Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5](=O)[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[NH:16][NH2:17]>CC(O)C>[C:20]([O:19][C:15]([NH:16]/[N:17]=[C:5](\[C:4]#[C:3][Si:2]([CH3:14])([CH3:13])[CH3:1])/[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NN
Reactant: C[Si](C)(C)C#CC(=O)CCCC(=O)O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N/N=C(\C#C[Si](C)(C)C)CCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 54.0 g (254 mmol) of 7-(trimethylsilyl)-5-oxohept-6-ynoic acid from step A in 750 mL of IPA under an atmosphere of nitrogen was added 33.6g (254 mmol) of tert-butyl carbazate. The reaction mixture was stirred for 4 h at ambient temperature then evaporated in vacuo to remove all volatiles. This afforded the title compound as a yellow gum which was used without further purification (77 g, 93%). LC-MS: m/z (ES) 327 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([CH3:17])=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:23](Cl)(=O)[C:24](Cl)=O.[CH2:29](Cl)Cl>CN(C=O)C.CC(O)C.CCOCC>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([CH3:17])=[C:15]([C:18]([F:19])([F:20])[F:21])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4]([O:6][CH:23]([CH3:24])[CH3:29])=[O:5]
Reactant: Cc1c(-c2cc(C(=O)O)c(Cl)cc2F)nn(C)c1C(F)(F)F
Reactant: ClCCl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Cc1c(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)nn(C)c1C(F)(F)F
Reaction time: 0.33 h

Procedure:
To a solution of 18 g of 2-chloro-5-[1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzoic acid (Ex. 2) in 400 mL of CH2Cl2 was added 10 g of oxalyl chloride and a few drops of DMF. After 20 minutes at room temperature, the reaction was heated to reflux for 2 hr and subsequently concd in vacuo. The resultant solid was dissolved in excess 2-propanol and heated overnight at reflux. The reaction mixture was concd, dissolved in ether, washed with 10% aq. NaOH and saturated brine and concd to give a solid. Recrystallization from cold hexanes gave 14 g of 2-chloro-5-[1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzoic acid, 1-methylethyl ester: mp 72° C.; 1HNMR (CDCl3) δ 1.36 (d, 6H, 6.4 Hz), 2.09 (quintet, 3H, 2.0 Hz), 5.25 (heptet, 1H, 6.0 Hz), 7.27 (d, 1H, 9.2 Hz), 7.94 (d, 1H, 7.6 Hz). Anal. Calcd for C16H15O2N2F4Cl: C, 50.74; H, 3.99; N, 7.40. Found: C, 50.85; H, 4.02; N, 7.41.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[C:12](I)[C:10]([NH2:11])=[N:9][C:7]1=[O:8].[CH2:15]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:16]#[CH:17].CO>ClCCl>[OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[C:12]([C:17]#[C:16][CH2:15][NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:10]([NH2:11])=[N:9][C:7]1=[O:8]
Reactant: C#CCNC(=O)C(F)(F)F
Reactant: Nc1nc(=O)n(COCCO)cc1I
Solvent: ClCCl
Solvent: CO
Product: Nc1nc(=O)n(COCCO)cc1C#CCNC(=O)C(F)(F)F
Yield: 23 %

Procedure:
Iodide 68 (311 mg, 1.00 mmol) was coupled to N-propargyltrifluoroacetamide (43) according to the general procedure described in EXAMPLE 1C. Flash chromatography on silica gel (3×20 cm) with 5%, 10% and 20% methanol in dichlormethane afforded alkynylamino nucleotide 69 as a pale yellow foam (77.4 mg, 23%).
Reaction SMILES: CO[CH:3](OC)[CH2:4]Br.Br.C(=O)(O)[O-].[Na+].[NH2:14][C:15]1[N:16]=[N:17][C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21]>O.C(O)C>[CH3:22][C:18]1[CH:19]=[C:20]([CH3:21])[C:15]2[N:16]([CH:3]=[CH:4][N:14]=2)[N:17]=1
Reactant: COC(CBr)OC
Reactant: Cc1cc(C)c(N)nn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2nccn2n1
Reaction time: 16 h
Yield: 44.6 %

