Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]2)[CH:20]=[N:19][CH:18]=1.CC1(C)C(C)(C)OB([C:45]2[CH:46]=[C:47]3[C:53]([C:54]([F:57])([F:56])[F:55])=[N:52][NH:51][C:48]3=[N:49][CH:50]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:45]3[CH:46]=[C:47]4[C:53]([C:54]([F:57])([F:56])[F:55])=[N:52][NH:51][C:48]4=[N:49][CH:50]=3)=[CH:10][CH:9]=2)[C:5]([C:17]2[N:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:25][CH2:24]3)[CH:20]=[N:19][CH:18]=2)=[N:6]1
Reactant: CC1(C)OB(c2cnc3[nH]nc(C(F)(F)F)c3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5cnc6[nH]nc(C(F)(F)F)c6c5)cc34)n2)CC1
Temperature: 120 °C
Yield: 52.7 %

Procedure:
A suspension of tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (compound 1e) (150 mg, 0.269 mmol), crude 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine 6a (177 mg, 0.57 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol, Strem) and aqueous Na2CO3, 2.0 M (0.27 mL, 0.54 mmol) in dioxane (3 mL) was capped, degassed and backfilled with argon. The reaction was heated at 120° C. in a microwave for 45 min. The reaction mixture was diluted with EtOAc (75 mL) and washed with saturated NaHCO3 solution (50 mL) and brine (75 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 0.5-3.5% MeOH/DCM), affording tert-butyl 1-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (94 mg, 52% yield). MS (ESI, pos. ion) m/z: 664.3 (M+1). A solution of tert-butyl 1-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (87 mg, 0.13 mmol) in dioxane (3 mL) was treated with HCl, 36.5-38.0% (0.11 mL, 1.31 mmol). The reaction mixture was heated at 90° C. After 3 h, the reaction mixture was cooled to 23° C. and concentrated. The residue (as HCl salt) was free-based using a Silicycle Si-propylsulfonic acid ion exchange column (catalog # R51230B). The compound was diluted in MeOH and added to a pad of the resin (wetted and flushed with 10 mL MeOH). It was flushed with MeOH (50 mL), and then the product was “released” using 2.0 M NH3 in MeOH solution (50 ml). The final filtrate was concentrated, affording 1-(6-(5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine. MS (ESI, pos. ion) m/z: 480.2 (M+1).
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br>CC(C)=O>[C:2]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:18][CH2:17]1)(=[O:1])[CH3:9]
Reactant: BrCCBr
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(C)=O)CC1
Yield: 59.9 %

Procedure:
To a solution of ethyl 3-oxobutanoate (26 g, 200 mmol) in acetone (500 mL) was added potassium carbonate (82.8 g, 600 mmol) followed by 1,2-dibromoethane (45.12 g, 240 mmol). The reaction was refluxed for 24 hrs, then the reaction mixture was filtered. The filtrate was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (1:50(v/v) EtOAc/n-hexane) to afford the title compound as colorless oil (18.7 g, 60%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[N:12][CH:11]=[N:10]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(Cn2cncn2)cc1

Procedure:
A mixture of 34.2 parts by weight of benzyl bromide, 13.8 parts by weight of 1,2,4-triazole and 41.4 parts by weight of potassium carbonate in 150 parts by weight of acetonitrile is refluxed for 10 hours while stirring. The mixture is filtered and the filtrate is evaporated to dryness and recrystallized from a mixture of toluene and cyclohexane. There is obtained 21 parts by weight of 1-benzyl-1,2,4-triazole; m.p.: 58° C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[OH2:12]>>[Cl:3][C:4]1[C:5]([CH2:6][OH:12])=[CH:8][CH:9]=[CH:10][N:11]=1
Reactant: O
Reactant: ClCc1cccnc1Cl
Agent: [BH4-]
Agent: [Na+]
Product: OCc1cccnc1Cl

Procedure:
In 100 ml of cold water was dissolved 8.98 g of sodium borohydride and with ice-cooling and stirring, 11.7 g (0.0665 mole) of 2-chloronicotinyl chloride was added in small portions. The mixture was further stirred at the same temperature for 30 minutes and, then, extracted with Et2O (100 ml×3). The extract was dried over MgSO4 and distilled to remove Et2O. The procedure gave 8.75 g of (2-chloro-3-pyridyl)methanol as a pale yellow oil. When left standing at room temperature, this product solidified thoroughly.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:18])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1C=CC=CC=1>[CH:19](=[N:1][CH2:2][P:3](=[O:18])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: NCP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: O=P(CN=Cc1ccccc1)(Oc1ccccc1)Oc1ccccc1

