Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1)=[O:7].ClC1C=CC=C(C(OO)=[O:25])C=1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1)(=[O:25])=[O:7]
Reactant: O=S(CCCCCl)c1cccc2nccn12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(CCCCCl)c1cccc2nccn12
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a solution of 0.88 g (3.47 mmol) of 5-(4-chlorobutylsulfinyl)imidazo[1,2-a]pyridine in 15 ml of dichloromethane, 0.90 g (5.20 mmol) of m-chloroperbenzoic acid was added at 0° C., followed by stirring at room temperature for 64 hours. 0.6 g (3.47 mmol) of m-chloroperbenzoic acid was further added to the reaction mixture, followed by stirring for 5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, extracted with dichloromethane and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 0.28 g (29.7%, yellow oily substance) of the desired product.
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH:40](=O)[CH2:41][CH2:42][CH2:43][C:44]#[CH:45]>ClCCl>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:45][CH2:44][CH2:43][CH2:42][C:41]#[CH:40])[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Reactant: C#CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C#CCCCCN1CC[C@@H](C(C(N)=O)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a stirred solution of (S)-3-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (64.4 g, 0.23 mol); sodium triacetoxyborohydride (50.9 g, 0.24 mol) and acetic acid (13 mL, 0.23 mol) in dichloromethane (511 mL) at room temperature, was added a solution of hex-5-yn-1-al (26.14 g, 0.27 mol) in dichloromethane (256 mL). The reaction mixture stirred at room temperature overnight (ca. 8 hours) and then the reaction mixture was quenched by addition of concentrated hydrochloric acid (30 mL) and stirring was continued for 1 hour at room temperature. The mixture was then diluted with water (750 mL) and made basic to pH 5 using 10 N sodium hydroxide (18 mL). The layers were separated and the organic layer was washed with 1 N sodium hydroxide (200 mL). The organic layer was dried over magnesium sulfate (10 g); filtered and then concentrated in vacuo to afford 67.6 g of the title intermediate as a yellow gummy solid (83% yield).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14](Br)=[C:13]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:12]=1)=[O:10].[CH:29]1([CH2:32][O-:33])[CH2:31][CH2:30]1.[Li+]>O1CCCC1>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14]([O:33][CH2:32][CH:29]2[CH2:31][CH2:30]2)=[C:13]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:12]=1)=[O:10]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F
Reactant: [O-]CC1CC1
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2ccc(Cl)cc2)c(OCC2CC2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.048 g 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide was added 1 ml of a 0.25 M solution of lithium cyclopropylmethoxide in tetrahydrofuran and the mixture was stirred at room temperature for 30 min. The orange reaction mixture was partitioned between 10% citric acid and ethyl acetate. The phases were separated and the organic phase was washed with brine. After evaporation the crystalline residue was triturated under methanol to yield 0.028 g of the title compound as white crystals. MS (M−H) at 468.2.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.[CH2:25]([NH2:27])[CH3:26]>CN(C)C=O.CCOCC>[CH2:25]([NH:27][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1)[CH3:26]
Reactant: CCN
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCNCc1nc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
0.66 g (1.9 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one was dissolved in 20 ml of N,N-dimethylformamide. A weak stream of ethylamine gas was introduced at room temperature, the reaction temperature rising to 36°. After stirring at room temperature for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol 19:1 as the eluent. After concentration there was obtained a beige foam which was taken up in ether. There was obtained 0.40 g (59%) of 3-(5-ethylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as beige crystals; m.p. 166°-168°.
