Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1.[CH2:26]([O:33][C:34]1[CH:61]=[CH:60][C:59](Br)=[CH:58][C:35]=1[C:36]([NH:38][C:39]1[CH:51]=[C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:49]=[CH:48][C:40]=1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(Cl)(Cl)Cl.O>[CH2:26]([O:33][C:34]1[CH:61]=[CH:60][C:59]([N:2]([CH3:1])[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[CH:58][C:35]=1[C:36]([NH:38][C:39]1[CH:51]=[C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:49]=[CH:48][C:40]=1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CNCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Br)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CN(CCN1CCOCC1)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 71.9 %

Procedure:
N-Methyl-2-(morpholin-4-yl)ethylamine (0.097 g), tripotassium phosphate (0.17 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to a toluene (2.3 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate (0.15 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then N-methyl-2-(morpholin-4-yl)ethylamine (0.019 g), tripotassium phosphate (0.029 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg) and palladium(II) acetate (1.2 mg) were added to the reaction mixture, followed by heating to reflux under a nitrogen atmosphere for 6 hours. The reaction mixture was cooled to room temperature, and then water and chloroform were added thereto. The insoluble substance was removed by filtration. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.12 g of tert-butyl 2-(2-(benzyloxy)-5-(methyl(2-(morpholin-4-yl)ethyl)amino)benzamido)-4-phenylbenzoate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:10]CC)=[O:9])[CH2:3][CH2:2]1.[ClH:19]>O1CCOCC1>[ClH:19].[O:1]1[CH2:2][CH2:3][N:4]([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:6]1
Reactant: CCOC(=O)C(c1ccccc1)N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C(c1ccccc1)N1CCOCC1
Yield: 62.8 %

Procedure:
Ethyl 2-morpholino-2-phenylacetate (0.34 g, 1.36 mmol) was dissolved in dioxane (11.4 ml) and 37% HCl (1.1 ml, 13.6 mmol) was added dropwise. The mixture was stirred at reflux overnight. 37% HCl (1.1 ml, 13.6 mmol) was added and the reaction was refluxed for additional 24 hours. The solvent was evaporated and the residue was triturated with acetonitrile (10 ml) to obtain 2-morpholino-2-phenylacetic acid hydrochloride (0.22 g, 63.7% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]=[CH:5][CH:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([CH3:29])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:7]1.[C:31]([OH:34])(=[S:33])[CH3:32].C(N(CC)CC)C>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([S:33][C:31](=[O:34])[CH3:32])[CH:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([CH3:29])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:7]1
Reactant: CC(O)=S
Reactant: COC(=O)C=CC1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Solvent: CCN(CC)CC
Product: COC(=O)CC(SC(C)=O)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
A suspension of the product from step 11a (1.0 g, 2.5 mmol), thioacetic acid (3.0 mL), and triethylamine (0.25 mL, 1.8 mmol) was stirred for 6 h at room temperature while slowly becoming a clear solution. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate (2×), brine, dried over magnesium sulfate, and concentrated to give the crude product. This was purified by FCC on silica gel eluting ethyl acetate:hexanes (gradient) to give 3-acetylsulfanyl-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester (0.74 g, 63%) as an oil. MS found: (M+H)+=479.
Reaction SMILES: [CH:1]1([CH2:10][CH2:11]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C([Br:16])C=C>C(#N)C>[CH:1]1([CH2:10][CH2:11][Br:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C=CCBr
Reactant: OCCC1CCc2ccccc21
Solvent: CC#N
Product: BrCCC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
N,N-Carbonyl diimidazole (2.0 g, 12.3 mmol) was added to a solution of 2-indanylethanol (2.0 g, 12.3 mmol) in acetonitrile. The reaction mixture was stirred at room temperature for 1 h and allyl bromide (8.93 g, 73.8 mmol) was added. The reaction mixture was heated to 70° C. for 24 h and was poured onto water. The aqueous solution was extracted with Et2O and the organic solution was washed with water (1×) followed by brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated to afford the title compound (2.54 g). 1H NMR (400 MHz, CDCl3) δ 7.10–7.25 (m, 4H), 3.48 (t, 2H), 3.11 (m, 2H), 2.63 (m, 3H), 2.07 (m, 2H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:14]=[C:13]([O:15][S:16]([C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])(=[O:18])=[O:17])[C:12]([CH2:28][C:29]2[CH:42]=[CH:41][C:32]([CH2:33][NH:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][C:30]=2[O:43][CH3:44])=[C:11]([CH3:45])[N:10]=1.C(N(CC)CC)C>C1COCC1>[NH2:8][C:9]1[N:14]=[C:13]([O:15][S:16]([C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])(=[O:18])=[O:17])[C:12]([CH2:28][C:29]2[CH:42]=[CH:41][C:32]([CH2:33][N:34]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:1](=[O:3])[CH3:2])=[CH:31][C:30]=2[O:43][CH3:44])=[C:11]([CH3:45])[N:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CNCc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN(Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1)C(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (6 μL) was added to a solution of the product from step (i) (23 mg) and triethyl amine (9 μL) in THF (1 mL), and the mixture was stirred at RT for 3 h. The mixture was quenched with water, extracted with EtOAc, combined organic layer was washed with brine, dried and concentrated under reduced pressure. The sub-title compound (25 mg) was obtained as a colourless gum, which was used for next reaction without further purification; LC-MS: m/z=585.
