Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[C:13]([CH3:29])=[N:14][C:15]2[C:16](=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:18][CH2:19][C:20]=2[CH:21]=1)=O)C>C1COCC1>[CH3:29][C:13]1[C:12]([CH2:10][OH:9])=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][C:16](=[CH:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:15]=2[N:14]=1
Reactant: CCOC(=O)c1cc2c(nc1C)C(=Cc1ccccc1)CCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2c(cc1CO)CCCC2=Cc1ccccc1
Yield: 79.5 %

Procedure:
A suspension of LiAlH4 (2.81 g) in THF (250 ml) is treated with 5,6,7,8-tetrahydro-2-methyl-8-(phenylmethylene)-3-quinolinecarboxylic acid ethyl ester (7.43 g) and reacted for 25 minutes. Excess reagent is quenched, the mixture is diluted with ethyl acetate and filtered. The filtrate is washed, dried and evaporated to yield crude 5,6,7,8-tetrahydro-2-methyl-8-(phenylmethylene)-3-quinolinemethanol (7.3 g). Crystallization from aqueous ethanol gives 5.10 g of pure 5,6,7,8-tetrahydro-2-methyl-8-(phenylmethylene)-3-quinolinemethanol (m.p. 102° C.-103° C.) as two crops.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].Cl[CH2:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:27][O:28][C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=1)=[O:8]
Reactant: O=C(OCCl)N1CCOCC1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1OCOC(=O)N1CCOCC1
Yield: 61.5 %

Procedure:
Using 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide 1 sodium salt (compound of Example 43(1)) and 4-[(chloromethoxy)carbonyl]morpholine as the raw materials, the same operation as the Example 98 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([I:22])[CH:18]=3)[N:13](C)[C:12]2=O)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.C1(CC#C)C=CC=CC=1.O>CN(C=O)C.[Cu]I>[I:22][C:17]1[CH:16]=[CH:15][C:14]([NH:13][CH3:12])=[C:19]([CH:18]=1)[C:20]([NH:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:25])=[CH:5][CH:6]=1)=[O:21]
Reactant: COC(=O)c1ccc(Cn2c(=O)c3cc(I)ccc3n(C)c2=O)cc1
Agent: [Cu]I
Agent: C#CCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1ccc(I)cc1C(=O)NCc1ccc(C(=O)OC)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 19.6 g (44.9 mmol) 4-(6-Iodo-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzoic acid methyl ester and 23.2 g (179.6 mmol) di-isopropyl ethylamine in 200 ml DMF is added bis-triphenylphosphine palladium di-chloride (1.0 g, catalytic) followed by CuI (0.4 g, catalytic). 7.3 g (62.9 mmol) 3-phenyl-propyne is added and the mixture is heated to 70° C. for 6 hrs. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filter and dry under reduced pressure. Solid from EtOAc.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:5][N:6]=1.[CH2:13]([O:15][C:16](=[O:28])[C:17](=[C:23](OCC)[CH3:24])[C:18](OCC)=[O:19])[CH3:14]>COCCOCCOC>[CH3:24][C:23]1[N:1]=[C:2]2[S:3][C:4]([N:7]3[CH2:8][CH2:9][O:10][CH2:11][CH2:12]3)=[N:5][N:6]2[C:18](=[O:19])[C:17]=1[C:16]([O:15][CH2:13][CH3:14])=[O:28]
Reactant: Nc1nnc(N2CCOCC2)s1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)OCC
Solvent: COCCOCCOC
Product: CCOC(=O)c1c(C)nc2sc(N3CCOCC3)nn2c1=O
Temperature: 0 °C

