Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)C)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[OH:39][C:40]1[CH:41]=[C:42]([CH:48]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:50]=1)[C:43]([N:45]([CH3:47])[CH3:46])=[O:44].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[OH:39][C:40]1[CH:41]=[C:42]([CH:48]=[C:49]([C:2]2[C:10]3[C:9]([NH:11][CH2:12][C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:50]=1)[C:43]([N:45]([CH3:47])[CH3:46])=[O:44]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CN(C)C(=O)c1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc(CNc3ncnc4c3c(-c3cc(O)cc(C(=O)N(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 46 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.13 mmol) was treated with 3-hydroxy-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (92 mg, 0.32 mmol), sodium carbonate (33 mg, 0.32 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (31 mg, 0.04 mmol) and 3 ml 1,2-dimethoxyethane and 0.75 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 44 mg (46% yield, 89% purity) of the title compound.
Reaction SMILES: O.C[CH2:3][CH2:4][CH:5]1[O:25][C@:24]2([C:26]([CH2:28][OH:29])=[O:27])[C@@H:7]([CH2:8][C@@H:9]3[C@:23]2([CH3:30])[CH2:22][C@H:21]([OH:31])[C@H:20]2[C@H:10]3[CH2:11][CH2:12][C:13]3[C@:19]2([CH3:32])[CH:18]=[CH:17][C:15](=[O:16])[CH:14]=3)[O:6]1>ClCCl>[CH3:3][CH2:4][CH:5]1[O:25][C@:24]2([C:26]([CH2:28][OH:29])=[O:27])[C@@H:7]([CH2:8][C@@H:9]3[C@:23]2([CH3:30])[CH2:22][C@H:21]([OH:31])[C@H:20]2[C@H:10]3[CH2:11][CH2:12][C:13]3[C@:19]2([CH3:32])[CH:18]=[CH:17][C:15](=[O:16])[CH:14]=3)[O:6]1
Reactant: CCCC1O[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(C(=O)CO)O1
Solvent: ClCCl
Solvent: O
Product: CCC1O[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(C(=O)CO)O1

Procedure:
Water (800 mL) was charged to a 1 L stirred crystallizer fitted with a thermo-regulation jacket. The temperature was adjusted to 45° C. Water was pumped around a recirculation loop using a diaphragm pump (operating at 20 L/h) and a 250 ml thermo-regulated glass ultrasonic flow-cell fitted with a 30 mm diameter 20 kHz ultrasonic probe. The probe was held at the highest position in the flow-cell and sealed/clamped at a point of zero vibration (null point). The flow-cell was thermo-regulated at 45° C. Continuous ultrasound was applied at 15 W power, 5 micron amplitude. Budesonide (0.8 g) was dissolved in dichloromethane (80 mL). The solution was dispersed in an aqueous phase held at 45° C. consisting of 800 ml of a 0.2% (w/v) solution of Tween 80. The dichloromethane solution was pumped into the ultrasonic flow-cell using a second inlet on the underside of the flow-cell at a rate of 20 ml/h. The resulting suspension was stirred for 30 minutes at 300 rpm with sonication. Product was collected as aqueous suspension.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].Cl.[C:13](=[NH:18])(OCC)[CH3:14]>>[ClH:1].[NH:18]=[C:13]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])[CH3:14]
Reactant: CCOC(C)=N
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Product: CC(=N)NCCCC[C@H](N)C(=O)O

