)F)c3)cs2)c1
Reactant: CC(=O)NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CI
Product: Cc1nnc(CCc2cc(-c3csc(Cn4cc(C(=O)O)cn4)n3)cc(C(F)(F)F)c2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.7 %

Procedure:
To a solution (3 mL) of the compound (300 mg, 0.64 mmol) obtained in Example 96c in acetone was added iodomethane (0.20 mL, 3.2 mmol), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and to a solution (4 mL) of the residue in ethanol was added acetylhydrazine (240 mg, 3.2 mmol), and the mixture was stirred at 80° C. for 6 hr. The solvent was evaporated under reduced pressure, and a solution (6 mL) of the residue in xylene was stirred at 150° C. overnight. The solvent was evaporated under reduced pressure, and to an ethanol/tetrahydrofuran mixed solution (v/v=1/1, 4 mL) of the residue was added 2N aqueous sodium hydroxide solution (0.45 mL, 0.91 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether. The obtained aqueous layer was neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by HPLC and recrystallization (hexane-ethyl acetate) to give the title compound (2 mg, 0.7%) as colorless crystals.
Reaction SMILES: [C:1]([O:4][CH:5]([C:9](=O)[CH:10]([CH3:12])[CH3:11])[C:6](=O)[CH3:7])(=[O:3])[CH3:2].C(O)(=O)C.[NH2:18][C:19]([NH2:21])=[NH:20]>CN(C)C=O>[C:1]([O:4][C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[N:18][C:19]([NH2:21])=[N:20][C:6]=1[CH3:7])(=[O:3])[CH3:2]
Reactant: N=C(N)N
Reactant: CC(=O)OC(C(C)=O)C(=O)C(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)Oc1c(C)nc(N)nc1C(C)C
Temperature: 100 °C
Yield: 30.1 %

Procedure:
A mixture of 3-acetoxy-5-methyl-2,4-hexanedione (5 g, 27 mmol) and guanidine acetate (6.4 g, 54 mmol) in 100 ml dimethylformamide (DMF) was heated at 100° C. for 3 hours. After cooling, the concentrated reaction was filtered through a pad of silica gel using an eluent consisting of equal volume parts of hexane and ethylacetate. The filtrate was concentrated and the residue was treated with excess acetic anhydride in the presence of triethylamine. The reaction mixture was concentrated and the residue was crystallized from boiling hexane to yield 1.7 g (31%) 5-acetoxy-2-amino4-isopropyl-6-methylpyrimidine, m.p. 141°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[C:7]([N+:16]([O-])=O)=[N:8][CH:9]=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].C(O)C.O.[Cl-].[NH4+]>C1COCC1.[Fe]>[NH2:16][C:7]1[C:6]([O:5][CH2:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=2[F:1])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1
Reactant: COC(=O)c1cnc([N+](=O)[O-])c(OCc2ccccc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COC(=O)c1cnc(N)c(OCc2ccccc2F)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a solution of 2.5 g of methyl 5-[(2-fluorobenzyl)oxy]-6-nitronicotinate in 25 ml of THF were added 50 ml of ethanol, 25 ml of water, 218 mg of ammonium chloride, and 1.37 g of iron, followed by heating to reflux for 2 hours. After leaving to be cooled at room temperature, the reaction mixture was filtered over Celite, and to the filtrate were added a saturated aqueous sodium hydrogen carbonate solution and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain 2.25 g of methyl 6-amino-5-[(2-fluorobenzyl)oxy]nicotinate.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[C:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=23)=[N:12]1)(O)=[O:2].Cl>O1CCCC1>[OH:2][CH2:1][CH2:4][C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[C:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=23)=[N:12]1
Reactant: O=C(O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Agent: Cl
Solvent: C1CCOC1
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1C1=C(CCO)CCCC1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 56.9 %