Procedure:
A mixture of 25 g (148 mmol) of bromoacetaldehyde dimethyl acetal, 5 mL of water and 5 mL of 48% HBr was refluxed 2 h. After cooling, it was poured into 50 mL of ethanol. Solid sodium bicarbonate was added until bubbling ceased. The mixture was filtered and to the filtrate was added 7.5 g (61 mmol) of 3-amino-4,6-dimethylpyridazine. After stirring 16 h, the ethanol was removed with a rotary evaporator. The residue was triturated with ethanol to give a brown solid which was dissolved in water and washed with dichloromethane. The aqueous layer was brought to pH 9 with sodium bicarbonate and extracted with dichloromethane. Drying (Na2SO4) and solvent removal with a rotary evaporator gave 4 g of the title compound as a brown solid, m.p. 70°-74° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.C([O:16][B:17](OC(C)C)[O:18]C(C)C)(C)C.C([Li])CCC.Cl>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([B:17]([OH:18])[OH:16])=[CH:4][N:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc2c(Cl)ncc(B(O)O)c2s1
Temperature: -75 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
4-Chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B) (2.35 g, 7.56 mmol) and triisopropylborate (1.8 ml, 7.94 mmol) were dissolved in 70 ml THF and cooled to −75° C. n-Butyllithium (1.6M in hexane) (5.0 ml, 7.94 mmol) was added drop wise at −70° C. The reaction mixture was stirred for 1 hour at −75° C. and for 1 hour without ice-bath. 10 ml 2N HCl-solution were added and extracted three times with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was crystallized in acetonitrile to get the desired compound as a red solid (520 mg, 30%), MS: m/e=229.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.Cl.[CH3:15]O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH3:15])=[O:12])=[CH:5]2
Reactant: CO
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Agent: Cl
Product: COC(=O)c1cc2cc(Br)ccc2[nH]1
Temperature: 25 °C

Procedure:
A solution of 5-Bromo-1H-indole-2-carboxylic acid (commercial, 10.0 g, 41.6 mmol) in methanol (200 ml) was cooled to 0° C. and saturated with HCl (g). The resulting solution was allowed to warm gradually to room temperature overnight. The solvent was removed in vacuo and the residue treated with 0.88 ammonia (500 ml). The resulting solution was extracted with dichloromethane (3-fold 150 ml) and the combined organics dried (magnesium sulphate) and the solvent removed in vacuo to give the required product as a colourless oil (8.35 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:11][CH3:12])[C:5]([O:13][CH3:14])=[C:4]([O:15][CH3:16])[CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:18].CCOCC>C1COCC1.CO>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:18])=[O:9])=[C:6]([O:11][CH3:12])[C:5]([O:13][CH3:14])=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1OC
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(N)cc(OC)c(OC)c1OC
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A solution of 6-amino-2,3,4-tris(methyloxy)benzoic acid (2.7 g, 11.88 mmol) in THF (20 mL) and MeOH (20 mL) at 25° C. was treated with a solution of 2M TMS-diazomethane in Et2O (14.85 mL, 29.7 mmol) and stirred for 10 minutes before being concentrated to give methyl 6-amino-2,3,4-tris(methyloxy)benzoate (2.87 g, 99%) as a brown solid. MS (m/z) 242.1 (M+H+).
Reaction SMILES: O[N:2]1C(=O)C2=CC=CC=C2C1=O.[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl.C1(C)C=CC=CC=1>[NH2:2][O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(NCCCCO)OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: NOCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
A solution of N-hydroxyphthalimide (3.36 g), benzyl (4-hydroxybutyl)carbamate (4.18 g) and triphenylphosphine (7.41 g) in dichloromethane (100 mL) was chilled in an ice bath and approximately two-thirds of a solution of diisopropylazodicarboxylate (DIAD, 5.68 g) in dichloromethane (50 mL) was slowly added with stirring. The internal temperature of the reaction was monitored and the addition of the DIAD solution was stopped when an exotherm could no longer be detected. The ice bath was removed and the reaction was allowed to warm to room temperature. The reaction was concentrated under reduced pressure and the resulting residue was dissolved in ethanol (200 proof, 100 mL). Hydrazine (1.98 g, 35% in water) was added and the reaction was stirred for 6 hours. The reaction was cooled in the freezer and the resulting solid was removed by filtration. The solid was washed with ethanol (50 mL). The combined filtrate was concentrated under reduced pressure and diethyl ether (100 mL) was added. Insoluble impurities were removed by filtration and 2.0 M HCl in ether (10 mL) was added to the solution. A precipitate formed immediately. The crude product was added to toluene (100 mL) and heated at reflux temperature for one hour. After cooling to room temperature, the solid product was recovered by filtration, washed with toluene, and dried under vacuum to yield 3.76 g of benzyl (4-aminooxybutyl)carbamate.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:19](O)=[O:20])[C:9]2=[O:26].[NH2:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1>>[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:19]([NH:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)=[O:20])[C:9]2=[O:26]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCN(C)C)cc2c1=O
Reactant: Nc1ccon1
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2ccc(OCCN(C)C)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 4, 3-[6-{2-[dimethylamino]ethoxy}-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid was reacted with 3-aminoisoxazole to give 3-[6-{2-[Dimethylamino]ethoxy}-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide; NMR Spectrum: (DMSOd6) 2.17 (s, 3H), 2.25 (s, 6H), 2.70 (m, 2H), 4.19 (m, 2H), 7.04 (s, 1H), 7.50 (d, 1H), 7.60 (m, 2H), 7.72 (m, 1H), 8.07 (m, 2H), 8.20 (m, 1H), 8.83 (s, 1H), 11.45 (s, 1H); Mass Spectrum: M+H+ 434.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14]([CH3:20])=[N:15][N:16]([CH3:19])[C:17]=1[CH3:18]>N1C=CC=CC=1>[CH3:19][N:16]1[C:17]([CH3:18])=[C:13]([NH:12][S:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:14]([CH3:20])=[N:15]1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: Cc1nn(C)c(C)c1N
Solvent: c1ccncc1
Product: Cc1nn(C)c(C)c1NS(=O)(=O)c1ccc(Cl)nc1
Yield: 75.3 %

