Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[CH:12](=O)[CH:13]([CH3:15])[CH3:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1/[N:5]=[CH:12]/[CH:13]([CH3:15])[CH3:14])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCc1cccc(CC)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCc1cccc(CC)c1/N=C/C(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Benzene (150 mL) was added to 2,6-diethylaniline (18.59 g, 124.6 mmol) and 3 angstrom molecular sieves (ca. 50 mL). Then isobutyraldehyde (9.43 g, 131 mmol) and p-toluenesulfonic acid monohydrate (20 mg, 0.011 mmol) were added. The flask was sealed and heated to 50° C. After stirring overnight the very pale yellow solution was filtered and the volatiles were removed under reduced pressure to afford the product as a clear, pale yellow oil. Yield: 22.5 g, 84.6%. 1H NMR (C6D6): δ 7.21 (1H, d), 7.02 (2H, m), 2.47 (4H, q), 2.39 (1H, m), 1.11 (6H, t), 1.01 (6H, d).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH3:26])[CH3:25])[N:16]=[CH:17][C:10]=2[N:9]([CH3:35])[C:8]1=[O:36])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:36])[N:9]([CH3:35])[C:10]=3[CH:17]=[N:16][C:15]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH:24]([CH3:26])[CH3:25])=[CH:33][CH:32]=1
Reactant: CC(C)c1ccccc1-c1ncc2c(c1Cc1ccc(Cl)cc1)c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccccc1-c1ncc2c(c1Cc1ccc(Cl)cc1)c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-(2-isopropylphenyl)-1-methyl-2,4-dioxo-1,2-dihydro pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (7 mg, 0.0138 mmol) in THF (0.5 mL) and water (0.5 mL) was added LiOH.H2O (1.2 mg, 0.0277 mmol). The reaction was stirred at RT for 30 min then diluted with EA (5 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:2) to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-6-(2-isopropylphenyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (2.4 mg, 36.4% yield) as a white solid. 1H NMR (CDCl3) δ: 8.79 (s, 1H), 7.38 (d, J=3.8 Hz, 2H), 7.20-7.12 (m, 1H), 7.10 (t, J=8.4 Hz, 2H), 6.97 (d, J=7.5 Hz, 1H), 6.71 (d, J=8.4 Hz, 2H), 5.34 (s, 1H), 4.79 (d, J=14.9 Hz, 1H), 4.19 (t, J=6.1 Hz, 2H), 3.76 (s, 3H), 3.48 (d, J=6.1 Hz, 2H), 2.77 (s, 1H), 2.01 (d, J=5.9 Hz, 1H), 1.92-1.80 (m, 2H), 1.10 (d, J=6.8 Hz, 3H), 1.02 (d, J=6.9 Hz, 3H). LCMS: MH+ 478 and TR=4.088 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][CH:10]([CH2:13][CH3:14])[CH2:11][OH:12]>O1CCOCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][OH:12])[CH:7]=1
Reactant: CCC(N)CO
Reactant: Clc1cc(Cl)ncn1
Solvent: C1COCCO1
Product: CCC(CO)Nc1cc(Cl)ncn1

Procedure:
4,6-Dichloropyrimidine (5.0 g) and 2-amino-1-butanol (6.5 mL) were heated under reflux in 1,4-dioxane (26 mL) for 1 hour. The reaction mixture was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10) to give the title compound (5.6 g) as a pale orange oil.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:19]3[C:14]([C:15](=[O:28])[NH:16][C:17]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])=[N:18]3)=[C:13]([CH2:29][CH3:30])[N:12]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:32].[K+].[K+].ClCCl>C(O)C.O>[C:1]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[N:19]3[C:14]([C:15](=[O:28])[NH:16][C:17]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]([NH2:24])=[O:32])=[N:18]3)=[C:13]([CH2:29][CH3:30])[N:12]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3cccc(C#N)c3)[nH]c(=O)c12
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3cccc(C(N)=O)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg (0.25 mmol) cis-3-[7-(4-tert-butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl]benzonitrile (Example 40A) are dissolved in 5 ml ethanol and 10 ml water. 342 mg (2.48 mmol) potassium carbonate and 281 mg (2.48 mmol) hydrogene peroxide are added. The reaction mixture is stirred at room temperature for 18 hours. Dichloromethane is added, the organic phase separated, dried over sodium sulfate and evaporated to dryness in vacuo.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1>C(O)C>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:34]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@H:2]2[CH3:1])=[O:35])=[CH:37][CH:38]=1
Reactant: C[C@@H]1COCCN1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCO
Product: C[C@@H]1COCCN1C(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
To a solution of (R)-3-methylmorpholine (2.02 g, 20 mmol) in ethanol (25 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (3.33 g, 17.4 mmol), hydroxybenzotriazole (HOBt) (2.35 g, 17.4 mmol), and 6-aminonicotinic acid (2.0 g, 14.5 mmol). After stirring for 18 h at room temperature, the reaction suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 3:1 ethyl acetate/petroleum ether to afford 132a as a white solid (1.6 g, 36%). MS-ESI: [M+H]+ 222.3.
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=1)[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:5]([OH:7])=O)=[N+]=[N-].[NH2:23][C:24]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[N:30](C(OC(C)(C)C)=O)[CH2:29]1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@H:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C@@H:4]([C:5]([NH:23][C:24]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=2[CH2:26][CH2:27][C@H:28]2[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:40])([F:42])[F:41])[NH:30][CH2:29]2)=[O:7])[NH:1][C:36]([O:35][CH3:34])=[O:43])=[CH:16][C:17]=1[F:22]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)c(F)c1)C1CCOCC1
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)c(F)c1)C1CCOCC1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 2 and 3 of Example 93 and steps 1 and 2 of Example 91. MS (ES) m/z=721 (M+H)+.
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][NH:3][CH:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:11][C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=CNC1c2ccccc2Oc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNC1c2ccccc2Oc2ccccc21
Reaction time: 8 h

