Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:17])([CH3:16])[CH:13]([NH2:15])[CH3:14]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:15][CH:13]([CH3:14])[C:12]([CH3:17])([CH3:16])[CH3:11])=[S:10])=[CH:4][CH:3]=1
Reactant: CC(N)C(C)(C)C
Reactant: S=C=Nc1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(NC(=S)Nc1ccc(Br)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of 4-bromophenyl isothiocyanate (1.50 g, 7.01 mmol) in THF (30 mL) at room temperature was added (±) 3,3-dimethyl-2-aminobutane (1.41 mL, 10.5 mmol) and the reaction was stirred overnight at room temperature. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 1.76 g (80%) of 1-(4-bromophenyl)-3-(1,2,2-trimethyl-propyl)-thiourea as a white solid which was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]([N:12]([C:28](=[O:31])[CH2:29][CH3:30])[C:13]1[C:18]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:17][CH:16]=[CH:15][C:14]=1[S:24](O)(=[O:26])=[O:25])[CH2:10][CH3:11].P(Cl)(Cl)(Cl)(Cl)[Cl:33].CCOCC>ClCCl>[O:8]=[C:9]([N:12]([C:28](=[O:31])[CH2:29][CH3:30])[C:13]1[C:18]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:17][CH:16]=[CH:15][C:14]=1[S:24]([Cl:33])(=[O:26])=[O:25])[CH2:10][CH3:11]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCC(=O)N(C(=O)CC)c1c(-c2cccs2)cccc1S(=O)(=O)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N(C(=O)CC)c1c(-c2cccs2)cccc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
To a solution of 2.8 g (6.1 mmol) of the N,N-diethylethanamine salt of 2-[bis(1-oxopropyl)amino]-3-thien-2-ylbenzenesulphonic acid in 6 ml of dichloromethane are added, at 0° C., 1.3 g (6.1 mmol) of phosphorus pentachloride and the reaction mixture is allowed to warm to room temperature. The mixture is then heated for 5 hours at the reflux temperature and then allowed to cool to room temperature. Ether is added, the mixture is filtered and the residue is precipitated from an ether/pentane mixture (1/1). The mixture is filtered and the filtrate is concentrated under reduced pressure and purified by chromatography on a column of florisil™. 2.2 g of product are obtained, which product is crystallized from an ether/pentane mixture.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1C
Product: Cc1sc2nc(-n3ccnc3C)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].[H-].[Na+].Cl[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1>C1COCC1>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])[C@@H:3]1[CH2:2][O:1][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CO)c(-c2ccc(F)cc2)s1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2COc2ccc(C(F)(F)F)cn2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of ((2S,3R)-2-(hydroxymethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone in THF was added NaH (4 equiv.) at 0° C. The reaction was allowed to warm to rt and stirred an additional 30 min. 2-Chloro-5-(trifluoromethyl)pyridine (2 equiv.) was then added and the solution was warmed to reflux for 2 h. The reaction was cooled and quenched with satd. aq. NH4Cl and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 460 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=2[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Yield: 94.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-methanesulfonylbenzoic acid (10.2 g) and piperazine-1-carboxylic acid tert-butyl ester (7.49 g), the title compound (15.4 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:35]([OH:55])[C:36]2[N:40](COCC[Si](C)(C)C)[C:39]3[CH:49]=[CH:50][C:51]([C:53]#[N:54])=[CH:52][C:38]=3[N:37]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[C:5]2[C:22]1[N:26](COCC[Si](C)(C)C)[N:25]=[CH:24][CH:23]=1.CC1C(C(O)C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2C1N(COCC[Si](C)(C)C)N=CC=1>Cl.CO.C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH:35]([OH:55])[C:36]2[NH:40][C:39]3[CH:49]=[CH:50][C:51]([C:53]#[N:54])=[CH:52][C:38]=3[N:37]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[CH:20][CH:21]=1)(=[O:14])=[O:13])[CH:6]=[C:5]2[C:22]1[NH:26][N:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccnn3COCC[Si](C)(C)C)c3c(C(O)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3ccnn3COCC[Si](C)(C)C)c3c(C(O)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccn[nH]3)c3c(C(O)c4nc5cc(C#N)ccc5[nH]4)c(C)cc(C)c32)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of a mixture of (±)-2-((5,7-dimethyl-1-tosyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (250 mg, 0.314 mmol) in 1M HCl in MeOH (2 mL) was stirred at 60° C. for 16 h. The reaction mixture was cooled to room temperature, and diluted with CH2Cl2. The layers were separated and the organic layer was washed with 5% aq. NaHCO3, H2O, and brine, dried over Na2SO4, and filtered. After concentration of the filtrate, the resulting residue was purified by silica gel flash column chromatography [CH2Cl2/(2M NH3 in MeOH)=94/6 then 93/7] to give the title compound. MS (ESI+) m/z 537.