Procedure:
A solution of diphenyl aminomethylphosphonate (102.8 g) and benzaldehyde (41.6 g) in benzene (1000 ml) is heated at reflux in a Dean-Stark apparatus until water separation ceases. The resulting solution is evaporated under reduced pressure to yield diphenyl N-benzylideneaminomethylphosphonate.
Reaction SMILES: S(=O)(=O)=O.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][OH:15].C(N(CC)CC)C.[Cl-].[Na+]>CS(C)=O.ClCCl>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH:14]=[O:15]
Reactant: COc1ccccc1CCO
Agent: O=S(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccccc1CC=O
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
A solution of pyridine complex with sulfur trioxide (134 g, 0.842 mol) in dimethylsulfoxide (150 mL) was slowly added to a solution of 2-(2-methoxy-phenyl)-ethanol (43 g, 0.28 mol) and triethylamine (86 g, 0.85 mol) in dichloromethane (500 mL) at 0° C. After being stirred 30 min, the mixture was poured into a saturated aqueous solution of sodium chloride and the organic layer was washed with dilute hydrochloric acid, a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness to give (2-methoxy-phenyl)-acetaldehyde (36 g, 0.24 mol, 86%) which was used in the next step directly.
Reaction SMILES: [CH3:1][C@@H:2]1[O:9]C(=O)[C@H](C)[O:5][C:3]1=[O:4].[C:11]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13][O:12]1.C(OC(=O)C)(=O)C>O>[C:11]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13][O:12]1.[C:3]([OH:5])(=[O:4])[CH:2]([CH3:1])[OH:9]
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Agent: O=C1OCCCO1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(O)C(=O)O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
L-Lactide (85.07 g; 0.945 moles) and water (100 mL; millipore) were placed in a 1 L 3-neck flask equipped with a mechanical stirrer, distillation head, and a thermometer. The reaction mixture was warmed to 80° C. and stirred under nitrogen overnight. The flask was then placed under vacuum (aspirator, 7 mmHg) and the temperature was raised to 140° C. to distill off water. After 2 hrs trimethylene carbonate (8.51 g, 0.083 moles) was added. Two hours later a second portion of trimethylene carbonate (8.52 g, 0.083 moles) was added and the reaction was allowed to proceed for 3 more hours. The reaction was cooled to 80° C. and 120 mL of acetic anhydride was added. The solution was stirred at 80° C. overnight under a slow nitrogen purge. After 18 hours the remaining acetic anhydride and acetic acid were removed under vacuum. After the acetic acid and acetic anhydride distillation was complete, 180 mL of tetrahydrofuran/water (85/15; v/v) was added with stirring and the flask temperature was allowed to drop to 60° C. After 15 min the reaction mixture was transferred to a round bottom flask and the tetrahydrofuran was removed under vacuum on a rotary evaporator. Chloroform (300 mL) was added and the resulting solution was extracted twice with 150 mL of millipore water in a separatory funnel and then dried with MgSO4. The mixture was filtered through a "d" fritted glass funnel and the solvent distilled from the oligomer by rotary evaporation. Final traces of solvents were removed under high vacuum (0.4 mmHg) on a Kugelrohr apparatus at 90° C. to yield acetyl-oligo(L-lactic acid-co-trimethylene carbonate) with trimethylene carbonate n=1.6, lactic acid n=7.6, MN =974, and MW =1684.
Reaction SMILES: [C:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][N:19]=2)=[CH:14][CH:13]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>C1COCC1.[Pd]>[C:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:23]=[CH:22][C:21]([OH:24])=[CH:20][N:19]=2)=[CH:16][CH:17]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC(=O)Oc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCC(=O)Oc1ccc(-c2ncc(O)cn2)cc1
Yield: 91 %

