Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([CH:18]([CH3:20])[CH3:19])([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH2:4][CH2:5][CH:6]=O)#[N:2].[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][NH2:30])=[CH:25][CH:24]=1.[BH4-].[Na+]>C(O)C>[CH:18]([C:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)([CH2:4][CH2:5][CH2:6][NH:30][CH2:29][CH2:28][O:27][C:26]1[CH:31]=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)[C:1]#[N:2])([CH3:20])[CH3:19]
Reactant: COc1ccc(OCCN)cc1
Reactant: COc1ccc(C(C#N)(CCC=O)C(C)C)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(OCCNCCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
A solution of 3.96 g of 4-cyano-4-isopropyl-4-(3,4-dimethoxyphenyl)butyraldehyde and 2.00 g of 2-(4-methoxyphenoxy)ethylamine in 50 ml of ethanol was refluxed for 1 hour. To the solution was added 0.55 g of sodium borohydride under ice-cooling, and the solution was stirred for 30 minutes at room temperature. The solvent was removed and the residue was dissolved in 10% hydrochloric acid and washed with ether. The aqueous layer was made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. The residue was chromatographed on silica gel using chloroform as an eluent to give 2.93 g of the desired compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[C:21]2[C:16]([NH:17][C:18]([CH3:36])([CH3:35])[C:19](=[O:34])[N:20]2[CH3:33])=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+].[CH:42]1[C:54]2[CH:53]([CH2:55][O:56][C:57](Cl)=[O:58])[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]=2[CH:45]=[CH:44][CH:43]=1>O1CCOCC1.O.C(OCC)(=O)C>[CH:42]1[C:54]2[CH:53]([CH2:55][O:56][C:57]([N:24]([CH2:23][C:22]3[C:13]([C:4]4[CH:5]=[CH:6][C:7]([O:9][CH2:10][O:11][CH3:12])=[CH:8][C:3]=4[O:2][CH3:1])=[CH:14][CH:15]=[C:16]4[C:21]=3[N:20]([CH3:33])[C:19](=[O:34])[C:18]([CH3:36])([CH3:35])[NH:17]4)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[O:58])[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]=2[CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COCOc1ccc(-c2ccc3c(c2CNc2ccccc2OC)N(C)C(=O)C(C)(C)N3)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1ccc(-c2ccc3c(c2CN(C(=O)OCC2c4ccccc4-c4ccccc42)c2ccccc2OC)N(C)C(=O)C(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
7-(2-Methoxy-4-methoxymethoxyphenyl)-8-(2-methoxyphenylaminomethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 8-4, 104 mg, 0.212 mmol) and sodium hydrogen carbonate (22.0 mg, 0.262 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.5 mL) and water (1 mL), and 9-fluorenylmethoxycarbonyl chloride (60.3 mg, 0.233 mmol) was added thereto. After the reaction mixture was stirred at room temperature for 30 minutes, the mixture was diluted with ethyl acetate (50 mL). The mixture was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (149 mg) as a colorless amorphous product. (Yield 99%)
Reaction SMILES: [CH2:1]([OH:7])[C@@H:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OC)(OC)OC.C(C(O)=O)(F)(F)F>C(Cl)Cl>[C:9]1([C@@H:8]2[O:6][C@@H:2]([CH2:1][OH:7])[CH2:3][CH2:4][O:5]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCC[C@H](O)CO
Reactant: O=Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COC(OC)OC
Product: OC[C@H]1CCO[C@H](c2ccccc2)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
A sample of 2.60 g (20.6 mmol) of commercially available (Aldrich) (S)-(−)-1,2,4-butanetriol 5, benzaldehyde (3.47 mL, 29 mmol), and trimethyl orthoformate (3.74 mL, 29 mmol) was dissolved in 80 mL of CH2Cl2, and 1 mL of CF3CO2H was added. After the reaction mixture was stirred for 24 hours at room temperature, the reaction was quenched by the addition of NaOMe (20 mg), diluted with 100 mL of ether, and filtered. After the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel, eluting with petroleum ether (PE)-EtOAc (5:1 to ˜1:1) to afford 3.6 g (90%) of the product as a colorless oil. 1H NMR (300 MHz, CDCl3) δ7.52-7.33 (m, 5H), 5.51 (s, 1H), 4.29 (dd, J=4.1, 10.7 Hz, 1H), 3.95 (m, 2H), 3.60 (m, 2H), 2.85 (s, 1H, OH), 1.85 (m, 2H). 13C-NMR (CDCl3, 75 MHz): δ139.10, 129.58, 128.90, 126.85, 101.96, 78.35, 67.36, 66.29, 27.69.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:17])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](I)[CH3:25]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:17][CH2:24][CH3:25])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(cnn2CC)c1OCC
Reaction time: 7 h