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][C:23]2[CH:24]=[C:25]([NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[C:27]([CH3:29])[CH:28]=2)=[CH:16][CH:15]=1)#[N:13].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:30]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:25]1[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([O:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)[CH:24]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)CNc1cc(C)cc(OCCc2ccc(C#N)cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)CN(c1cc(C)cc(OCCc2ccc(C#N)cc2)c1)S(=O)(=O)c1ccccc1Cl
Reaction time: 2 h
Yield: 62 %

Procedure:
2-Chlorobenzenesulfonyl chloride (0.225 g; 1.06 mmol) was added to a cold solution (ice:water temperature) of 3-[2-(4-cyanophenyl)ethoxy]-5-methyl-phenylaminoacetic acid, ethyl ester (0.30 g; 0.88 mmol; from step (i) above) in pyridine (10 mL). After 2 hours stirring the temperature was allowed to rise to ambient. After 4 hours at this temperature more 2-chloro-benzenesulfonyl chloride (0.056 g; 0.26 mmol) was added and the mixture was left overnight. The mixture was then poured into aqueous saturated NaHCO3 and extracted twice with Et2O. The combined ether phases where washed with HCl/aq (2M), H2O and brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (SiO2; EtOAc:heptane (1:3)) to give 0.28 g (62%) of the sub-title compound.
Reaction SMILES: [C:1]1([C:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:24]1([CH2:29][CH2:30]O)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[C:1]1([C:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:30][CH2:29][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(C2=C(c3ccccc3)Sc3ccccc3O2)cc1
Reactant: OCCN1CCCC1
Product: c1ccc(C2=C(c3ccc(OCCN4CCCC4)cc3)Oc3ccccc3S2)cc1

Procedure:
The entitled compound was obtained according to the method of Example 3 but using 4-(3-phenyl-1,4-benzoxathiin-2-yl)phenol synthesized in Reference Example 1-1 and 2-pyrrolidin-1-ylethanol as the starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[S:6][C:7]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]4)=[CH:16][CH:15]=3)(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:35]I>C1COCC1>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[S:6][C:7]([S:10]([N:13]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:23]4)=[CH:16][CH:15]=3)[CH3:35])(=[O:11])=[O:12])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: Cc1c(S(=O)(=O)Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)sc2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(S(=O)(=O)N(C)c2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)sc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 3-(4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonamido)phenyl)azetidine-1-carboxylate (216 mg, 0.44 mmol) was stirred in THF (5 ml) and NaH (25 mg, 0.53 mmol) was added. After stirring at r.t. for 15 min, methyl iodide (0.028 ml, 0.44 mmol) was added and stirring was continued for 116 h. The solution was concentrated in vacuo, dissolved in water (pH 11) and extracted with EtOAc. The organic extracts were dried (MgSO4), filtered and concentrated to give tert-butyl 3-(4-(5-chloro-N,3-dimethylbenzo[b]thiophene-2-sulfonamido)phenyl)azetidine-1-carboxylate (=starting compound methylated at the amido-N) (185 mg, 83%).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:21]([OH:23])=O)[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2)#[N:2].[Cl-].[O:25]1[CH2:29][CH2:28][CH:27]([NH3+:30])[CH2:26]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([C:3]1[N:4]=[C:5]([C:21]([NH:30][CH:27]2[CH2:28][CH2:29][O:25][CH2:26]2)=[O:23])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2)#[N:2]
Reactant: COc1ccc2c(C(=O)O)nc(C#N)c(-c3ccccn3)c2c1
Reactant: [NH3+]C1CCOC1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(C(=O)NC3CCOC3)nc(C#N)c(-c3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
DMF was added to a vial containing 3-cyano-6-methoxy-4-pyridin-2-ylisoquinoline-1-carboxylic acid (0.028 g, 0.092 mmol), tetrahydrofuran-3-aminium chloride ( 0.068 g, 0.550 mmol), EDC (0.105 g, 0.550 mmol) and HOAT (0.0437 g, 0.275 mmol). DIEA (0.071 g, 0.550 mmol) was added to this mixture and stirred at rt overnight. Partitioned between half-saturated bicarb and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated, then purified by reverse phase HPLC to give a tan solid (0.019 g, 55%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccc(F)cc3)C2=O)cn1
Yield: 33 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-4-fluorobenzene. Yield 33%. MS M+H calculated 384.1; found 384.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an I IC50 of 0.05 uM.