Procedure:
A solution of 9-formamidoxanthen (30.5 g.) in tetrahydrofuran (400 ml.) was added to a suspension of lithium aluminium hydride (5.2 g.) in tetrahydrofuran (100 ml.) at room temperature. The mixture was stirred and refluxed for 5 hours, left to stand at room temperature overnight and then decomposed by the addition of water (5.2 ml.), 5N sodium hydroxide solution (4 ml.) and water (16.8 ml.). The suspension was filtered, the solid was washed with ether, and the combined filtrate and washings were evaporated. The residual syrup was dissolved in ether and extracted into 3N acetic acid solution (500 ml.) at 5° - 10°C. The aqueous extract was basified, the oil which separated was collected in ether and the dried, ethereal extract was evaporated. The residue was distilled to give 9-methylaminoxanthen, b.p. (bath) 110°C./0.1 mm.
Reaction SMILES: [I:1][C:2]([F:18])([F:17])[C:3]([F:16])([F:15])[O:4][C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[S:7](F)(=[O:9])=[O:8].[OH-].[K+].C1C[O:24]CC1.O.[Br-].[C:28]1([S+:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.C(Cl)Cl>[I:1][C:2]([F:18])([F:17])[C:3]([F:16])([F:15])[O:4][C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[S:7]([O-:24])(=[O:9])=[O:8].[C:41]1([S+:34]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)I
Reactant: C1CCOC1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=S(=O)([O-])C(F)(F)C(F)(F)OC(F)(F)C(F)(F)I
Temperature: 80 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
12.56 grams (0.03 mol) of 5-iodooctafluoro-3-oxapentanesulfonyl fluoride (Synquest) was taken in a flask in water and excess amount of KOH (0.06 mol, 3.31 grams) was added and the resulting mixture was heated under stirring at 80° C. for six hours. To this reaction mixture (after cooling to room temperature) was added 1:2 v/v THF/water solution of triphenyl sulfonium bromide (0.03 mol, 10.14 grams) dropwise over a period of one hour with stirring. After the addition, the reaction mixture was further stirred for additional 3 hours at room temperature. Upon completion, the target compound triphenylsulfonium 5-iodooctafluoro-3-oxapentafluoro sulfonate was extracted using methylene chloride. It was washed at least three times with DI water. Methylene chloride was evaporated to get a pale yellow liquid. It was redissolved in methylene chloride and precipitated into hexanes. Yield was 82%. Melting point (capillary) 110-112° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:19])([F:18])[F:17])[C@@H:14]3[C@H:20]([O:23][Si](C(C)(C)C)(C)C)[CH2:21][CH2:22][N:13]3[C:12]2=[O:31])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl-].[NH4+].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:18])([F:19])[F:17])[C@@H:14]3[C@H:20]([OH:23])[CH2:21][CH2:22][N:13]3[C:12]2=[O:31])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(N2C(=O)N3CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(N2C(=O)N3CC[C@@H](O)[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To 66D (956 mg, 2.02 mmol) in THF (20 mL) was added a 1 M THF solution of TBAF (2.02 mL, 2.02 mmol). After stirring at rt for 1 h, additional TBAF was added (500 μL) and the reaction was stirred for 45 min. Saturated aqueous ammonium chloride and EtOAc were added and the layers were separated. The organic layer was washed with brine then dried (MgSO4), filtered and concentrated. The resulting residue was purified via preparative HPLC (YMC ODS C-18, 30×250 mm, eluting with 50-80% solvent B (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH) over 15 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (617 mg) as a white solid. MS: m/z 358 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([O:19]CC)=[O:18])=[C:15]([CH:22]4[CH2:24][CH2:23]4)[N:14]=[C:13]3[CH2:25][CH3:26])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35]>CO.[OH-].[Na+].[Cl-].[Na+].O.O>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([OH:19])=[O:18])=[C:15]([CH:22]4[CH2:23][CH2:24]4)[N:14]=[C:13]3[CH2:25][CH3:26])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][S:34]([C:37]([F:40])([F:38])[F:39])(=[O:36])=[O:35]
Reactant: CCOC(=O)c1c(C2CC2)nc(CC)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc(C2CC2)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 104.6 %