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.[H-].[Na+].[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(Br)C=C>O>[CH2:5]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15])[CH:1]=[CH2:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C=CCBr
Product: C=CCC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a THF suspension (50 ml) containing sodium hydride (0.92 g, 21 mmol, 55% in oil) was added dropwise at 0° C. diethyl malonate (3.2 g, 20 mmol). The reaction liquid was heated to room temperature and stirred for 1 hour. The reaction liquid was stirred overnight together with allyl bromide (2.9 g, 24 mmol). With water added, the reaction liquid was extracted with ether. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. After solvent removal, the residues were purified by silica gel chromatography. Thus there was obtained 2.88 g of diethyl allylmalonate (yields: 72%). This product was identical with commercial one.
Reaction SMILES: COCC[CH:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10].[C:11]([O:14][C:15](=O)[CH3:16])(=[O:13])[CH3:12]>>[C:6]([O:7][CH2:8][CH2:9][CH:12]1[CH2:16][CH2:15][O:14][C:11]1=[O:13])(=[O:10])[CH3:5]
Reactant: CC(=O)OC(C)=O
Reactant: COCCC1CCOC1=O
Product: CC(=O)OCCC1CCOC1=O
Temperature: 120 °C
Reaction time: 69 h
Yield: 61 %

Procedure:
In a stirred vessel, a mixture of 20 g of 3-(2'-methoxyethyl)-dihydro-2(3H)furanone, 100 g of acetic anhydride, and 10 of Nafion is heated to 120° C. Following a period of 69 h, the reaction is terminated (conversion: 100%) and the catalyst is separated by filtration. Following purification by distillation, there is obtained 61% of 3-(2'-acetoxyethyl)-dihydro-2(3H)furanone.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11](OCC)=[O:12].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.[O-2].[O-2].[Mn+4].C(O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH:11]=[O:12]
Reactant: CCOC(=O)c1sc2cnccc2c1C
Agent: [Mn+4]
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C=O)sc2cnccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a mixture of ethyl 3-methylthieno[2,3-c]pyridine-2-carboxylate (2.00 g) synthesized above, calcium chloride (2.01 g), ethanol (30 mL) and tetrahydrofuran (30 mL) was added sodium borohydride (1.37 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a pale-yellow solid. To a solution (40 mL) of the obtained solid in tetrahydrofuran was added active manganese dioxide (8.10 g), and the mixture was stirred at 50° C. for 8 hr. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure to give the title object compound (1.39 g, 87%) as a pale-brown solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O)([O-:14])=[O:13]>C(O)C>[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[N:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)([O-:14])=[O:13]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1C=Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
A mixture of 4-(trifluoromethyl)aniline (5 g) and 2-nitrobenzaldehyde (5.2 g) in anhydrous ethanol was heated to reflux for 3 h; the reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was washed with diethyl ether and petro-ether to give N-(2-nitrobenzylidene)-4-(trifluoromethyl)aniline as yellow solid (6.6 g, yield 72.3%). LC/MS m/e obsd. (ESI+) [(M+H)+] 295.1.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH:1]1([CH:6]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)CC1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(c1ccc(F)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under argon, a solution of 2.0 g (10.85 mmol) of tert-butyl cyclopentylacetate in 5 ml of abs. toluene was added dropwise to 16.3 ml of a 1 M solution, cooled to −10° C., of lithium hexamethyl-disilazide in toluene (16.3 mmol). After 10 min at −10° C., the ice bath was removed and the mixture was warmed to RT. A mixture of 2.47 g (14.1 mmol) of 1-bromo-4-fluorobenzene, 73.1 mg (0.326 mmol) of palladium(II) acetate and 269 mg (0.684 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl in 10 ml of abs. toluene was then added to this reaction mixture. After 1 h at RT, the reaction mixture was stirred at 80° C. overnight. After cooling to RT, the precipitated salts were filtered off with suction, the residue was washed with toluene and the combined filtrates were concentrated under reduced pressure. The crude product obtained was purified chromatographically on silica gel (mobile phase first cyclohexane, then cyclohexane/ethyl acetate 50:1). This gave 2.0 g of the title compound (61.6% of theory).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C