Reaction SMILES: C(Cl)([Cl:3])=O.[CH3:5][N:6]([CH3:13])[CH2:7][CH2:8][S:9]([O-])(=[O:11])=[O:10].[Na+].CN(C=O)C>C(Cl)Cl>[CH3:5][N:6]([CH3:13])[CH2:7][CH2:8][S:9]([Cl:3])(=[O:11])=[O:10]
Reactant: O=C(Cl)Cl
Reactant: CN(C)CCS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)CCS(=O)(=O)Cl

Procedure:
Phosgene (12 ml, 1M in toluene) was added to a solution of the subtitle product of step i) in DCM (20 ml) and DMF (2.5 ml) and stirred for 3 h before concentrating in vacuo to afford the subtitle compound as an oil that was used directly in the next step. 1H NMR δ(CD3OD) 3.30 (2H, m), 2.80 (2H, m) and 2.31 (6H, s).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:14][C:15]=3[N:16]([CH2:21][C:22]([O:24]C)=[O:23])[C:17]2=[O:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].[ClH:34]>O1CCCC1.O>[ClH:34].[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:14][C:15]=3[N:16]([CH2:21][C:22]([OH:24])=[O:23])[C:17]2=[O:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2[nH]c(C3CCCC3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2[nH]c(C3CCCC3)nc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
Compound 66 (1.87 g, 4.21 mmol) obtained in Example 66 was dissolved in 1,4-dioxane (30 mL), to the solution was added 2 mol/L aqueous sodium hydroxide (15 mL), and the mixture was stirred with heating at 70° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and then the residue was neutralized by addition of concentrated hydrochloric acid. The deposited crystals were collected by filtration, washed with water and dried to obtain (R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77a, 1.61 g, 90%). Compound 77a (500 mg, 1.08 mmol) was dissolved in N,N-dimethylformamide (5 mL), to the solution were added potassium carbonate (192 mg, 1.41 mmol, 1.2 equivalents) and bromoacetic acid methyl ester (140 μL, 1.41 mmol, 1.2 equivalents), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water was added to the concentrate, the mixture was extracted with chloroform, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=90:10) to obtain (R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77b, 400 mg, 69%). From Compound 77b (850 mg, 1.71 mmol), (R)-8-benzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77c, 220 mg, 29%) was obtained in a manner similar to the method by which Compound 40 was obtained from Adduct 40a in Example 40. Compound 77c (200 mg, 0.49 mmol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL) and water (1 mL), to the solution was added lithium hydroxide hydrate (0.04 g, 0.98 mmol), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was adjusted to pH 3 with 1 mol/L hydrochloric acid, and the resulting solid was washed with ethanol and collected by filtration to obtain the title compound (180 mg, 93%).
Reaction SMILES: C([CH:3]([C:13]1[C:18]([N:19]([CH3:21])[CH3:20])=[C:17]([O:22][CH3:23])[N:16]=[C:15]([O:24][CH3:25])[N:14]=1)[C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:7]#[N:8])#N.[H-].[Na+].CN(C=[O:32])C>>[CH3:20][N:19]([CH3:21])[C:18]1[C:13]([C:3]([C:4]2[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=2)[C:7]#[N:8])=[O:32])=[N:14][C:15]([O:24][CH3:25])=[N:16][C:17]=1[O:22][CH3:23]