Procedure:
To a solution on of 3-[2-(2-carboxymethyl-1-cyclohexenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (2.07 g) in tetrahydrofuran (40 ml) was added dropwise under nitrogen atmosphere a solution of borane-tetrahydrofuran complex in tetrahydrofuran (1M solution, 9.72 ml) at −100° C. over a period of 10 minutes. The reaction mixture was allowed to stir at room temperature for 5.5 hours. Then, the mixture was cooled to 10° C. in an ice bath and treated with 1N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined extracts were washed with 1N aqueous sodium hydroxide solution, water, and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (toluene:MeOH=10:1) to give colorless crystals of: 3-[2-{2-(2-hydroxyethyl)-1-cyclohexenyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (1.14 g).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]=1[C:10]#[N:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[OH-]>CO.[Ni]>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]=1[CH2:10][NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(Oc2ccccc2)cccc1N1CCCCC1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCc1c(Oc2ccccc2)cccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-phenoxy-6-(piperidin-1-yl)benzonitrile (250 mg, 0.9 mmol) from Step 1 in 20 mL of MeOH was added Raney Nickel (5%) and NH4OH (2 mL). The reaction was stirred under 1 atm of H2 at RT for 2 h. The solid was filtered away and the filtrate was concentrated in vacuo to provide the title compound as a viscous oil.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10]([OH:12])=O)[CH2:6][CH2:7][S:8][CH3:9])(=[O:3])[CH3:2].ClC(OCC(C)C)=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[C:32]([OH:34])[C:31]([C:35]([OH:37])=[O:36])=[CH:30][N:29]=2)=[CH:24][CH:23]=1.CC(N(C)C)=O>C(N(CC)CC)C.ClCCl>[C:1]([NH:4][CH:5]([C:10]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:33]=[C:32]([OH:34])[C:31]([C:35]([OH:37])=[O:36])=[CH:30][N:29]=2)=[CH:26][CH:27]=1)=[O:12])[CH2:6][CH2:7][S:8][CH3:9])(=[O:3])[CH3:2]
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reactant: CSCCC(NC(C)=O)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CSCCC(NC(C)=O)C(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Temperature: -15 °C
Yield: 57.1 %

Procedure:
A suspension of 14.34 g (75 mmol) of N-acetyl-DL-methionine and 150 ml of dichloromethane is stirred at -15° C. and 10.5 ml (75 mmol) of triethylamine is added followed by 9.75 ml (75 mmol) of isobutyl chloroformate. After stirring for 20 minutes at -15° C., a solution of 11.6 g (50 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid in 200 ml of dimethylacetamide containing 7.7 ml (55 mmol) of triethylamine is added at -15° C. The mixture is stirred at 0° C. for 3 hrs and overnight at room temperature. The mixture is evaporated and the residue triturated with water. The aqueous suspension, after adjusting the pH to 2.5 with dilute HCl is filtered, washed with water, and dried to give 11.54 g of 2-[4-(N-acetyl-DL-methionylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid; mp 259° C. dec.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([N:17]([CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[C@H:18]([C:20]([NH:22][CH:23]([C:32](=[O:45])[CH2:33][O:34][C:35]1[C:40]([F:41])=[C:39]([F:42])[CH:38]=[C:37]([F:43])[C:36]=1[F:44])[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[O:21])[CH3:19])=[O:16].C(O)(C(F)(F)F)=O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([N:17]([CH:46]1[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]1)[C@H:18]([C:20]([NH:22][CH:23]([C:32](=[O:45])[CH2:33][O:34][C:35]1[C:36]([F:44])=[C:37]([F:43])[CH:38]=[C:39]([F:42])[C:40]=1[F:41])[CH2:24][C:25]([OH:27])=[O:26])=[O:21])[CH3:19])=[O:16]
Reactant: CC(C)Cc1c(C(=O)N(C2CCCCC2)[C@@H](C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc2c(F)c(F)cc(F)c2F)n(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1c(C(=O)N(C2CCCCC2)[C@@H](C)C(=O)NC(CC(=O)O)C(=O)COc2c(F)c(F)cc(F)c2F)n(C)c2ccccc12