Procedure:
3.5 g of 4-(5-benzyloxypyrimidin-2-yl)pheny1 nonanoate are dissolved in 100 ml of THF, 0.5 g of 10% Pd on activated charcoal is added, and the mixture is hydrogenated at 25° C. with stirring. The mixture is filtered through corolite, and the solvent is removed in vacuo, giving 2.5 g of 4-(5-hydroxyprimidin-2-yl)phenyl nonanoate.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][NH:18][CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23]([CH3:32])[C:24]1[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][N:25]=1>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][N:18]([CH2:30][C:28]5[CH:27]=[CH:26][N:25]=[C:24]([N:23]([CH3:32])[CH3:22])[N:29]=5)[CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1
Reactant: CN(C)c1nccc(C=O)n1
Product: C[C@@H]1CN(Cc2ccnc(N(C)C)n2)C[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-cyclopentyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 2-(dimethylamino)pyrimidine-4-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.24-8.21 (m, 1H), 8.00-7.99 (m, 1H), 6.52-6.50 (m, 1H), 5.13-5.10 (m, 1H), 3.72-3.68 (m, 1H), 3.56-3.52 (m, 1H), 3.46-3.40 (m, 3H), 3.17-3.11 (m, 7H), 2.84-2.82 (m, 1H), 2.64-2.60 (m, 1H), 2.44-2.38 (m, 1H), 2.06-1.92 (m, 5H), 1.66-1.65 (m, 2H), 1.20-1.16 (m, 3H). MS: (M+H m/z=423.1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=3)=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[H][H].O.C>C(OCC)(=O)C.[Pd].Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=3)=[CH:19][CH:18]=2)([C:13]([F:14])([F:15])[F:16])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Nc1ccc(C(c2ccc(Oc3cccc([N+](=O)[O-])c3)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(C(c2ccc(Oc3cccc(N)c3)cc2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 20 °C

Procedure:
22.8 g (0.05 mol) of 2-(4-aminophenyl)-2-[4-(3-nitrophenoxy)phenyl]hexafluoropropane were dissolved in 600 cm3 of ethyl acetate, 1 g of palladium on charcoal was added, and the mixture was reduced in a 1 dm3 steel autoclave at about 25° C. using hydrogen (100 bar). When the take-up of hydrogen was complete, the catalyst was filtered off and all the ethyl acetate was removed. The oily, brown crude product was chromatographed over basic alumina using ethyl acetate as eluent. The principal fraction was evaporated to dryness, giving 18 g of a highly viscous, pale yellow residue. 9.5 g of the pale yellow residue were suspended in 100 cm3 of hydrochloric acid (1:1), and 400 cm3 of water were added at the boiling point. The turbid solution was treated twice at the boiling point with 5 g of activated charcoal in each case. The clear, colorless solution was cooled to 20° C., a white solid precipitating out. The suspension was adjusted to a pH of 8-9 under a protective gas (nitrogen) using dilute ammonia solution. The solid was, under a protective gas, filtered off, washed with water and dried.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[SH:7].[H-].[Na+].Br[C:11]1[CH:12]=[C:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.O>CC(N(C)C)=O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:13]2[C:14]([C:17]#[N:18])=[N:15][CH:16]=[C:11]([S:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:12]=2)=[CH:25][CH:24]=1
Reactant: Sc1ccccn1
Reactant: N#Cc1ncc(Br)cc1Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ncc(Sc2ccccn2)cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.6 %