Procedure:
Essentially by the methods of Example 1 L-lysine hydrochloride (7.3 g, 4 mmol) was converted to the copper complex which was reacted with ethyl acetimidate hydrochloride (7.5 g, 60 mmol). The title compound, isolated as described in Example 1, was obtained as a hygroscopic amorphous powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](/[CH:12]=[CH:13]/[C:14]([O:16]CC)=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/C1CN(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(/C=C/C(=O)O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
3-((E)-2-Ethoxycarbonylvinyl)azetidine-1-carboxylic acid tert-butyl ester (0.95 g; 3.72 mmol) was dissolved in 1,4-dioxane (15 mL). Lithium hydroxide (0.098 g; 4.1 mmol) and water (10 mL) were added. The reaction mixture was stirred for 12 hours at room temperature. Water (70 mL) was added and the reaction mixture was washed with tert-butyl methyl ether (70 mL) and the phases were separated. The aqueous phase was adjusted to pH 2 with an aqueous solution of sodium hydrogensulfate (10%) and extracted with tert-butyl methylether (3×70 mL). The combined organic phases were dried (magnesium sulfate) and the solvent evaporated in vacuo to afford 0.76 g of 3-((E)-2-carboxyvinyl)azetidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH2:11][CH3:12])([CH3:10])[CH2:8][CH3:9])[CH:3]=1.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:16]=1[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[CH2:8]([C:7]([C:4]1[CH:3]=[C:2]([NH:1][C:17](=[O:18])[C:16]2[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][CH3:13])[O:6][N:5]=1)([CH3:10])[CH2:11][CH3:12])[CH3:9]
Reactant: CCC(C)(CC)c1cc(N)on1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: Cc1ccccc1
Product: CCC(C)(CC)c1cc(NC(=O)c2c(OC)cccc2OC)on1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To a stirred solution of 3.36 Kg of 5-amino-3-(1-ethyl-1-methylpropyl)isoxazole in 65 liters of toluene was added portion-wise over thirty minutes 4.015 Kg of 2,6-dimethoxybenzoyl chloride. The reaction mixture was heated to reflux and stirred for forty-eight hours. It was then cooled to room temperature and concentrated to a volume of about 25 liters by evaporation of the solvent under reduced pressure. The product precipitated and was collected by filtration, washed with fresh toluene, and air dried to provide 6.084 Kg of N-[3-(1-ethyl-1-methylpropyl]-5-isoxazolyl]-2,6-dimethoxybenzamide. M.P. 172°-174° C. Yield 91%.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:24]=1)[C:19](Cl)=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH:40]([CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH2:41][C:42]([O:44][CH3:45])=[O:43]>>[CH3:50][O:49][C:47](=[O:48])[CH2:46][N:40]([C:19](=[O:20])[C:18]1[CH:17]=[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:22]=1)[CH2:41][C:42]([O:44][CH3:45])=[O:43]
Reactant: COC(=O)CNCC(=O)OC
Reactant: CCCCCCCCCCCCCCOc1cc(OCCCCCCCCCCCCCC)cc(C(=O)Cl)c1
Product: CCCCCCCCCCCCCCOc1cc(OCCCCCCCCCCCCCC)cc(C(=O)N(CC(=O)OC)CC(=O)OC)c1

Procedure:
The reaction of 3,5-bis(tetradecyloxy)benzoyl chloride with dimethyl iminodiacetate as in Example 10 gave N-[3,5-bis (tetradecyloxy)benzoyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester as an oil. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])OC(C)(C)C)[C:3]=1[CH:16]=O.[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].CC(O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[CH:16]3[N:22]([C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[CH2:21][CH2:20][CH2:19][N:18]3[C:9](=[O:15])[NH:8][C:4]=2[N:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCN2C(=O)Nc3nccc(Cl)c3C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (4-chloro-3-formylpyridin-2-yl)carbamate (1.2 g, 4.67 mmol), tert-butyl (3-amino-propyl)carbamate (855 mg, 4.91 mmol), and AcOH (0.28 g, 4.67 mmol) were suspended in toluene (50 mL), and stirred overnight at room temperature. The reaction mixture was concentrated. The crude intermediate was dissolved in NMP (8 mL) in a 40 mL sealed tube, and stirred for 30 min. at 160 ° C. The reaction mixture was cooled, and the resulting precipitate was filtered, washed with MeOH, and dried under vacuum. LC-MS (M+H=339, obsd.=339).
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[NH:5])#[N:2].[OH:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.Cl>C(#N)C.O>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][NH:6][C:4]([NH:3][C:1]1[O:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:2]=1)=[NH:5]
Reactant: COc1ccccc1CNC(=N)NC#N
Reactant: O=C(CO)c1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: COc1ccccc1CNC(=N)Nc1nc(-c2ccccc2)co1
Temperature: 45 °C
Yield: 10.6 %

Procedure:
The cyclization of 0.60 g (2.94 mmol) N-cyano-N′-(2-methoxybenzyl)guanidine with 0.44 g (2.94 mmol) 2-hydroxyacetophenone was performed in 20 ml acetonitrile and water (1:1). The pH value of the mixture was adjusted with 1 N hydrochloric acid to pH 1.5 and the mixture was then heated in the microwave at 45° C. (100 Watt) for 4.5 hours. After workup and purification, analogously to. 190.2, 0.10 g of pure product was obtained.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([CH3:35])[CH:27]=1)#[N:25].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH:3]=2)=[C:28]([CH3:35])[CH:27]=1)#[N:25]
Reactant: Cc1cc(I)cc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Reactant: Cc1cc(C#N)ccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccc(C#N)cc2C)cc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1,3-bis(1,1-dimethylethyl) 2-(3-iodo-5-methylphenyl)propanedioate (the product of Step A, 320 mg, 0.74 mmol), 4-cyano-2-methylphenylboronic acid (178 mg, 1.11 mmol), sodium carbonate (78 mg, 0.74 mmol), bis(triphenylphosphine)palladium(II) dichloride (52 mg, 0.074 mmol), dioxane (5 mL), and water (1 mL) was heated to 80° C. and stirred for 20 minutes. The reaction mixture was then cooled to room temperature, and filtered through a plug of silica gel eluting with 20% ethyl acetate in hexanes. Concentration of the eluant under reduced pressure provided a brown oil (430 mg) containing the crude product, which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([I:21])C(=O)C1>C(O)(=O)C>[I:21][C:10]1[C:11]([OH:13])=[N:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccnc(-c2ccccc2)n1
Solvent: CC(=O)O
Product: Oc1nc(-c2ccccc2)ncc1I
Temperature: 50 °C
Yield: 69.4 %