Procedure:
Prepared from 6-chloropyridine-3-sulfonyl chloride (4.8 g, 22.7 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (2.84 g, 22.7 mmol) in pyridine (35 ml) according to the method of intermediate 1, to give the title compound as a white solid (5.13 g, 17.1 mmol, 75%). δH (D-6 DMSO, 300K) 9.51 (1H, s), 8.59 (1H, d J 2.3 Hz), 8.03 (1H, dd J 7.6 Hz 2.3 Hz), 7.77 (1H, d J 7.6 Hz), 3.58 (3H, s), 1.84 (3H, s), 1.63 (3H, s). m/z (ES+, 70V) 301.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:5][N:6]=1.[C:15](OC1C(Cl)=CC(Cl)=CC=1Cl)(=[O:20])[CH2:16][C:17]([O-])=[O:18]>C1(C)C(C)=CC=CC=1>[CH:9]1([CH2:8][CH2:7][C:4]2[S:3][C:2]3=[N:1][C:15]([OH:20])=[CH:16][C:17](=[O:18])[N:6]3[N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1nnc(CCC2CCCCC2)s1
Reactant: O=C([O-])CC(=O)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: Cc1ccccc1C
Product: O=c1cc(O)nc2sc(CCC3CCCCC3)nn12
Yield: 82 %