Reactant: COc1nc(OC)c(N(C)C)c(C(C#N)c2cc(C)cc(C#N)c2)n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(N(C)C)c(C(=O)c2cc(C)cc(C#N)c2)n1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 3-[cyano-(5-dimethylamino-2,6-dimethoxy-pyrimidin-4-yl)-methyl]-5-methyl-benzonitrile (0.0872 g, 0.258 mmol) in DMF (1.0 mL) was added 60% sodium hydride (0.0114 g, 0.284 mmol) and stirred for 30 min. Oxygen was bubbled into reaction mixture overnight. The reaction was quenched with saturated ammonium chloride solution. The pH was adjusted to ˜6.0 with 1N HCl and mixture was extracted with ethyl acetate. The organic layer was washed with water (2×), dried (MgSO4) and concentrated to give a yellow solid (0.0834 g, 99%). 1H NMR (300 MHz, CDCl3): δ 7.91 (s, 1H), 7.85 (s, 1H), 7.64 (s, 1H), 4.08 (s, 3H), 3.93 (s, 3H), 2.53 (s, 6H), 2.44 (s, 3H). Mass spectrum: 327.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[NH2:16][C:17]([CH2:23][CH3:24])=[CH:18][C:19]([O:21][CH3:22])=[O:20]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:16][C:17]([CH2:23][CH3:24])=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:10](=[O:12])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: CCC(N)=CC(=O)OC
Solvent: Cc1ccccc1C
Product: CCc1[nH]c(-c2ccc(Cl)cc2)cc(=O)c1C(=O)OC

Procedure:
2.00 g (8.82 mmol) of ethyl 3-(4-chlorophenyl)-3-oxopropanoate and 1.25 g (9.71 mmol) of methyl 3-aminopent-2-enoate [Pena et al., J. Am. Chem. Soc. 124, 14552-14553 (2002)] were taken up in 12 ml of xylene, 3.50 g molecular sieve (4 Å) which had been dried by heating were added and the mixture was reacted at reflux temperature overnight. The molecular sieve was removed by filtration and washed with methanol/chloroform (1/1). The combined organic phases were concentrated on a rotary evaporator and the crude product was purified by preparative MPLC (Biotage 40M cartridge; mobile phase: isohexane/ethyl acetate 4/1). This gave 550 mg (21% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][CH3:12])[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])(O)=O.[Na+]>C(N(CC)CC)C>[C:18]([CH2:17][CH2:16][NH:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][CH3:12])[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1ccc(N)c(C(C)=O)c1OC
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1ccc(OC)c(OC)c1C(C)=O
Yield: 140.1 %

Procedure:
Triethylamine (3.80 g, 5.35 mL, 38.46 mM) was at once added under N2 to a stirred mixture of 6'-amino-2',3'-dimethoxyacetophenone (2.5 g, 12.8 mM) and ethyl 3-bromopropionate (13.93 g, 9.86 mL, 76.93 mM) at room temperature. Immediately the reaction mixture solidified. This was heated under N2 to 135°-145° C. (bath temperature) for a period of 3 hours, while periodically stirring the solid reaction mixture to form a uniformly soft, semisolid mass. After cooling, the reaction was treated with 10% NaHCO3 (50 mL) and extracted with CH2Cl2 (3×60 mL). The organic layer, after the H2O wash, drying (Na2SO4), and the removal of the solvent in vacuo, gave a dark brown oily residue (5.3 g). This was chromatographed on a column of SilicAR CC-7 (350 g, 57 cm×5 cm) packed in hexane and eluted with increasing proportions of ethyl acetate/hexane, collecting 1 L fractions. Fraction 6, eluting with 15% ethyl acetate/hexane gave, upon removal of the solvent in vacuo, purified 6'-(N-2-carbethoxyethylamino)-2',3'-dimethoxyacetophenone (0.452 g, 12%) as a light yellow oil. IR (neat) μ: 2.97 (NH), 5.75 (C=O), 6.10.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[OH:23][C@@H:24]1[CH2:29][CH2:28][C@H:27]([N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35](B4OC(C)(C)C(C)(C)O4)[CH:36]=3)[C:31]2=[O:48])[CH2:26][CH2:25]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:35]3[CH:36]=[C:37]4[C:32](=[CH:33][CH:34]=3)[C:31](=[O:48])[N:30]([C@H:27]3[CH2:26][CH2:25][C@@H:24]([OH:23])[CH2:29][CH2:28]3)[CH2:38]4)[C:16]2=[CH:15][N:14]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CN([C@H]2CC[C@@H](O)CC2)C3=O)OC1(C)C
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN([C@H]4CC[C@@H](O)CC4)C5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-(cis-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=522.1.