Procedure:
To a solution of 2-phenylpyrimidin-4-ol (1.0 g, 5.8 mmol, 1 eq) in acetic acid (20 mL), was added NIS (1.3 g, 5.8 mmol, 1 eq), then heated at 50° C. for 1 h. The reaction solution was concentrated in vacuo and the residue was purified by silica gel chromatography (CH2Cl2/MeOH=97/3 as eluent) to obtain 5-iodo-2-phenylpyrimidin-4-ol (1.2 g, 69.8%) as a white solid. LC-MS (m/z): 298.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 7.35-7.51 (m, 3H), 8.10-8.18 (m, 2H), 8.43 (s, 1H), 13.32 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[N:8][N:7]4[C:2]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20]1
Reactant: COCCN
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CC3)n2)cc1
Product: COCCNc1cccc2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(OC)cc3)nn12
Temperature: 140 °C
Yield: 95 %

Procedure:
A mixture of 4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine (75 mg, 0.19 mmol) and 2-methoxyethylamine (5 mL, 58 mmol) was heated in a sealed tube at 140° C. for 24 hours. After cooling to room temperature, the mixture was concentrated. Flash chromatography (1:1 to 1:3 hexanes-ethyl acetate) provided 3-[2-(cyclopropylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine (77.7 mg, 95%) as a yellow solid. 1H NMR (CDCl3): δ 8.03 (d, 1 H), 7.96 (d, 1 H), 7.60 (d, 2 H), 7.31 (t, 1 H), 7.00 (d, 2 H), 6.41 (d, 1 H), 6.31 (t, 1 H), 6.04 (d, 1 H), 5.40 (broad, 1 H), 3.89 (s, 3 H), 3.72 (t, 2 H), 3.57 (q, 2 H), 3.43 (s, 3 H), 2.88 (m, 1 H), 0.88 (m, 2 H), 0.64 (m, 2 H); MS m/z 431 (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][F:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:22]=1>N1CCCCC1.C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:29]#[C:28][C@:26]([C:23]4[N:22]=[C:21]([CH3:20])[O:25][N:24]=4)([OH:30])[CH3:27])[CH:10]=3)[C:6]([CH2:18][F:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: Nc1nccc(-n2nc(CF)c3ccc(Br)cc32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(CF)nn(-c4ccnc(N)n4)c3c2)no1
Temperature: 66 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[6-bromo-3-(fluoromethyl)-1H-indazol-1-yl]pyrimidin-2-amine (70 mg, 0.21 mmol) in piperidine (2 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.02 mmol), copper(I) iodide (3 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (90 mg, 0.41 mmol). The reaction mixture was warmed to 66° C. for 2 hr, re-treated with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (45 mg, 0.20 mmol) and warming continued at 66° C. for a further 1 hr. Following cooling to RT, the reaction mixture was concentrated in vacuo, DCM (10 mL) was added and the solution re-evaporated to dryness in vacuo (re-evaporation process repeated twice). Purification of the residue by column chromatography (Biotage, DCM containing a 0-10% gradient of methanol) furnished a brown oil which was suspended in acetonitrile and concentrated in vacuo. The residue was slurried in diethyl ether (0.5 mL) to which was introduced acetonitrile until a fine cream precipitate resulted. Filtration furnished the title compound as a cream solid: 1H NMR (500 MHz, DMSO) delta 1.90 (3H, s), 2.62 (3H, s), 5.85 (2H, d, J=47.45 Hz), 6.82 (1H, s), 6.95-7.23 (3H, m), 7.43 (1H, dd, J=8.28, 1.18 Hz), 7.98 (1H, d, J=8.20 Hz), 8.33 (1H, d, J=5.36 Hz), 8.94 (1H, s); LC-MS: m/z=+394.00 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=4)=[C:21]3[N:20]=2)=[CH:5][CH:4]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc(C)n1
Yield: 46.8 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (102 mg, 47%). MS (ISP) 437.2 [(M+H)+]; mp 257° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.Br[CH2:18][C:19](=O)[CH2:20][CH3:21]>C(#N)C>[Br:1][C:2]1[C:3]([C:14]2[S:16][CH:18]=[C:19]([CH2:20][CH3:21])[N:15]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCC(=O)CBr
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Solvent: CC#N
Product: CCNC(=O)Nc1cc(-c2nc(CC)cs2)c(Br)cn1
Temperature: 0 °C