Procedure:
2-Amino-5-(2-cyclohexylethyl)-[1,3,4]thiadiazole (9.50 g) and 21.8 g of 2,4,6-trichlorophenyl malonate were stirred in 70 ml of xylene at a bath temperature of from 140° to 150° C. for 2 hours. After cooling, the precipitate formed was collected by filtration and washed successively with ethanol and diethyl ether to obtain 10.3 g of 2-(2-cyclohexylethyl)-7-hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as a colorless plate-like crystal.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5]1(=O)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].[OH-:13].[K+].[OH-].[Na+]>C(OCC)(=O)C>[CH2:1]([CH:5]1[C:6](=[O:11])[CH2:7][CH2:8][CH2:9][C:10]1=[O:13])[CH:2]=[CH2:3]
Reactant: O=C1CCCCC1=O
Reactant: C=CCBr
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=CCC1C(=O)CCCC1=O
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Allyl bromide (195 g., 1.62 mol.) was added over a 15 minute period to a stirred ice-cold mixture of cyclohexanedione (165 g., 1.47 mol.), copper-bronze (4.5 g.), and 330 ml. of 20% by weight aqueous potassium hydroxide. After 6 hours, the reaction was mixed with 1500 ml. of a 5% by weight aqueous sodium hydroxide solution and 1000 ml. of ethyl ether, filtered and the separated water layer acidified with 4 N aqueous hydrochloric acid to pH 1. A brown solid (188 g.) formed upon refrigeration at 0° C. The solid was taken up in ethyl acetate and the solution was washed with water (3× 150 ml.), dried (MgSO4), treated with charcoal, and condensed until turbid. Upon cooling, 126 g. (57%) of 2-allyl-1,3-cyclohexanedione was collected, m.p. 125°-127° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.C(N(CC)CC)C.Br[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:22])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[CH2:38][C:39]([NH2:41])=[O:40])=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCCCN4)cc3C)ncc2Cl)n[nH]1
Reactant: NC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCCCN4CC(N)=O)cc3C)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 5-Chloro-N2-(2,5-dimethyl-4-(piperidin-2-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (83 uL, 0.6 mmol) in DMF (1.5 mL), was added 2-bromoacetamide (35 mg, 0.24 mmol). The mixture was stirred at room temperature for 3 h. The reaction was filtered and the filtrate was purified by RP-HPLC to afford 2-(2-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)acetamide as a white solid; 1H NMR (400 MHz, MeOD-d4) 8.09 (s, 1H), 7.65 (d, 1H), 7.43 (s, 1H), 6.41 (s, 1H), 4.79-4.74 (m, 2H), 3.83-3.48 (m, 2H), 2.71 (s, 3H), 2.42 (s, 3H), 2.34 (s, 6H), 2.15-1.84 (m, 7H); ESMS m/z 469.2 (M+H+).
Reaction SMILES: C(S([C:10]1[N:15]=[C:14]2[N:16]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:17](=[O:27])[N:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH2:19][C:13]2=[CH:12][N:11]=1)=O)C1C=CC=CC=1.[NH2:34][C@@H:35]([CH3:38])[CH2:36][OH:37].ClCCl.CO>COCCOC>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:18]1[CH2:19][C:13]2[C:14](=[N:15][C:10]([NH:34][C@@H:35]([CH3:38])[CH2:36][OH:37])=[N:11][CH:12]=2)[N:16]([CH:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]2)[C:17]1=[O:27]
Reactant: O=C1N(c2ccccc2Cl)Cc2cnc(S(=O)Cc3ccccc3)nc2N1C1CCNCC1
Reactant: C[C@H](N)CO
Solvent: COCCOC
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](CO)Nc1ncc2c(n1)N(C1CCNCC1)C(=O)N(c1ccccc1Cl)C2
Temperature: 100 °C
Yield: 63.3 %

Procedure:
To a suspension of 7-benzylsulfinyl-3-(2-chlorophenyl)-1-(piperidin-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (650 mg, 1.136 mmol) in 1,2-dimethoxyethane (0.5mL) was added (S)-(+)-2-amino-1-propanol (250 mg, 3.33 mmol). The reaction was warmed to 100° C. under argon for 2 hours. The reaction was placed directly on a flash silica column using 92:8-90:10 dichloromethane/methanol as eluant to give 300 mg of the (S)-3-(2-chlorophenyl)-7-(2-hydroxy-1-methylethylamino)-1-(piperidin-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one, which was redissolved in 5 mL of dichloromethane and 5 mL trifluoroacetic acid. After 5 hours the solvents were removed in vacuo and 5 mL of ethyl acetate and 5 mL of 10% sodium bicarbonate were added. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 130 mg of the title compound as a white foam that was dissolved in ethyl acetate and treated with 1 equivalent of hydrochloric acid in 1.0M ether. The precipitate was collected, washed with ether and dried in vacuo to give 115 mg of the hydrochloride salt of (S)-3-(2-chloro-phenyl)-7-(2-hydroxy-1-methylethylamino)-1-(piperidin-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:12])[CH3:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:13]([Cl:17])(=O)(=[O:15])[OH:14]>>[C:10]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:13]([Cl:17])(=[O:15])=[O:14])=[CH:5][CH:4]=1)(=[O:12])[CH3:11]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)NCCc1ccccc1
Product: CC(=O)NCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
N-Phenethylacetamide (4.50 g, 27.6 mmol) was added to sulfurochloridic acid (30 mL) slowly at 0-5° C. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ice-water and stirred for 10 min. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound as a brown solid (3.30 g, 12.64 mmol, 45% yield). MS (ESI) m/z 262.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[C:6]2[C:7]([C:13]([OH:15])=O)=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[N:5]2[N:4]=1)[CH3:2].Cl.CN[O:20][CH3:21].C(P(=O)(OCC)OCC)#N.C([N:34]([CH2:37]C)CC)C>CN(C)C=O.O>[CH3:21][O:20][CH2:37][NH:34][C:13]([C:7]1[C:6]2[N:5]([N:4]=[C:3]([CH2:1][CH3:2])[CH:16]=2)[C:10]([O:11][CH3:12])=[CH:9][CH:8]=1)=[O:15]
Reactant: CCN(CC)CC
Reactant: CCc1cc2c(C(=O)O)ccc(OC)n2n1
Reactant: CNOC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(C(=O)NCOC)ccc(OC)n2n1
Reaction time: 0.5 h