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][NH:11][CH2:10][CH2:9]2.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(O)C>[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([CH2:21][C:17]1[S:16][CH:20]=[CH:19][CH:18]=1)[CH2:10][CH2:9]2
Reactant: Oc1ccc2c(c1)CCNC2
Reactant: O=Cc1cccs1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Oc1ccc2c(c1)CCN(Cc1cccs1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.6 g of sodium cyanoborohydride is added to a solution of 1.5 g of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline, 1.2 g of thiophene-2-aldehyde and 1.8 g of toluenesulfonic acid monohydrate in 30 ml of ethanol. The mixture is stirred at room temperature for 8 hours, the solvent is removed in vacuo, and the residue is taken up with water/methylene chloride. The organic phase is again skaken with water, dried and evaporated in a rotary evaporator. The crude oily product is purified by chromatography on silica gel using a mixture of ethyl acetate/methylene chloride in the ratio 1:2. 1.7 g of a colorless oil, which crystallizes on standing (69% of theory), is obtained. Melting point: 110°-112° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH3:10])=[CH:4][N:3]=1.[C:20]([C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1)#[N:21].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[N:28]([C:24]3[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=3)[C:20]#[N:21])[C:29](=[O:30])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:9]([CH3:10])[C:5]2=[CH:4][N:3]=1
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: COc1ccc(NC(C)c2cnc(Cl)nc2Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Cl)ncc3C2C)cc1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
To a solution of (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-(4-methoxy-phenyl)-amine (0.10 g; 0.34 mmol) (from Example 1d supra) in toluene (1 mL) was added 3-cyanophenyl isocyanate (66.6 mg; 0.46 mmol) (Aldrich). The mixture was heated in an oil bath at 110° C. for two hours. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was triturated with hexanes and dried briefly. The solid residue (intermediate urea) was taken up in freshly distilled tetrahydrofuran (1.5 mL), cooled in an ice-brine bath and treated with potassium tert-butoxide (1.0 M in tetrahydrofuran; 370 μL; 0.37 mmol) (Aldrich). After 15 minutes in the cold the reaction was complete by TLC analysis and was filtered through a silica gel pad (0.5 g) and washed with ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography (Biotage, 12M, 40:60 ethyl acetate-hexanes) to give (±)-3-[7-chloro-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile as a solid. (Yield 0.13 g; 85.6%).
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26](O)=[O:27])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:29][CH2:30][CH2:31][CH2:32][S:33]([NH2:36])(=[O:35])=[O:34]>>[C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([CH:24]=[CH:25][C:26]([NH:36][S:33]([CH2:32][CH2:31][CH2:30][Cl:29])(=[O:35])=[O:34])=[O:27])=[CH:22][CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)CCCCl
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Product: O=C(C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1)NS(=O)(=O)CCCCl

Procedure:
Prepared by coupling 2e and 3-chloropropanesulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (65%); 1H NMR (d6-DMSO) δ 11.83 (s, 1H), 7.54 (d, J=15.7 Hz, 1H), 7.34-7.09 (m, 10H), 6.87 (d, J=8.1 Hz, 2H), 6.70 (d, J=7.3 Hz, 1H), 6.51 (d, J=15.7 Hz, 1H), 3.72 (t, J=6.4 Hz, 2H), 3.54 (t, J=6.4 Hz, 2H), 2.77 (t, J=7.0 Hz, 2H), 2.26 (t, J=7.0 Hz, 2H), 2.08 (m, 4H); APCI m/z: 504 (M−H−).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[N:18]=[C:17]3[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:16]3=[N:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1nc2cccc(C)c2n1
Product: Cc1cccc2nn(CCC#Cc3cccc(CF)n3)nc12