Procedure:
A mixture of the product of Example 3 (1.72 g) and 2N aqueous sodium hydroxide (15 ml) in methanol (30 ml) was stirred at room temperature for 6 h. After standing overnight, the solution was diluted with further 2N aqueous sodium hydroxide (10 ml), stirred for a further 2 h at room temperature and then heated at 40° for 90 mins. After cooling, the solution was diluted with brine (80 ml) and water (50 ml) before being washed with ether (100 ml). The aqueous phase was then acidified with 2N hydrochloric acid to pH 1 and the cloudy solution was extracted with ethyl acetate (3×90 ml). The combined ethyl acetate extracts were dried and concentrated in vacuo to afford the title compound (1.72 g) as an off-white foam.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH2:7].[C:15]([NH:22][C@H:23]([C:31](O)=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(N(CC)CC)C>[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH:7][C:31](=[O:32])[C@H:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:22][C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A slurry of 36.4 g. L-histidine methyl ester dihydrochloride in dichloromethane (1 l.) was cooled to 5° C. and treated with 52 ml. triethylamine. After 10 minutes 40 g. Boc-L-phenylalanine was added followed by 1-hydroxybenzotriazole (30.6 g.), then after another 5 minutes by dicyclohexylcarbodiimide (30.8 g.), and the mixture was stirred at 0° C. for 4 hours and at 20° C. for 90 hours. The mixture was then filtered and the filtered solid was washed with dichloromethane, and the combined organic layers were concentrated and the residue was dissolved in 1 l. ethyl acetate. After 10 minutes of stirring the mixture was filtered and the filtrate was washed with 1N sodium hydroxide (3×150 ml.), brine, dried over magnesium sulfate and concentrated giving 45.9 g. of a colorless solid which was used without additional purification in Step B.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N.[OH-].[K+].Cl>C(O)(C)(C)C.C(O)C.O>[C:5]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)([CH3:11])([CH3:6])[CH3:4]
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)Nc1ccc(C(=O)O)cc1
Reaction time: 16 h
Yield: 24.3 %

Procedure:
Ethyl 4-aminobenzoate (165 g) and 95% sulfuric acid (24.5 g) were refluxed in tert-butanol (560 ml) with stirring for 16 hours. The reaction mixture neutralized with 28% aqueous ammonia, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1), thereby yielding an oil. The oil was dissolved in ethanol (100 ml) and then potassium hydroxide (23.5 g) and water (20 ml) were added thereto. The mixture was refluxed with stirring for 2 hours, neutralized the mixture with hydrochloric acid , and then extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from ethyl acetate to yield 23.5 g of the aimed compound.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH:5]2[C:9]3([CH2:18][C:19]4[C:24]([N:4]2[C:3]1=[O:33])=[CH:23][CH:22]=[C:21]([NH:25]C(=O)OC(C)(C)C)[CH:20]=4)[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]3=[O:17].[ClH:34].O1CCOCC1>C(Cl)Cl>[ClH:34].[NH2:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:4]1[C:3](=[O:33])[CH:2]([CH3:1])[O:7][CH:6]([CH3:8])[CH:5]1[C:9]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17])[CH2:18]2
Reactant: CC1OC(C)C2N(C1=O)c1ccc(NC(=O)OC(C)(C)C)cc1CC21C(=O)NC(=O)NC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1OC(C)C2N(C1=O)c1ccc(N)cc1CC21C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
A suspension of tert-butyl 1,1′,2,3′,4,4′,4a,6′-octahydro-2,4-dimethyl-2′,4′,6′-trioxospiro[[1,4]oxazino[4,3-a]quinolone-5(6H),5′(2′H)-pyrimidin]-8-ylcarbamate (from Example 15) (7.4 g, 16.65 mmoles) in 250 mL of CH2Cl2 at room temperature is treated via pipette with a solution of 4.0 N HCl in dioxane (20 mL, 80 mmoles). The resulting slurry is stirred at room temperature for 2 days and then concentrated. The residue is dissolved in hot 1:1 EtOAc/methanol (˜300 mL) and recrystallized from heptane. After cooling to room temperature and then stirring at 0° C. for 30 minutes, the solid is isolated by filtration and dried (20 torr, 60° C., for 18 h) to give 6.31 g (99%) of the title compound as a beige solid. 1H NMR (DMSO-d6): δ 11.78, 11.47, 9.83, 7.06, 6.92, 6.87, 4.03, 3.67, 3.60, 3.50, 3.41, 2.90–2.82, 1.13, 0.91.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.C(OCC)(=O)C>[CH2:25]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c(OCc2ccccc2)ccc2ccccc12
Temperature: 60 °C
Yield: 86.2 %