Procedure:
The compound of Example 348 (11.13 g) was dissolved in N,N-dimethylformamide (505 mL) in an argon atmosphere. While this solution was chilled in an ice bath, N,O-dimethylhydroxyamine hydrochloride (6.15 g) and diethyl cyanophosphonate were added, followed by dropwise addition of triethylamine (17.5 mL). The mixture was stirred first in an ice bath for 30 min and then at room temperature for 5 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification of the residue by silica gel chromatography (ethyl acetate) afforded the title compound as a brown oil (12.12 g).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=1)[C:14]#[N:15].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=1)#[CH:18]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:27][C:26]([F:28])([F:29])[O:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])[CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: C#Cc1cccc(OC(F)(F)F)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1cncc(C#Cc2cccc(OC(F)(F)F)c2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 14.7 %

Procedure:
Add triethylamine (1.73 mL, 12.28 mmol), copper (I) iodide (34.0 mg, 0.180 mmol) and bis(triphenylphosphine)palladium (II) dichloride (107.7 mg, 0.150 mmol) to a solution of 5-bromonicotinonitrile (562.2 mg, 3.07 mmol) and 1-ethynyl -3-trifluoromethoxybenzene, (prepared as described in PREPARATION 28), (571.4 mg, 3.07 mmol) in ethyl acetate (3 mL). Stir in a sealed tube at 50° C. for 18 h, concentrate and purify the residue by silica gel chromatography, eluting with 100:0 to 100:50 hexanes:ethyl acetate, to give the title compound (130 mg, 15%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[N:40][CH:39]=[CH:38][N:37]=1)CCC>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:36]4[CH:41]=[N:40][CH:39]=[CH:38][N:37]=4)=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1c2cc(Cc3ccc(-c4cnccn4)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Temperature: 25 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one (Example 1, 0.050 g, 0.12 mmol) in 1 mL of dioxane under an atmosphere of nitrogen was added 2-(tributylstannyl)-pyrazine (0.175 g, 0.475 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.014 g, 0.012 mmol). The mixture was irradiated in a microwave reactor at 160° C. for 1 h, cooled to rt, and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 464.9 for [M+H]: 1H NMR (400 MHz, CD3OD) δ 9.84 (s, 1H), 9.51 (s, 1H), 9.32 (d, J=6.2 Hz, 1H), 8.84 (d, J=6.2 Hz), 8.75-8.64 (m, 4H), 8.41 (d, J=8.2 Hz, 1H), 8.34 (s, 1H), 7.96-7.94 (m, 1H), 4.86 (s, 2H), 4.16 (br s, 1H), 2.19 (br s, 1H), 2.03 (br s, 1H), 1.96-1.86 (m, 3H), 1.56-1.42 (m, 4H).
Reaction SMILES: [Br-].[H-].[Na+].[CH2:4]([O:6][C:7](=[O:16])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)[CH3:5].[CH3:17]N(C=O)C>>[CH2:4]([O:6][C:7](=[O:16])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[CH2:17])[CH3:5]
Reactant: CN(C)C=O
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: C=C1CCCCC1CC(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Triphenylphosphoniummethyl bromide (6.9 g, 19.5 mmol) was added to a suspension of sodium hydride (0.78 g, 60% oil dispersion, 19.5 mmol) (hexane washed) in DMF (50 mL) cooled to 0° C. under a nitrogen atmosphere. The reaction was stirred for 1 h, and then (2-oxo-cyclohexyl)-acetic acid ethyl ester (3.0 g, 16.2 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give a residue. The product was purified by FCC on silica gel eluting with hexane:ethyl acetate (95:5) to give (2-methylene-cyclohexyl)-acetic acid ethyl ester (1.5 g, 50%) as an oil.