Procedure:
To a solution of pyridine-2-thiol (2.5 g, 23 mmol) in DMA (25 mL) cooled to 0° C. was added NaH (0.90 g, 23 mmol) and the reaction stirred at ambient temperature for 20 min, followed by addition of the 5-bromo-3-(4-fluorophenoxy)picolinonitrile (6.6 g, 23 mmol) and stirring over night at ambient temperature. The reaction was poured into water (250 mL) and a solid formed. The solid was collected, washed with water, and dried in vacuo to yield 3-(4-fluorophenoxy)-5-(pyridin-2-ylthio)picolinonitrile (5 g, 16 mmol, 70%).
Reaction SMILES: [P:1](Cl)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2].[CH2:10]([NH2:12])[CH3:11]>ClC(Cl)C>[CH2:10]([NH:12][P:1](=[O:2])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5])[CH3:11]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCN
Solvent: CC(Cl)Cl
Product: CCNP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
To a solution of 5.0 g (29.0 mmol) of diethyl chlorophosphate in 70 mL dichloroethane cooled on an ice bath was added 4.1 g (63.8 mmol) of ethylamine (70% aq). The mixture was allowed to stir at RT for 30 min and was then partitioned between ether and water. The organic layer was washed with brine, dried (MgSO4), and was filtered. The filtrate was evaporated in vacuo and the residue was kugelrohr distilled (0.8 torr, 90° C.) to yield 2.7 g (52%) of diethyl N-ethylphosphoramidate as a colorless oil.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][C:4](=O)[O:5]C1C=C2C(=CC=1)C(CN(CCC(N1CCC3C=C(OC)C(OC)=CC=3CC1)=O)C)C2.[CH3:37][O:38][C:39]1[C:65]([O:66][CH3:67])=[CH:64][C:42]2[CH2:43][CH2:44][N:45]([C:48](=[O:63])[CH2:49][CH2:50][N:51]([CH2:53][CH:54]3[C:61]4[C:56](=[CH:57][CH:58]=[C:59]([OH:62])[CH:60]=4)[CH2:55]3)[CH3:52])[CH2:46][CH2:47][C:41]=2[CH:40]=1>>[ClH:1].[CH3:2][NH:3][C:4](=[O:5])[O:62][C:59]1[CH:60]=[C:61]2[C:56](=[CH:57][CH:58]=1)[CH2:55][CH:54]2[CH2:53][N:51]([CH2:50][CH2:49][C:48]([N:45]1[CH2:46][CH2:47][C:41]2[CH:40]=[C:39]([O:38][CH3:37])[C:65]([O:66][CH3:67])=[CH:64][C:42]=2[CH2:43][CH2:44]1)=[O:63])[CH3:52]
Reactant: CNC(=O)Oc1ccc2c(c1)CC2CN(C)CCC(=O)N1CCc2cc(OC)c(OC)cc2CC1
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3ccc(O)cc31)CC2
Agent: Cl
Product: CNC(=O)Oc1ccc2c(c1)C(CN(C)CCC(=O)N1CCc3cc(OC)c(OC)cc3CC1)C2

Procedure:
Obtained in the same manner as the compound of Example 44 but using the compound of Example 45 instead of the compound of Example 43.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[N:25]=[C:26]=[O:27].Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[N:25]1[C:8](=[O:10])[C:7]2[C:2](=[N:3][C:4]([S:13][CH3:14])=[N:5][CH:6]=2)[NH:1][C:26]1=[O:27]
Reactant: CCOC(=O)c1cnc(SC)nc1N
Reactant: Cc1cccc(Cl)c1N=C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ncc2c(=O)n(-c3c(C)cccc3Cl)c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.7 %

Procedure:
To a solution of 100 mg of ethyl 4-amino-2-(methylsulfanyl)pyrimidine-5-carboxylate in 4 mL of N,N-dimethylformamide, 56 mg of sodium hydride was added, and the resulting mixture was stirred at room temperature for 5 minutes. To the reaction mixture, 118 mg of 2-chloro-6-methylphenyl isocyanate was added, and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture, ethyl acetate and a 1 N aqueous hydrochloric acid solution were added and the organic layer was separated. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The precipitated solid was solidified with methanol and collected by filtration, whereby 100 mg of the title compound was obtained as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[CH:6]=[C:7]([CH2:11]O)[CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:33]>>[Cl:33][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:6]=1
Reactant: OCc1cccc(CC2CC2)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1cccc(CC2CC2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of [3-(cyclopropylmethyl)phenyl]methanol (1.67 g, 10.3 mmol) in carbon tetrachloride (100 mL) was added polystyrene bound triphenyl phosphine (2.15 mmol/g, 9.57 g, 20.6 mmol). After stirring at 100° C. overnight the resin was filtered of and the solvent was removed under vacuum to afford the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]=[CH:5][C:6]1[NH:7][C:8](=[O:30])[C:9]2[C:10]3[N:19]([CH3:20])[C:18]([NH:21][C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])=[N:17][C:11]=3[CH:12]=[CH:13][C:14]=2[C:15]=1[CH3:16]>CCO.CC(O)=O.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[NH:7][C:8](=[O:30])[C:9]2[C:10]3[N:19]([CH3:20])[C:18]([NH:21][C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])=[N:17][C:11]=3[CH:12]=[CH:13][C:14]=2[C:15]=1[CH3:16]
Reactant: COC(=O)C=Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)CCc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Reaction time: 12 h
Yield: 32.7 %