Procedure:
2-amino-5-morpholino-1,3,4-thiadiazole (5 g) was reacted with diethyl(1-ethoxy-ethylidene)-malonate (6.2 g) in diglyme (40 ml) at 150° C. for 20 hours. After cooling the reaction mixture was diluted with ice water and extracted with ethyl acetate; after evaporation in vacuo to dryness, the residue was purified over a SiO2 column using chloroform-methanol 98:2 as eluent. Crystallization from isopropyl ether gave 7-methyl-2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid, ethyl ester, m.p. 196°-198° C. (2.6 g), which was reacted with 2-amino-pyridine (2.25 g) in polyphosphoric acid (130 g) under stirring at 120° C. for 4 hours. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered and washed with water to give 1.9 g of 7-methyl-2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m.p. 285°-287° C.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1>>[CH3:13][C:12]1[C:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1cccc(N)c1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1cccc(Nc2nc(NCc3ccccn3)nc(C)c2C)c1

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using m-toluidine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.07 (s, 3H), 2.28 (s, 3H), 2.33 (s, 3H), 4.74 (d, J=3.0 Hz, 2H), 5.79 (bs, 1H), 6.31 (s, 1H), 6.84 (d, J=8.1 Hz, 1H), 7.10-7.17 (m, 2H), 7.30-7.40 (m, 3H), 7.60 (t, J=7.8 Hz, 1H), 8.57 (d, J=2.8 Hz, 1H); MS (ESI) m/z 320.7 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH2:8][CH2:9][C:10](=O)[CH2:11][C:6]=2[S:5][C:4]=1[NH:13][C:14](=[O:20])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])#[N:2].[NH2:21][CH:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:23][OH:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[C:7]2[CH2:8][CH2:9][CH:10]([NH:21][CH:22]([CH2:23][OH:24])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][C:6]=2[S:5][C:4]=1[NH:13][C:14](=[O:20])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])#[N:2]
Reactant: CC(C)(C)C(N)CO
Reactant: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(=O)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(NC(CO)C(C)(C)C)C2

Procedure:
To a solution of the intermediate isolated in Example 9, Step C, in 40 mL of dichloromethane was added 0.452 g (3.90 mmol) of 2-amino-3,3-dimethylbutan-1-ol, followed by 1.24 g (5.9 mmol) of sodium triacetoxyborohydride and 0.468 mL (7.80 mmol) of acetic acid. After 16 h at ambient temperature the reaction was diluted with an equal volume of saturated aqueous NaHCO3. The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification by preparative reversed phase HPLC afforded the title compound (TFA salt).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:33])(=O)=O)=CC=1.[Cl-].[NH4+]>O1CCCC1.O>[F:33][CH:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CC1CCOCC1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(F)C1CCOCC1
Reaction time: 0.25 h

Procedure:
Ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate (2.0 g) was dissolved in tetrahydrofuran (20 ml). A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 17 ml) was added dropwise under nitrogen atmosphere under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. Then, a solution of N-fluorobenzenesulfonimide (7.3 g) in tetrahydrofuran (20 ml) was added and the mixture was stirred at the same temperature for 3 hours. A saturated aqueous ammonium chloride solution and water were added under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated. Chloroform-diethyl ether was added to the residue, and insoluble matter was removed by filtration. Thereafter, the solvent was evaporated and the residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane and with chloroform) to give the title compound containing insoluble matter (0.9 g) as a pale orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH:26](O)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[N:19]=[CH:26]2)=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2c(N)c1OC
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)N=CN3c1ccc(Cl)cc1

Procedure:
A solution of N4-(4-chloro-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (160 mg, 0.48 mmol) (from Example 13, Step B, supra) in formic acid (2 mL) was heated at 110° C. for 2 hours. Aqueous NaOH solution was added to the reaction mixture to a pH 10–12. The solution was diluted with chloroform (100 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This residue was purified by chromatography using EtOAc/Et3N (1:0.05) as eluent to give the desired 3-(4-chloro-phenyl)-8,9-dimethoxy-3H-1,3,4,6-tetraaza-phenalene as an off white solid. (Yield 96 mg, 59%).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][S:9][S:10][CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C)=[O:5]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:13][CH2:12][CH2:11][S:10][S:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=1[OH:1]
Reactant: CC(C)(C)OC(=O)NCCSSCCNC(=O)c1ccccc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCSSCCNC(=O)c1ccccc1O
Reaction time: 3 h