Yield: 62.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (73 mg, 0.39 mmol) and 2-but-3-ynyl-4-methyl-2H-benzo[d][1,2,3]triazole (65 mg, 0.35 mmol, 163(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 65 mg (0.22 mmol, 63%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-4-methyl-2H-benzo[d][1,2,3]triazole as a yellow semi-solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[Cl:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[NH:26][C:27]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:28]
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Reactant: O=C=Nc1cccc(Cl)c1
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2cccc(Cl)c2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and 3-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[C:12]1([C:9]2[N:10]=[C:11]3[CH:2]=[CH:3][CH2:4][N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:6]3=[N:7][C:8]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=Cc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-Butyl 8-bromo-2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (Intermediate H) (5 g, 10.72 mmol) in DCM (250 ml) was treated with DBU (1.939 ml, 12.87 mmol) and was stirred at RT under an atmosphere of nitrogen overnight. The solvent was removed in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-20% EtOAc/iso-hexane to afford the title compound;
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].[CH3:9]C([OH:12])C.C(OCC)(OCC)OCC.[ClH:23]>O>[OH2:4].[OH2:12].[ClH:23].[OH:4][C:3]1[NH:5][CH:9]=[N:1][C:2]=1[C:6]([NH2:8])=[O:7]
Reactant: CC(C)O
Reactant: NC(=O)C(N)C(N)=O
Agent: Cl
Solvent: CCOC(OCC)OCC
Solvent: O
Product: NC(=O)c1nc[nH]c1O
Temperature: 80 °C
Reaction time: 0.83 h

Procedure:
Under the nitrogen atmosphere, 5.00 g of 2-aminomalonamide was added to 100 mL of 2-propanol. After heating to 80° C., 17.7 mL of triethyl orthoformate was added dropwise to the mixture over 30 minutes. Subsequently, the reaction mixture was stirred for 7 hours and 50 minutes at 83 to 84° C. Subsequently, after cooling to 50 to 60° C., the reaction mixture was added with an aqueous solution prepared with 4 mL of conc. hydrochloric acid and 5 mL of water. After cooling the mixture to 20 to 30° C., the crystal was collected by filtration and then washed with 25 mL of acetone to give 8.04 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate as a pale yellow crystal.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[F:17])[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:5].[BH4-].[Na+]>CO>[NH2:2][CH2:3][CH:4]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[F:17])[NH:9][S:10]([CH3:13])(=[O:11])=[O:12])[OH:5]
Reactant: CS(=O)(=O)Nc1ccc(F)c(C(=O)CN)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(F)c(C(O)CN)c1
Yield: 91.1 %

Procedure:
3'-(2-Aminoacetyl)-4'-fluoromethanesulfonanilide hydrochloride (3 g) was dissolved in 30 ml of methanol, 0.20 g of sodium borohydride was added at 0°-5° C. and the mixture was made to react at the same temperature for 1 hour. The solvent was evaporated and the residue was made into free base using ion exchange resin (Dowex 50W X2), concentrated to dryness and the residue was recrystallized from methanol to give 2.4 g of (±)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide, m.p. 176°-179° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.[C-:10]#[N:11].[K+].C1OCCOCCOCCOCCOCCOC1.C(P(CCCC)CCCC)CCC>C(#N)C.O>[C:10]([CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1)#[N:11]
Reactant: [C-]#N
Reactant: Cc1cc(CO)ccn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(CC#N)ccn1
Temperature: 25 °C
Reaction time: 25 h
Yield: 62 %

Procedure:
To a stirred mixture of 4-hydroxymethyl-2-methyl-pyridine [CAS No. 105250-16-6] (3.37 g, 27.4 mmol), potassium cyanide (3.56 g, 54.7 mmol) and 18-crown-6 (0.72 g, 2.74 mmol) in acetonitrile (75 ml) was added dropwise at 15-20° C. a solution of tributylphosphine (7.16 g, 30.1 mmol) in acetonitrile (25 ml). The reaction mixture was stirred at room temperature for 25 h, poured into water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water (3×100 ml), brine (100 ml) dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate) to yield 4-cyanomethyl-2-methyl-pyridine (2.26 g, 62%) as a brown oil.