Procedure:
Treatment of N-[(1-methyl-3-isobutyl-indole-2-cabonyl)cyclohexylalaninyl]-3-amino-4-oxo-5-(2,3,5,6-tetrafluorophenyloxy)-pentanoic acid, tert-butyl ester with TFA as described in Example 80 gave the titled product (55.5 mg) as a white powder. MS C34H39F4N3O6, [M+Na]+=684, [M−H]−=660. TLC (CH2Cl2/MeOH, 90/10): Rf=0.24.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][N:8]1[CH2:12][C@H:11]([CH2:13][O:14]CC2C=CC=CC=2)[O:10][C:9]1=[O:22])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[OH:14][CH2:13][C@@H:11]1[O:10][C:9](=[O:22])[N:8]([NH:7][C:6](=[O:23])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NN1C[C@H](COCc2ccccc2)OC1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NN1C[C@H](CO)OC1=O
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a suspension of (R)-tert-butyl-5-(benzyloxymethyl)-2-oxooxazolidin-3-ylcarbamate (1.908 g, 5.92 mmol) and 10% Pd/C (315 mg, 0.296 mmol) in ethanol (25 mL), ammonium formate (933 mg, 14.80 mmol) was added and the reaction was refluxed, under nitrogen, while stirring for 3 h 30 min. The catalyst was filtered away and the solvent evaporated. The residue was triturated with diisopropyl ether:MeOH=10:1. The title compound was obtained as a white solid (852 mg, 3.67 mmol). Yield=62%.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[C:5](=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:24])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(OCc2cccc(OC)c2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(COc2cccc(C(=O)O)c2C(=O)O)c1

Procedure:
A solution of 3-(3-methoxy-benzyloxy)-phthalic acid dimethyl ester (2.0 g crude, 5.5 mmol) in reagent alcohol (100 mL) and 3 N sodium hydroxide (35 mL) was refluxed for two hours. The solution was evaporated and the residue was dissolved in water (80 mL) and washed with methylene chloride (3×70 mL) then acidified to pH around 4. The resulting mixture was extracted with ethyl acetate (2×60 mL) and the combined organic layers was washed with water (2×70 mL), dried and concentrated to give 3-(3-methoxy-benzyloxy)-phthalic acid as an off-white solid (1.6 g, 98% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[I:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[CH3:1][O:2][C:3]1[C:4]([NH:10][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[I:11])(=[O:20])=[O:19])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: COc1nc(C)cnc1N
Reactant: O=S(=O)(Cl)c1ccccc1I
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1I

Procedure:
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine and 2-iodobenzenesulphonyl chloride.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:23][C:24]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:25][CH:26]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:32]1[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33]1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:23][C:24]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:25][CH:26]=3)[C:2]([N:32]3[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O[C@@H]1CCNC1
Reactant: CN(C)C(=O)c1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2Cl)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(C)C(=O)c1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)[nH]1

Procedure:
A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(5-(dimethylcarbamoyl)-1H-pyrrol-2-yl)nicotinamide (Stage 73.1, 60 mg, 0.102 mmol), (R)-pyrrolidin-3-ol (17.82 mg, 0.205 mmol), DIPEA (71.5 μL, 0.409 mmol) and iPrOH (205 μL) in a sealed vial was subjected to MW irradiation at 140° C. for 1 h. The RM was purified by preparative SFC (Column NH2, isocratic 24% in 6 min.) to yield the title compound as a white solid. UPLC-MS (Condition 3) tR=1.03 min, m/z=520.1 [M+H]+, m/z=564.2 [M+FA−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.78 (m, 1H) 1.78-1.89 (m, 1H) 2.96 (d, J=11.74 Hz, 1H) 3.13 (br. s, 6H) 3.25-3.31 (m, 2H) 3.38-3.51 (m, 1H) 4.20 (br. s, 1H) 4.86 (d, J=2.57 Hz, 1H) 6.11-6.21 (m, 1H) 6.57-6.66 (m, 1H) 7.33 (d, J=9.17 Hz, 2H) 7.82-7.92 (m, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.71 (d, J=2.45 Hz, 1H) 10.15 (s, 1H) 11.66 (br. s, 1H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C@@H:24]1[N:29]([CH3:30])[CH2:28][CH2:27][N:26]([C:31]2[C:36]([F:37])=[C:35]([NH:38][NH2:39])[N:34]=[C:33]([CH3:40])[N:32]=2)[CH2:25]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([NH:39][NH:38][C:35]2[C:36]([F:37])=[C:31]([N:26]3[CH2:27][CH2:28][N:29]([CH3:30])[C@@H:24]([CH3:23])[CH2:25]3)[N:32]=[C:33]([CH3:40])[N:34]=2)=[O:10])[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: Cc1nc(NN)c(F)c(N2CCN(C)[C@@H](C)C2)n1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCN(C)[C@@H](C)C2)n1
Reaction time: 8 h
Yield: 67.4 %