Procedure:
In a solution of 259 g. 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (1.1 mol.) in 1700 ml. dimethylformamide, 400 g. of well pulverized potassium carbonate and 300 g. of ethyl iodide are introduced. The reaction mixture is stirred for 7 hours at 65° and filtered under suction, while hot, to remove excess potassium carbonate. Upon standing over night, 165 g. of 4-ethoxy-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester crystallize out of the solution, m.p. 112°-115°. After evaporation of the mother liquor, an additional 80 g. are obtained. The total yield amounts to 85% of theory. The compound is recrystallized from ligroin (90°-100°), m.p. 113°-115°.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:3]1.[N+](C1C=CC([O:30][C:31]([N:33]2[CH:37]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=3)[CH2:36][O:35][C:34]2=[O:46])=O)=CC=1)([O-])=O>C1COCC1>[CH3:1][CH:2]1[CH2:3][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:31]([N:33]1[CH:37]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=2)[CH2:36][O:35][C:34]1=[O:46])=[O:30]
Reactant: C[C@H]1CN(c2ccccc2[N+](=O)[O-])CCN1CCCN
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC1CN(c2ccccc2[N+](=O)[O-])CCN1CCCNC(=O)N1C(=O)OCC1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of (S)-(+)-3-methyl-1-(2-nitrophenyl)-4-(3-aminopropyl)-piperazine (35 mg, 0.126 mmol) in 10 mL of THF, 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (50 mg, 0.137 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by MeOH:EtOAc=1:9 (Rf=0.58, MeOH:EtOAc=1:3 ) to obtain 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {3-[2-methyl-4-(2-nitro-phenyl)-piperazin-1-yl)-propyl)-amide (55 mg, 87%). The compound was dissolved in CH2cl2 (3 mL) and was treated with 1N HCl in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a pale yellow solid. M.P. 115-119° C.; [α]D=+38.3, (c=0.22, CH2Cl2); Anal. Calcd. For C24H28N5O5F2Cl.0.72 C6H12: C, 56.50; H, 6.38; N, 11.63. Found: C, 56.63; H, 6.35; N, 10.08.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][O:12][CH2:13][CH2:14][O:15]C(=O)C1C=CC=CC=1.[NH3:24]>CO>[OH:15][CH2:14][CH2:13][O:12][CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:24]
Reactant: O=C(OCCOCn1cnc2c(Cl)ncnc21)c1ccccc1
Reactant: N
Solvent: CO
Product: Nc1ncnc2c1ncn2COCCO
Yield: 70 %