Reaction SMILES: [CH2:1]([N:3]1[CH:15]=[C:14]2[C:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)=[N:4]1)[CH3:2].CN(CCN(C)C)C.C([Li])CCC.Cl.CN([CH:34]=[O:35])C>C(#N)C.C1COCC1>[CH2:1]([N:3]1[C:15]([CH:34]=[O:35])=[C:14]2[C:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)=[N:4]1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCn1cc2c(n1)c(=O)[nH]c1ccccc12
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCn1nc2c(=O)[nH]c3ccccc3c2c1C=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, a mixture of 2-ethyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (10 g, 46.8 mmol), N,N,N,N-tetramethylethylenediamine (31 mL), and THF (520 mL) was chilled to 0° C. A solution of n-butyllithium in hexanes (56 mL of 2.5 M) was added dropwise. After the addition was complete the reaction mixture was stirred for 5 minutes and then DMF (72 mL) was added dropwise. The reaction mixture was warmed to ambient temperature and stirred for 1 hour. 1 N hydrochloric acid was added and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to about half the original volume and then diluted with water and extracted with dichloromethane. The combined extracts were dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide a dark yellow oil. The oil was combined with acetonitrile and stirred for 20 minutes. A bright yellow solid was isolated by filtration to provide 4 g of 2-ethyl-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinoline-1-carbaldehyde as a yellow powder. An additional 3 g of material was isolated from the mother liquor.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:45][C:46]([NH2:48])=[O:47])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.N>>[OH:1][C:2]1[CH:3]=[C:4]([NH:45][C:46]([NH2:48])=[O:47])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NC(N)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(O)cc(NC(N)=O)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 80.9 %

Procedure:
(S)-1-(3-Hydroxy-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)urea (18 mg, 0.03 mmol) was treated with trifluoroacetic acid (360 μl, 4.07 mmol) and a solution of ammonia (7N in methanol, 360 μl, 2.52 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 15% dichloromethane-2-propanol) to obtain 13 mg (90% yield) of the title compound.
Reaction SMILES: Cl.Cl.[C:3]1([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH:11]2[C:23]([O:25]CC)=[O:24])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[C:3]1([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][CH:11]2[C:23]([OH:25])=[O:24])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 74.3 %

Procedure:
To ethyl 1,4-bis(phenylmethyl)-2-piperazine carboxylate dihydrochloride (21 g, 52 mmol) were added ethanol (300 mL) and a 1 M aqueous sodium hydroxide solution (300 mL, 0.30 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction solution was concentrated, and then 1 M hydrochloric acid was added thereto until the pH was adjusted to 5. The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the resulting crystals was added diethyl ether, collected by filtration, and washed with diethyl ether to obtain the title compound (12 g, yield 76%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH:11]1[CH2:16][CH2:15][C:14]2([CH:21]=[CH:20][C:19]3[CH:22]=[C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:25][C:18]=3[O:17]2)[CH2:13][CH2:12]1>C(O)C.[Pd]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH:11]1[CH2:16][CH2:15][C:14]2([CH2:21][CH2:20][C:19]3[CH:22]=[C:23]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:24]=[CH:25][C:18]=3[O:17]2)[CH2:13][CH2:12]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C=CC1(CCC(N3CCc4ccccc4C3)CC1)O2
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)CCC1(CCC(N3CCc4ccccc4C3)CC1)O2
Temperature: 25 °C

Procedure:
To a stirred suspension of 5% Pd/C (10 wt. %, 1.7 mg) in ethanol (25 ml ) was added the olefin from step A above. The system was evacuated and purged with hydrogen twice and the reaciton mixture stirred at r.t. under 1 atm. of hydrogen. After three hours another portion of Pd/C (20 wt.%, 3.4 mg) was added and the reaction stirred overnight at r.t. It was then filtered through celite, the pad rinsed with ethanol and evaporated under reduced pressure. The resulting oil was chromatographed over silica gel with eluting with 5% MeOH:CHCl3. The pure material was recrystallized from EtOH to give 100 mg of off white crystals. 60.1%. mp 183°-185 ° C. 1H NMR (CDC13)δ7.11-6.79 (m, 8H), 4.14 (s,2H), 2.93 (s, 5H), 2.91 (s, 2H), 2.76 (t, J=7 Hz, 2H), 2.66-2.54 (m, 1H), 2.00 (d, J=9 Hz, 2H), 1.90-1.72 (m, 6H), 1.46-1.20 (m, 2H) Anal. Calcd for C24H30N2O3S.0.15H2O: C, 67.14; H, 7.11; N, 6.53. Found: C, 67.17; H, 6.99; N, 6.45. ##STR10##
Reaction SMILES: [CH2:1]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][O:5]1)[CH:2]=C.C[N+]1([O-])CC[O:20]CC1.I([O-])(=O)(=O)=O.[Na+].CCOC(C)=O>C1COCC1.O.CO.O=[Os](=O)(=O)=O>[C:10]1([C:4]2([CH2:1][CH:2]=[O:20])[CH2:9][CH2:8][CH2:7][CH2:6][O:5]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CCC1(c2ccccc2)CCCCO1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=CCC1(c2ccccc2)CCCCO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution of 2-allyl-2-phenyltetrahydro-2H-pyran (370 mg, 1.829 mmol, Int. 10B) in THF (2.5 mL) was added a solution of N-methylmorpholine-N-oxide (321 mg, 2.74 mmol) in water (2.5 mL), and then 0.37 mL of 2.5% OsO4 in water was also added. The mixture was stirred at room temperature for 1 day. The reaction was quenched with aq Na2S2O3 and the product was extracted with EtOAc. The extract was washed with brine, and the combined aqueous layers were back extracted with EtOAc once and combined. The extracts were dried over Na2SO4 and evaporated to give an oily residue. The residue was dissolved in MeOH (5 mL). A solution of sodium periodate (469 mg, 2.195 mmol) in water (5 mL) was added dropwise at 0° C. As soon as the addition started, white precipitate formed. The mixture was stirred for 30 mins at the same temperature and poured into EtOAc. The extract was washed with brine, and the combined aqueous layers were back extracted with EtOAc and combined. The extracts were dried over Na2SO4 and evaporated to give an oily residue. The residue was purified by Combiflash (40 g silica gel) eluting with 1:9 EtOAc-hexane to give 2-(2-phenyltetrahydro-2H-pyran-2-yl)acetaldehyde as an oil (239 mg). 1H NMR (400 MHz, CDCl3) δ ppm 9.64-9.68 (1 H, m), 7.36-7.46 (4 H, m), 7.25-7.31 (1 H, m), 3.74-3.81 (1 H, m), 3.55-3.64 (1 H, m), 2.58-2.75 (2 H, m), 2.29-2.39 (1 H, m), 1.80-1.92 (1 H, m), 1.59-1.75 (2 H, m), 1.40-1.58 (2 H, m).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:17])[C:5]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([C:15]#N)[CH:9]=[N:8][C:6]=2[N:7]=1.C(O)=[O:19]>[Ni]>[NH2:1][C:2]1[N:3]=[C:4]([NH2:17])[C:5]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([CH:15]=[O:19])[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: O=CO
Reactant: CCCc1c(C#N)cnc2nc(N)nc(N)c12
Agent: [Ni]
Product: CCCc1c(C=O)cnc2nc(N)nc(N)c12
Reaction time: 8 h
Yield: 8 %

Procedure:
Raney Ni (1.2 g damp) was added with the aid of 95-97% HCO2H (7 mL) to a solution of 2,4-diamino-5-propylpyrido[2,3-d]pyrimidine-6-carbonitrile (I-4a) (500 mg, 2.19 mmol) in 95-97% HCO2H (5 mL). The stirred mixture was heated at 75°-80° C. for 1.5 h. Raney Ni was removed by filtration, and the filtrate was evaporated. The residue was dissolved in hot H2O (20 mL), and the solution was filtered, then cooled, and treated with concentrated NH4OH to pH 7 to cause solid to precipitate. The mixture was kept at 0°-5° C. overnight before the solid was collected and washed with cold H2O. This crude material was applied to a silica gel column and eluted with CHCl3 --MeOH (7:1). Evaporation of the product fractions afforded the aldehyde compound 2,4-diamino-5-propylpyrido[2,3-d]pyrimidine-6-carboxaldehyde; yield 8% (41 mg).