Procedure:
tert-Butyl 2-(2-(2-(2-hydroxybenzamido)ethyl)disulfanyl)ethylcarbamate (400 mg, 1.08 mmol) was taken up in 25% TFA in CH2Cl2 (10 mL) and allowed to stand at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to afford a quantitative yield of N-(2-(2-(2-aminoethyl)-disulfanyl)-ethyl)-2-hydroxybenzamide as the TFA salt.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.[CH:17](O)=[O:18]>CCOCC>[CH:17]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2)=[O:18]
Reactant: O=CO
Reactant: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Solvent: CCOCC
Product: Nc1nc2c(ncn2COCCOC=O)c(=O)[nH]1

Procedure:
A solution of 9-(2-hydroxyethoxymethyl)guanine (4.73 g) in 97% formic acid (24 ml) was stirred at room temperature overnight. The amber solution was diluted with about 200 ml of dry ether and chilled. The resulting white precipitate was filtered, dried and recrystallized from dry dimethylformamide to give 9-(2-formyloxyethoxymethyl)guanine (3.6 g, m.p. 225°-227° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]=O)[C:5]([OH:7])=[O:6].[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].C1C=CC=CC=1>O>[Cl:1][CH:2]1[C:10](=[C:11]=[N:17][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3]1
Reactant: CCCCN
Reactant: O=Cc1ccc(C(=O)O)cc1Cl
Solvent: O
Solvent: c1ccccc1
Product: CCCCN=C=C1C=CC(C(=O)O)=CC1Cl

Procedure:
3-Chloro-4-formylbenzoic acid (5 g, 0.027 mole), butylamine (2 g, 0.027 mole) and benzene (75 ml) were refluxed for 2 hours using a flask fitted with a Dean-Stark water separator. The solvent was removed by distillation in vacuo to give 3-chloro-4-(butyliminomethylene) benzoic acid to which was added nitropropane (8.9 g, 0.1 mole) and acetic acid (21 ml). The mixture was refluxed for 10 minutes then cooled in ice. The mixture was treated with water and the solid that separated removed by filtration, washed with water, dried and recrystallized from a mixture of acetic acid and water (2:1) to give 4.7 g of the desired product, m.p. 179°-180° C.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[O:12][C:13]([N:15]3[CH2:19][CH2:18][C@H:17](O)[CH2:16]3)=[O:14])[CH2:3]1)[CH2:9]2.[O:21]=[C:22]1[CH2:27][C:26]([C:28]#[N:29])=[CH:25][CH2:24][NH:23]1>>[OH:1][C:2]12[CH2:3][CH:4]3[CH2:10][CH:8]([CH2:7][CH:6]([CH:5]3[O:12][C:13]([N:15]3[CH2:19][CH2:18][C@@H:17]([N:23]4[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:22]4=[O:21])[CH2:16]3)=[O:14])[CH2:11]1)[CH2:9]2
Reactant: O=C(OC1C2CC3CC1CC(O)(C3)C2)N1CC[C@H](O)C1
Reactant: N#CC1=CCNC(=O)C1
Product: N#Cc1ccn([C@@H]2CCN(C(=O)OC3C4CC5CC3CC(O)(C5)C4)C2)c(=O)c1
Yield: 2 %