Procedure:
5-Bromo-2-(3-ethylureido)pyridine-4-carbothioamide (Intermediate 3, 6.06 g, 20 mmol) was suspended in acetonitrile (150 ml). 1-Bromobutan-2-one (30 mmol) was added and the reaction mixture was heated at reflux for 16 h. The reaction was cooled to 0° C. and the suspension was filtered. The solid was washed with acetonitrile (50 ml), collected, and dried in a vacuum oven at 50° C. for 4 hours to give an off white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[CH:22]=[C:23]([CH:49]=[CH:50][CH:51]=2)[C:24]([NH:26][C:27]2[CH:28]=[C:29]([CH:45]=[CH:46][C:47]=2[CH3:48])[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH:34]=2)=[O:31])=[O:25])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:48][C:47]1[CH:46]=[CH:45][C:29]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[CH:34]=2)=[O:31])=[CH:28][C:27]=1[NH:26][C:24](=[O:25])[C:23]1[CH:49]=[CH:50][CH:51]=[C:21]([O:20][CH:17]2[CH2:18][CH2:19][NH:15][CH2:16]2)[CH:22]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)C2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCNC2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (0.6 ml) was added to a stirred solution of 3-[3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzamido]-4-methyl-N-(3-morpholinophenyl)benzamide (0.3 g) in methylene chloride (6 ml) which had been cooled to 0° C. The reaction mixture was stirred at ambient temperature for 3 hours. The mixture was evaporated and the residue was triturated under diethyl ether to give the title compound, as its trifluoroacetate salt. The solid so obtained was dissolved in water (15 ml) and basified by the addition of potassium carbonate. The resultant precipitate was collected, washed with water and dried under vacuum to give the title compound (0.18 g); NMR Spectrum: (DMSOd6) 1.76 (m, 1H), 2.02 (m, 1H), 2.23 (s, 3H), 2.83 (m, 2H), 3.06 (m, 5H), 3.55 (m, 1H), 3.76 (t, 4H), 4.98 (m, 1H), 6.62 (d, 1H), 7.12 (m, 2H), 7.31 (d, 1H), 7.4 (m, 3H), 7.52 (m, 2H), 7.78 (d,. 1H), 7.99 (s, 1H), 10.07 (s, 1H), 10.08 (s, 1H); Mass Spectrum: M+H+ 501.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH:15]=[N:16][CH:17]2[C:21]([O:23]CC1C=CC=CC=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+:35].[K+]>O1CCCC1.O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH:15]=[N:16][CH:17]2[C:21]([O-:23])=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[K+:35]
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)N=CSC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)[O-])N=CSC12
Temperature: 25 °C
Reaction time: 1.8 h
Yield: 110.5 %

Procedure:
To a solution of benzyl 7-phenoxyacetamido-8-oxo-5-thia-1,3-diazabicyclo[4,2,0]oct-3-ene-2-carboxylate (400 mg.) in tetrahydrofuran (12 ml.) was added a solution of potassium carbonate (195 mg.) in water (12 ml.) at 0° C. After the mixture was stirred at the same temperature for an hour and at room temperature for 1.8 hours, the reaction mixture was neutralized to pH 7 with cation-exchange resin Amberlite IRC-50 (Trade Mark; manufactured by Rohm & Haas Co., Ltd.) and then filtered. The filtrate was concentrated and lyophilized to give a powder (388 mg.) of potassium 7-phenoxyacetamido-8-oxo-5-thia-1,3-diazabicyclo[4,2,0]oct-3-ene-2-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][O:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:9][C@H:8]1[CH2:7][O:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1COc2ccccc2NC1=O
Yield: 100 %

Procedure:
To a solution of (S)-tert-butyl 4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (2 g, 7.19 mmol, Eq: 1.00) in DCM (16.7 mL) at 0° C. was added trifluoroacetic acid (TFA, 16.4 g, 10.7 mL, 144 mmol, Eq: 20.00). After 1 h the mixture was concentrated, and the residue was triturated with 5 mL of Et2O and 35 ml of pentane to give a gum. The solution was removed and this gummy residue material was dried to give the title compound (2.1 g) as a pink foam which was used without purification.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH3:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30].N1C=CC=CC=1>C(OCC)(=O)C>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([CH3:18])[C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CC(C)C(=O)Cl
Reactant: CNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)C(=O)N(C)C1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To 1.8 g (4.5 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-(N-methylamino)-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 116) in 10 ml of ethyl acetate cooled to 0° C. was added 0.5 g (4.7 mmole) of isobutyryl chloride and 0.4 g of pyridine. After stirring overnight the mixture was diluted with ethyl acetate, washed with water and brine and dried over anhydrous magnesium sulfate. Concentration in vacuo and trituration with diethyl ether gave 1.7 g of the title compound, a white solid, mp 180°-182° C.