Reactant: c1cn[nH]c1
Product: Cc1sc2nc(-n3cccn3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Cl:7][C:8]1[NH:9][C:10]2[C:15]([CH2:16][C:17]=1[CH:18]=[O:19])=[CH:14][C:13]([F:20])=[C:12]([F:21])[C:11]=2[F:22].[OH-].[K+].S(S([O-])=O)([O-])=[O:26].[Na+].[Na+]>O>[Cl:7][C:8]1[C:17]([C:18]([OH:26])=[O:19])=[CH:16][C:15]2[C:10](=[C:11]([F:22])[C:12]([F:21])=[C:13]([F:20])[CH:14]=2)[N:9]=1
Reactant: O=CC1=C(Cl)Nc2c(cc(F)c(F)c2F)C1
Reactant: O=S([O-])S(=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 257.5 %

Procedure:
A solution of 69.65 g of potassium permanganate in 730 cm3 of water is added in the course of 1 hour, while keeping the temperature between 10° and 14° C., to a stirred suspension, cooled to about 10° C., of 45.7 g of 2-chloro-6,7,8-trifluoro-3-formyl-1,4-dihydroquinoline in 585 cm3 of N potassium hydroxide solution. The mixture is stirred for a further 30 minutes at about 10° C. 12 g of sodium dithionite are added and the mixture is stirred for 10 minutes at a temperature close to 10° C. and filtered through diatomaceous silica and the filter cake is washed with 3 times 400 cm3 of water. The filtrate and the washings are combined and 70 cm3 of a 35% aqueous solution of hydrochloric acid are added. The precipitate formed is extracted with 3 times 500 cm3 of ethyl acetate. The combined organic extracts are dried over magnesium sulphate, filtered and concentrated under reduced pressure (20 kPa) at 50° C. The residue is taken up in a mixture of 100 cm3 of diethyl ether and 100 cm3 of diisopropyl ether, drained and washed with 100 cm3 of the same mixture. 46.43 g of 2-chloro-6,7,8-trifluoroquinoline-3-carboxylic acid are obtained in the form of a colourless solid which decomposes at 225°-230° C. and which is used for the subsequent steps without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH3:10]>CO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:10])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: N
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: CO
Product: Cc1cc(N)nc(N)n1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A mixture of 50.0 grams (0.348 mole) of 2-amino-4-chloro-6-methylpyrimidine (commercially available) and 100 mL of aqueous 30% ammonia in 400 mL of methanol was placed in a high pressure vessel and heated to 130°-165° C. under a pressure of 140-250 psig, where it was stirred for 13 hours. After this time, the reaction mixture was allowed to cool to ambient temperature. The reaction vessel was then opened and the reaction mixture was removed. The reaction vessel was washed with 200 mL of methanol, and the wash was combined with the reaction mixture. The combination was concentrated under reduced pressure to a residual solid. The solid was then stirred for 2 hours at ambient temperature with 100 mL of aqueous 30% ammonia. The mixture was cooled to 0° C., and the solid was collected by filtration. The solid was dried, yielding 40.8 grams of 2,4-diamino-6-methylpyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH3:1].[CH:2]([N:15]1[CH2:18][CH:17](OS(C)(=O)=O)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[CH:2]([N:15]1[CH2:18][CH:17]([NH2:1])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: N
Solvent: CO
Product: NC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h

Procedure:
Ammonia gas was bubbled through a solution of methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (952.4 mg, 3 mmol) in MeOH (15 mL). After 2 hours, TLC showed the reaction to be complete. The title compound was obtained as a white solid (643.5 mg, 90%) after removal of the solvent. MS: 239 (MH+); HPLC Rf: 3.54 min; HPLC purity: 98%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)=[O:19])=[CH:16][C:10]=3[CH:9]=2)=[CH:6][C:5]([C:32]2[N:33]=[N:34][N:35]([CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)[N:36]=2)=[CH:4][N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)=[O:19])=[CH:16][C:10]=3[CH:9]=2)=[CH:6][C:5]([C:32]2[N:33]=[N:34][N:35]([CH2:37][CH2:38][OH:39])[N:36]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1nnc(-c2cnc(N)c(-c3cc4cc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)ccc4s3)c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1ncc(-c2nnn(CCO)n2)cc1-c1cc2cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 1-(2-(2-amino-5-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H-tetrazol-5-yl)pyridin-3-yl)benzo[b]thiophen-5-yl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (60 