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.184 g, 0.60 mmol), 4-[(3S)-3,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine (0.161 g, 0.63 mmol), NMM (0.21 mL, 1.89 mmol), HOAt (0.086 g, 0.63 mmol), and EDC (0.121 g, 0.63 mmol) were dissolved in DMF (4 mL), and the reaction was stirred overnight. Purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[(3S)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.219 g, 64%). LCMS: (M+H)+=542.7.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[N:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[N:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[N:25][C:20]2=[N:19][CH:18]=1)CCC>>[CH:9]([O:8][C:4]1[N:3]=[C:2]([C:17]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]([F:27])([F:28])[F:29])=[N:25][C:20]3=[N:19][CH:18]=2)[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1cccc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: CC(C)Oc1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 35.7 %

Procedure:
2-Bromo-6-isopropoxypyridine (0.32 g, 1.58 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.13 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (20-40%) and trituration with isohexane gave 3-(6-isopropoxypyridin-2-yl)-7-(trifluoromethyl)imidazo[1,2-α]pyrimidine (130 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 1.45 (6H, d, J 6), 5.29 (1H, quin, J 6), 6.69 (1H, d, J 8), 7.34 (1H, d, J 7), 7.39 (1H, d, J 7), 7.70 (1H, dd, J 8 and 7), 8.46 (1H, s), 10.26 (1H, d, J 7); m/z (ES+) 323 (M++H).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>C1(C)C=CC=CC=1>[C:1]([N:5]([C:23]([C:19]1[O:18][CH:22]=[CH:21][CH:20]=1)=[O:24])[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
N'-t-butyl-N-benzoylhydrazine (1 g) was dissolved in 20 ml toluene. Water (5 ml) and 50% aqueous sodium hydroxide (1.25 g) was added followed by 2-furoylchloride (0.68 g). After stirring for 7 hours at room temperature, 0.3 g 2-furoylchloride was added and the mixture stirred for a further 6 hours. The solid product, N'-t-butyl-N-benzoyl-N'-(2-furoyl)hydrazine, was removed by filtration and washed with water: m.p. 155°-175° C.
Reaction SMILES: CS([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[C:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26]3)[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)=O.BrC1C=CC(C(=C2CC(C)(C)CC(C)(C)C2)C2C=CC(O)=CC=2)=CC=1.[C:60](C1C=CC(B(O)O)=CC=1)#[N:61].C([O-])([O-])=O.[Na+].[Na+]>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.O.C1COCC1>[OH:24][C:21]1[CH:22]=[CH:23][C:18]([C:17](=[C:25]2[CH2:30][C:29]([CH3:31])([CH3:32])[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)[C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:60]#[N:61])=[CH:10][CH:9]=3)=[CH:12][CH:13]=2)=[CH:19][CH:20]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC(C)(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccc(C#N)cc3)cc2)CC(C)(C)C1
Yield: 74 %

Procedure:
The Suzuki protocol described for (163) was employed. A round-bottomed flask was charged with 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.200 g, 0.5 mmol), PdCl2(PPh3)2 (0.035 g, 0.05 mmol), (4-cyanophenyl)boronic acid (0.165 g, 1.0 mmol), aqueous 2 M Na2CO3 (1.0 mL, 0.106 g, 1.0 mmol) solution, and 4:1 THF:H2O (5 mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 12 h. Regular work-up and purification gave 0.155 g (74%) of the title compound (238) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.87 (d, J=4.8 Hz, 2H), 7.85 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.0 Hz, 3H), 7.25 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.67 (d, J=8.4 Hz, 2H), 1.92 (br s, 4H), 1.25 (s, 2H), 0.88 (s, 12H). LCMS (APCI): m/z 419.97 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17]O)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[F:27][CH2:28][CH2:29][NH2:30]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:16][CH2:17][NH:30][CH2:29][CH2:28][F:27])([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: NCCF
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCNCCF)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and 2-fluoroethylamine following procedures analogous to those described in Example 178. LC-MS Method 2 tR=1.1 min, m/z=489; 1H NMR (CDCl3) 1.50 (d, 3H), 1.97-2.38 (m, 7H), 2.41-2.56 (m, 1H), 2.79-2.98 (m, 3H), 4.45 (m, 1H), 4.54 (m, 1H), 5.61 (m, 1H), 6.80 (d, 2H), 7.03-7.14 (t, 2H), 7.21-7.31 (m, 6H).