Procedure:
A solution of 6-chloro-9-(2-benzoyloxyethoxymethyl)purine (50 g) and ammonia (31 g) in methanol (120 ml) was heated in a bomb at 95° C. for 18 hours. The reaction mixture was removed from the bomb and the solvent evaporated under reduced pressure at 50° C. The resulting solid was triturated first with water and then, after drying, with chloroform. The solid, 9-(2-hydroxyethoxymethyl)adenine, was retained, and the aqueous triturate was extracted several times with chloroform. The aqueous extracts were treated with a strongly basic ion exchange resin and then evaporated to dryness under reduced pressure. The remaining solid was combined with that from the trituration step and recrystallized from isopropanol to give 22 g (70% of theoretical) of white 9-(2-hydroxyethoxymethyl)adenine, m.p. 199.5°-200° C.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[B]1OC2C(=CC=CC=2)[O:17]1>ClCCl.[Rh]>[C:10]1([C@@H:9]([OH:17])[CH3:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [B]1Oc2ccccc2O1
Reactant: C=Cc1ccccc1
Agent: [Rh]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A solution of rhodium-complex (3.4 mg, 4 μmol) obtained in Example 28 in dichloromethane degassed with argon was transferred with a syringe to the reaction vessel. Dichloromethane was evaporated in vacuo, then dry toluene (1 ml) degassed with argon, styrene (41.7 mg, 0.4 mmol) and freshly distilled catecholborane (56 μl, 0.45 mmol) were added. The reaction mixture was stirred at room temperature for 2 hrs, cooled with ice-bath, and quenched with EtOH (1 ml). 2M aqueous sodium hydroxide solution (1 ml) and 30% aqueous hydrogen peroxide (1 ml) were added. The mixture was allowed to warm up to room temperature over 30 min and then stirred for 2 hrs at this temperature. Diethyl ether (10 ml) was added to the mixture, and the orange organic layer was then washed with 1M aqueous sodium hydoxide solution and then dried over sodium sulfate. After evaporation of the solvent, the product was purified by chromatography on silica gel (pentane/diethyl ether 2:1) to give 35.7 mg of the title compound. (Yield: 73%, optical purity: 92% ee)
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=[CH:37][C:38](/[CH:39]=[C:40]4/[C:41](=O)[NH:42][C:43](=O)[NH:44]/4)=C3N=C(S(C)=O)N=2)CC1.[CH3:50]C(O)C>>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7]([NH:42][CH:41]([C:40]3[CH:39]=[CH:38][CH:37]=[CH:43][N:44]=3)[CH3:50])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reactant: CC(C)O
Reactant: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Product: CC(Nc1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1)c1ccccn1
Temperature: 90 °C
Reaction time: 6.5 h

Procedure:
A (2:1) mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (1.0 eq, 3.6 g, 10.08 mmol) was suspended in 2-propanol (40 ml). Rac-1-pyridinil-2-yl-ethylamine (2.0 eq, 2.47 g, 20.22 mmol) was added and the mixture stirred at 90° C. for 6.5 hours. The mixture was cooled down and the solid isolated by filtration. After drying in a vacuum oven, (Z)-5-((4-(cyclopropylamino)-2-(1-(pyridin-2-yl)ethylamino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione was isolated as a pale yellow solid (3.60 g, 88%). LCMS (ES): >95% pure, m/z 406 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][N:7]=[C:6]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:5]=1)=[N+]=[N-].[H][H]>CN(C=O)C.[Pd]>[NH2:1][C:4]1[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][N:7]=[C:6]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:5]=1
Reactant: CCOC(=O)Cc1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N

Procedure:
10.15 g (23.482 mmol) of the crude product from Example 18A were hydrogenated overnight in DMF (400 ml) using palladium on carbon (10%) at a hydrogen pressure of 1 atmosphere. The mixture was then filtered through Celite and concentrated. The residue was used without further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:8][O:10][N+:9]=2[O-:11])[N:7]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: CC(C)=O
Product: [O-][n+]1onc2nc(Cl)ccc21
Temperature: 80 °C
Reaction time: 6 h