Procedure:
450 ml of a dimethylformamide solution containing 100 g (0.58 mole) of 2-hydroxy-1-naphthaldehyde and 96.3 g (0.7 mole) of anhydrous potassium carbonate was stirred with heating at 60° C. To the solution was added dropwise 88.3 g (0.7 mole) of benzyl chloride. After the completion of the dropwise addition, the mixture was stirred at 60° C. for 2 hours. Then 870 ml of ethyl acetate heated at 60° C. and 1.2 liters of warm water at 60° C. were added to the mixture and it was extracted at 60° C. and separated. The organic layer was concentrated under reduced pressure to about 550 ml. 440 ml of methanol was added to the concentrate, and the solution was cooled to 5° C. to crystallize. The precipitated crystals were collected by filtration, and washed with methanol to obtain 131 g (0.5 mole) of 2-benzyloxy-1-naphthaldehyde.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[I-].C([Zn+])C(C)(C)C.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:29][CH2:30][O:31][CH3:32])=[C:20]([C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:29][CH2:30][O:31][CH3:32])=[C:20]([C:22](=[N:7][S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=1
Reactant: CCOC(=O)C(=O)c1cc(Br)ccc1OCOC
Reactant: CC(C)(C)[S@@](N)=O
Agent: CC(C)(C)C[Zn+]
Agent: [I-]
Product: CCOC(=O)C(=N[S@@](=O)C(C)(C)C)c1cc(Br)ccc1OCOC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
A flask was charged with (S)-2-methylpropane-2-sulfinamide (0.764 g, 6.31 mmol) and neopentylzinc(II) iodide (0.5 M in THF, 10.0 mL, 5.00 mmol) was added under nitrogen atmosphere. The mixture was stirred at RT for 15 minutes and ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate (1.00 g, 3.15 mmol) was added in one portion. The reaction mixture was quenched with saturated aqueous ammonium chloride after 8 h. The reaction was partitioned between EtOAc and water. The organic phase was separated, washed with NH4Cl, water and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (10-30% EtOAc/hexane) to provide 0.675 g (S)-ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(tert-butylsulfinylimino)acetate.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[O:16][CH3:17])(O)=[O:2].Cl.CN.O[N:22]1[C:26]2C=CC=CC=2N=N1.O>CN(C)C=O>[CH3:17][O:16][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:4]=1[C:1](=[O:2])[NH:22][CH3:26])[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: On1nnc2ccccc21
Reactant: COC(=O)C=Cc1ccc(C(=O)O)c(OC)c1
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)OC)cc1OC
Reaction time: 18 h
Yield: 75.6 %

Procedure:
To a solution of methyl 4-carboxy-3-methoxycinnamate (400 mg) in N,N-dimethylformamide were added methylamine hydrochloride (126 mg), I-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (390 mg) and 1-hydroxybenzotriazole (320 mg) at ambient temperature, and the mixture was stirred for 18 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform: methanol=40:1, v/v) to give methyl 3-methoxy-4-(methylcarbamoyl)cinnamate (319 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH3:26])[NH:22][N:21]=2)=[N:4][C:5]([NH:9][C@H:10]([C:12]2[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)[CH3:11])=[N:6][C:7]=1Cl.C[C:28]([N:30](C)C)=O>[Zn].[C-]#N.[Zn+2].[C-]#N.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.[Fe+2].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]>[Cl:1][C:2]1[C:7]([C:28]#[N:30])=[N:6][C:5]([NH:9][C@H:10]([C:12]2[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)[CH3:11])=[N:4][C:3]=1[NH:19][C:20]1[CH:24]=[C:23]([O:25][CH3:26])[NH:22][N:21]=1
Reactant: CC(=O)N(C)C
Reactant: COc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(Cl)c2Cl)n[nH]1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(C#N)c2Cl)n[nH]1
Temperature: 100 °C

Procedure:
A mixture of 5,6-dichloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (Example 30, 100 mg), zinc (17 mg), zinc cyanide (31 mg), DPPF (7 mg) and Pd2(dba)3 (12 mg) in DMA (2.0 ml) was degassed and heated at 100° C. for 2 hours. The solution was separated between ethyl acetate and water. Organic solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (42.5 mg). 1H NMR δ 10.20 (s, 1H) 8.89 (s, 2H) 8.56 (bs, 1H) 5.63 (s, 1H) 5.03-5.29 (m, 1H) 3.75 (s, 3H) 1.47 (d, 3H); m/z 390.