mg, 0.087 mmol, 1 eq) in anhydrous tetrahydrofuran (2 mL) under nitrogen atmosphere at 0° C. was added dropwise a solution of tetrabutylammonium fluoride (1.0 M in THF, 0.26 mL, 3 eq). After the reaction was stirred at room temperature for 2 hours, it was partitioned between ethyl acetate and aqueous ammonium chloride. The organic layer was isolated, further washed with saturated aqueous sodium bicarbonate, brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated down with silica gel. The mixture was subject to a gradient column chromatography (EtOAc-Hex 4:1 to MeOH-EtOAc 1:25) to yield 1-(2-{2-amino-5-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]pyridin-3-yl}-1-benzothien-5-yl)-3-[4-chloro-3-(trifluoromethyl)phenyl]urea as a white solid in the amount of 11 mg.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[N:16]=1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[N:16]=1)=[O:11]
Reactant: CCOC(=O)[C@H](Cc1cccc(OC)n1)NC(=O)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cccc(OC)n1)NC(=O)CN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 100-mL round-bottomed flask was added ethyl N-(tert-butoxycarbonyl)glycyl-3-(6-methoxy-2-pyridinyl)alaninate (1.28 g, 3.36 mmol) and trifluoroacetic acid (5 mL, 67.3 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo to give the crude ethyl glycyl-3-(6-methoxy-2-pyridinyl)alaninate as a colorless viscous oil, which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:16]=[CH:17][C:18]4[C:22]([CH:23]=3)=[N:21][N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=4)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13]O)[N:6]2[N:5]=[CH:4][N:3]=1.C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>C1COCC1>[CH2:24]([N:20]1[CH:19]=[C:18]2[C:22]([CH:23]=[C:15]([C:8]3[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][Br:32])[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:16]=[CH:17]2)=[N:21]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ncnn2c(CCCO)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncnn2c(CCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
To a solution of 3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]propan-1-ol (step 4, example 24, 3.40 g, 8.53 mmol) in anhydrous THF (85 mL) at 0° C. was added carbon tetrabromide (3.68 g, 11.0 mmol, 1.3 eq) and triphenylphosphine (2.46 g, 9.4 mmol, 1.1 eq), and the reaction mixture was stirred at RT for 16 h. The reaction was poured into EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated at reduced pressure. The crude product was purified by MPLC eluted with 15% acetone/DCM to give 2.45 g (62.4%) of desired product as a white solid. 1H-NMR (DMSO-d6) 8.52 (s, 1H), 7.89 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.15 to 7.35 (m, 5H), 7.13 (d, 1H), 6.62 (s, 1H), 5.74 (s, 2H), 3.61 (t, 2H), 3.03 (t, 2H), 2.22 to 2.26 (m, 2H); LC-MS [M+H]+=461/463, RT=3.16 min.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[F:9].C([Mg]Cl)(C)C.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[Cl:15][CH2:16][CH2:17][C:18]([C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[F:9])=[O:19]
Reactant: O=C(Cl)CCCl
Reactant: Fc1ccc(Cl)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(CCCl)c1cc(Cl)ccc1F
Temperature: 25 °C
Yield: 19.2 %

Procedure:
In a flame-dried 3-neck flask, 2-bromo-4-chloro-1-fluorobenzene (2.0 g, 9.55 mmol) was dissolved in THF (anhydrous) (28.9 mL) under argon. Isopropylmagnesium chloride (2 M in THF) (5.01 mL, 10.03 mmol) was added, and the reaction was stirred at rt. To this solution was added zinc chloride (0.5 M in THF) (20.44 mL, 10.22 mmol) and the mixture was stirred at ambient temperature for 40 min. To the reaction was then added Pd(PPh3)4 (0.276 g, 0.239 mmol), and the mixture was cooled to 0° C. A solution of 3-chloropropanoyl chloride (0.981 mL, 10.22 mmol) in THF (2.89 mL) was added, and the reaction was stirred for 2 h at 0° C. The reaction mixture was then quenched with 3 N HCl, diluted with water, and extracted with Et2O (3×). The combined organics were dried (MgSO4), filtered and evaporated to yield a grainy yellow liquid, which was purified using silica gel chromatography to obtain a colorless oil, 3-chloro-1-(5-chloro-2-fluorophenyl)propan-1-one (0.405 g, 19%). MS (ESI) m/z: 221.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J=6.3, 2.8 Hz, 1H), 7.51 (ddd, J=8.8, 4.3, 2.8 Hz, 1H), 7.13 (dd, J=10.2, 8.7 Hz, 1H), 3.94-3.88 (m, 2H), 3.46 (td, J=6.6, 3.2 Hz, 2H) ppm.