Procedure:
The title compounds were prepared from (S)-3-hydroxy-pyrrolidine-1-carboxylic acid 5-hydroxy-adamantan-2-yl ester (ca. 1:1 mixture of cis- and trans-isomer) and 2-oxo-1,6-dihydro-pyridine-4-carbonitrile following a procedure analogous to that described in Example 77. The isomers were separated by HPLC on reversed phase (acetonitrile/water containing 1.36% trifluoroacetic acid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[NH2:32][CH2:33][CH2:34][OH:35].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:32][CH2:33][CH2:34][OH:35])=[O:18])=[N:14][CH:15]=1
Reactant: NCCO
Reactant: COc1ccc(S(=O)(=O)C(c2cnc(C(=O)O)cc2C)c2cc(F)ccc2F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)C(c2cnc(C(=O)NCCO)cc2C)c2cc(F)ccc2F)cc1F
Temperature: 25 °C
Reaction time: 19 h
Yield: 80 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(3-fluoro-4-methoxyphenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (113 mg, 0.25 mmol) in methylene chloride (3 ml), 2-aminoethanol (0.017 ml, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0.030 ml, 0.28 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol) were added at room temperature. After stirring for 19 hours at room temperature, the reaction mixture was washed with water and then with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with ethyl acetate was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and was collected by filtration, to obtain the title compound (99 mg, 0.20 mmol, 80%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Reactant: Cc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)Cc2ccc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 500 mL round-bottom flask were combined 2-(6-chloropyridin-3-yl)acetic acid (10.3 g, 60.0 mmol; Oakwood), p-toluidine (6.43 g, 60.0 mmol; Aldrich) and N,N-diisopropylethylamine (34.3 mL, 198 mmol; Aldrich) in tetrahydrofuran (220 mL). The mixture was stirred at room temperature for 1 hour, and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; 25.1 g, 66.0 mmol; Aldrich) was added. After 16 hours, the reaction was concentrated, the residue dissolved in ethyl acetate (500 mL) and washed with water (50 mL). The organic phase was concentrated and purified by flash chromatography (silica gel, hexanes/ethyl acetate, 2:1) to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.28 (s, 3H), 3.71 (s, 2H), 7.11 (d, J=8 Hz, 2H), 7.37-7.46 (m, 3H), 7.81 (dd, J=8, 3 Hz, 1H), 8.33 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 261 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[N:30]([CH:33]([CH3:35])[CH3:34])=[C:31]=[O:32]>C(Cl)Cl>[CH:33]([NH:30][C:31]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:32])([CH3:35])[CH3:34]
Reactant: CC(C)N=C=O
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (70 mg, 0.252 mmol, example 9 (step 3) and DIEA (44 μL, 0.252 mmol) in DCM (1.6 mL) was added 2-isocyanatopropane (25 μL, 0.252 mmol). The resulting mixture was reacted under the same conditions as described for example 10 to give the title compound as a white solid. MS (ESI, positive ion) m/z: 363 (M+H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:18][CH2:19][CH2:20]O)[N:6]=1)[CH:2]=[CH2:3].S(Cl)([Cl:24])=O>ClCCl>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:18][CH2:19][CH2:20][Cl:24])[N:6]=1)[CH:2]=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=CCNc1nc(NCCO)nc2ccc([N+](=O)[O-])cc12
Solvent: ClCCl
Product: C=CCNc1nc(NCCCl)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
To a solution of 50 mg (0.173 mmol) of 4-allylamino-2-(2-hydroxyethylamino)-6-nitroquinazoline in dichloromethane was added 1.63 g (13.7 mmol) of thionyl chloride, and then the resulting mixture was stirred at room temperature for 4 hours. After the mixture was subjected to heating under reflux for further one hour, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography to give 25 mg (yield: 46.8%) of the title compound.