Procedure:
To a solution of the product of Example 12 (30 mg, 0.06 mmol) in EtOH (3 mL) and AcOH (4 mL) in a Parr reactor was added PtO2 (2 mg, 0.007 mmol). The Parr reactor was charged with 50 psi of H2 and shaken for 12 h. The crude reaction was filtered through diatomaceous earth with EtOH and concentrated in vacuo. Column chromatography (2% MeOH—CH2Cl2) provided the title compound (9 mg, 30%), mp 268° C.(dec); MS(ES) 459, 461 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][O:24][C:25](=[O:27])[N:26]=3)=[CH:12][CH:11]=2)[C:7]2[C:28]([C:32]([O:34]C)=[O:33])=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH3:2].[OH-].[Na+].Cl>>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][O:24][C:25](=[O:27])[N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nc(=O)o[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nc(=O)o[nH]2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 54.8 %

Procedure:
A mixture of the compound (0.47 g) obtained in Example (54h) and 1N NaOH (3 ml) in methan61 (3 ml) was heated for 30 minutes under reflux. The reaction mixture was adjusted to pH 3-4 with 1N HCl. Resulting crystalline precipitates were collected by filtration and recrystallized from ethyl acetate--hexane. The crystals were suspended in water (2 ml), and the suspension was stirred for 2 hours at 60° C. Insoluble materials were collected by filtration and dried to afford colorless crystals (0.25 g, 54%). This product was in agreement with that obtained in Example 1.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=CC=CC=1.[CH3:21]C(=NO)C(=O)CC.CC1C=C(C=CC=1C)C=O>>[CH3:21][C:18]1[CH:19]=[C:14]([C:5]2[O:6][C:7]([CH2:8][CH3:13])=[C:3]([CH2:2][I:1])[N:4]=2)[CH:15]=[CH:16][C:17]=1[CH3:20]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: CCC(=O)C(C)=NO
Agent: Cc1ccc(C=O)cc1C
Product: CCc1oc(-c2ccc(C)c(C)c2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, pentane-2,3-dione-2-oxime and 3,4-dimethylbenzaldehyde gave 2-(3,4-dimethylphenyl)-5-ethyl-4-iodomethyloxazole.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][N:3]=1)[NH2:13]
Reactant: NN
Reactant: Clc1nccc2ncnn12
Solvent: CCO
Solvent: O
Product: NNc1nccc2ncnn12
Reaction time: 1.5 h

Procedure:
A solution of 155 mg (1 mmol) of 5-chloro[1,2,4]triazolo[1,5-c]pyrimidine [D. J. Brown and K. Shinozuka, Aust. J. Chem., 33, 1147 (1980)] in 6 mL of dry ethanol was added gradually to a vigorously stirred solution of 198 mg (204 mg, 4 mmol) of hydrazine monohydrate in 2 mL of dry ethanol. A white precipitate separated during the addition. After 1.5 h, the solid was collected on a filter. It was suspended in 2 mL of concentrated ammonium hydroxide and agitated for a few minutes. The solid was then collected on a filter and washed with some additional concentrated ammonium hydroxide, then with some ethanol, and finally with a large volume of diethyl ether. After drying, the title compound was obtained as a white solid, mp 245-246° C. (decomposition). LC-MS 151 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[N:19]=[CH:18][N:17]=[C:16]([N:20]3[C:28]4[C:23](=[CH:24][C:25]([C:29](O)=[O:30])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:14]2[CH:15]=[C:16]([N:20]3[C:28]4[C:23](=[CH:24][C:25]([CH2:29][OH:30])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[N:17]=[CH:18][N:19]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(C(=O)O)ccc43)ncn2)CC1
Agent: CC(C)OC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(CO)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19c was dissolved in 1 mL of THF with 0.5 mL of triethylamine (3.59 mmol). Isopropyl chloroformate (1M in toluene, 2.25 mL, 2.25 mmol) was added and the mixture was stirred at room temperature for 2 h. Water (1 mL) was added followed by NaBH4 (0.5 g, 13.2 mmol) and the mixture was sonicated for 2 minutes and stirred at room temperature for 1 h. THF was removed under vacuum and the aqueous mixture was acidified with 1N HCl, extracted with DCM (3×10 mL) and the combined extracts were washed with brine (10 mL). The solution was dried, filtered and evaporated. The residue was purified by preparative HPLC to afford 19-1 (tR=3.0, Method 5) as well as a small amount of 4-[6-(5-hydroxymethyl-2,3-dihydro-indol-1-yl)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 19-2. tR=5.21 (Method 5).