Reaction SMILES: [OH-].[K+].[CH2:3]([NH:5][C:6]1[C:11]([CH:12]=O)=[C:10]([CH3:14])[N:9]=[C:8]([S:15][CH3:16])[N:7]=1)[CH3:4].C(N1[C:24]2[N:25]=[C:26]([NH:30][CH2:31]C)[N:27]=[C:28](C)[C:23]=2C=C(C2N(C(OC(C)(C)C)=O)C=CC=2)C1=O)C.N1C(CC#N)=CN=C1>C(O)C>[CH2:3]([N:5]1[C:6]2[N:7]=[C:8]([S:15][CH3:16])[N:9]=[C:10]([CH3:14])[C:11]=2[CH:12]=[C:23]([C:24]2[NH:25][CH:26]=[N:30][CH:31]=2)[C:28]1=[NH:27])[CH3:4]
Reactant: CCNc1nc(C)c2cc(-c3cccn3C(=O)OC(C)(C)C)c(=O)n(CC)c2n1
Reactant: CCNc1nc(SC)nc(C)c1C=O
Agent: N#CCc1cnc[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(=N)c(-c2cnc[nH]2)cc2c(C)nc(SC)nc21
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution of potassium hydroxide (0.139 g, 2.48 mmol) in absolute ethanol (3.0 mL) was added to a pressure tube charged with 4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde (0.229 g, 1.08 mmol), prepared using procedures similar to those described for Intermediate 1, and 2-(1H-imidazol-5-yl)acetonitrile (0.174 g, 162 mmol) and heated to 70° C. After 12 h, the reaction was allowed to cool to room temperature and concentrated in vacuo affording 8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-imine as a solid. The product was used in the subsequent step without further purification.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[O:11]=[C:12]([C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>O>[OH:11][C@@H:12]([C:23]1[N:24]=[CH:25][CH:26]=[CH:27][N:28]=1)[CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CN(CC(=O)c1ncccn1)C(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CN(C[C@@H](O)c1ncccn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
In a glove box, triethylamine (6.6 g) was added carefully with stirring to formic acid (4.6 g) in a glass vial and stirring was continued until the mixture had cooled to room temperature. A 50 mL Schlenk flask was charged with [(η6C6H6)RuCl2]2 (200 mg), (R)(R)-TsDPEN (350 mg), anhydrous i-PrOH (10 mL), and triethylamine (0.35 mL). The Schlenk flask was removed from the glove box and placed on a Schlenk line, a reflux condenser attached, and the reaction mixture was heated to 75° C. for 1 h under nitrogen. The reaction was then cooled to 0° C. giving a solid which was collected by filtration. The solid was washed with diethyl ether and air-dried giving 228 mg of (η6C6H6)Ru[(R,R)-TsDPEN]Cl. To a 50 mL RB flask in a glove box was added (β6C6H6)Ru[(R,R)-TsDPEN]Cl (17 mg) followed by the mixture of the triethylamine/formic acid solution prepared above. The mixture was allowed to stir at room temperature for 20 min and tert-butyl 2-oxo-2-pyrimidin-2-ylethyl(methyl)carbamate (1.33 g) was added. The mixture was stirred at room temperature for 17 h, poured into water (75 mL), and extracted with EtOAc (3×100 mL). The combined organic layers were washed with 1 M aq. NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford 1.17 g of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH2:23][C:24](OC)=[O:25])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.Cl>O1CCCC1>[C:1]([O:5][C:6]([C@@:8]12[CH2:22][CH2:23][C:24](=[O:25])[C@@H:12]1[C:11](=[O:13])[N:10]([C@@H:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CC[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CCC(=O)[C@@H]2C1=O
Reaction time: 1 h
Yield: 69.4 %

Procedure:
(3S)-3-(2-Methoxycarbonyl-1-ethyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (35.0 g, 93.2 mmol) was dissolved in tetrahydrofuran (1 L). A 2 M lithium diisopropylamide/heptane/tetrahydrofuran/ethylbenzene solution (100 mL, 200 mmol) was added dropwise in a nitrogen atmosphere at an internal temperature of −69° C. over 30 minutes. After stirring at the same temperature for one hour, the reaction solution was poured into a 1N hydrochloric acid solution (2 L) in an ice bath, followed by extraction with ethyl acetate (2 L, 1 L). The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the precipitated solid was collected by filtration to give 22.2 g of the title compound as pale red crystals. The filtrate was further concentrated to give 2.88 g of the title compound as pale red crystals. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to give 2.09 g of the title compound as colorless crystals.