Procedure:
6-Chloro-3-nitropyridin-2-amine (1.25 g, 7.06 mmol) and iodobenzene diacetate (5.80 g, 17.65 mmol) were taken-up in acetone (70.6 ml) and stirred at 80° C. for 6 hours. The reaction was then concentrated directly, and the resulting crude product was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to afford 5-chloro[1,2,5]oxadiazolo[3,4-b]pyridine 1-oxide. LRMS (APCI) calc'd for (C5H3ClN3O2) [M+H]+, 172. found 172.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[NH:5][C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)=[C:7]([C:9]2[CH:18]=[CH:17][C:12]3=[N:13][N:14]([CH3:16])[N:15]=[C:11]3[CH:10]=2)[N:8]=1.Cl.O.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:16][N:14]1[N:13]=[C:12]2[CH:17]=[CH:18][C:9]([C:7]3[N:8]=[C:4]([CH:3]=[O:2])[NH:5][C:6]=3[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)=[CH:10][C:11]2=[N:15]1
Reactant: COC(OC)c1nc(-c2ccc3nn(C)nc3c2)c(-c2cccc(C)n2)[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(-c2[nH]c(C=O)nc2-c2ccc3nn(C)nc3c2)n1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
5-[2-Dimethoxymethyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-2-methyl-2H-benzotriazole (700 mg, 1.92 mmol) was dissolved in 40 ml anhydrous tetrahydrofuran. 6M hydrochloric acid solution in water (3.2 ml, 19.2 mmol) was added. The reaction was refluxed for 3 hours and then cooled to room temperature. Saturated aqueous sodium hydrogen carbonate solution was added until approximately pH 8. The organic solvent was removed by rotary evaporation. The residue was dissolved in water and then extracted three times with chloroform. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to afford 4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carbaldehyde (600 mg, 98% yield) as a brown solid. Step C. [4-(2-Methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl]-methanol
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O:13][C:14]1[CH:15]=[C:16]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[O:17][CH2:18][CH2:19][CH2:20][O:21][N:22]1C(=O)C2=CC=CC=C2C1=O)(=[O:12])=[O:11])([O-:3])=[O:2].C(O)C.[BH4-].[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O:13][C:14]1[CH:15]=[C:16]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[O:17][CH2:18][CH2:19][CH2:20][O:21][NH2:22])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: Cc1cc(OCCCON2C(=O)c3ccccc3C2=O)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(OCCCON)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A solution of N-[3-[3-(2-nitrophenylsulfonyloxy)-5-methylphenoxy]propoxy]-phthalimide (2.33 g, 4.55 mmol), as prepared in the preceding step, in tetrahydrofuran (30 mL) and ethanol (30 mL) was treated with sodium borohydride (524 mg, 13.9 mmol). The reaction mixture was stirred at room temperature overnight, quenched carefully with 2N HCl (14 mL) and heated at 50° C. for 90 min. The reaction mixture was then concentrated to ¼ volume, basified with 2N NaOH, diluted with water, and extracted into ethyl acetate. The organic phase was dried (K2CO3) and purified by flash chromatography (1:4 to 1:2 diethyl ether/dichloromethane to give 1.12 g (64%) of the title compound as a pale yellow oil. 1H-NMR (300 MHz, CDCl3) δ7.98-8.01 (m, 1H), 7.79-7.87 (m, 2H), 7.66-7.74 (m, 1H), 6.64 (m, 1H), 6.60 (s, 1H), 6.57 (t, 1H, J=2 Hz), 3.96 (t, 2H, J=6 Hz), 3.80 (t, 2H, J=6 Hz), 2.27 (s, 3H), 2.02 (penet, 2H, J=6 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid) calcd. for C16H18N2O7S: 405.1 (M+Na). Found 405.2.
Reaction SMILES: C([O:4][C:5](=[O:38])[C@@H:6]([NH:25][C:26](=[O:37])[C:27]1[C:32]([F:33])=[CH:31][C:30]([CH2:34][NH2:35])=[CH:29][C:28]=1[F:36])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)CC.[OH-].[Li+].C(O)(C(F)(F)F)=O>C1COCC1.O>[NH2:35][CH2:34][C:30]1[CH:29]=[C:28]([F:36])[C:27]([C:26]([NH:25][C@@H:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=3[CH3:20])=[CH:12][CH:13]=2)[C:5]([OH:38])=[O:4])=[O:37])=[C:32]([F:33])[CH:31]=1
Reactant: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cc(CN)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CN)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Reaction time: 15 h
Yield: 96.4 %

Procedure:
To a suspension of (S)-2-(4-aminomethyl-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid propyl ester (508 mg, 0.96 mmol) in THF (10 mL) was added a solution of lithium hydroxide (240 mg, 10 mmol) in water (2 mL) at room temperature. The mixture was stirred for 15 h at which time TLC analysis indicated the absence of starting material. Then, the THF was removed under reduced pressure and the residue was diluted with water (100 mL) and the mixture was acidified with TFA. The crude product was purified by HPLC to afford 450 mg (78% yield) of (S)-2-(4-aminomethyl-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid as a TFA salt as a white solid. ES-LRMS m/e calcd for C24H24F2N4O5 (M+H)+ 487, found 487.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[NH3:24]>>[NH2:24][N:11]1[C:12](=[O:13])[C:6]2[C:7](=[N:8][CH:3]=[N:4][CH:5]=2)[N:9]=[C:10]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][CH2:22][CH3:23]
Reactant: N
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Product: CCCOc1ccccc1-c1nc2ncncc2c(=O)n1N
Reaction time: 8 h

Procedure:
7-Methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (1.55 g) was heated in ethanolic ammonia (50 ml) in a pressure vessel for 8 hours at 90° C. and then for 8 hours at 145° C. After cooling a grey solid (0.64 g) was collected and was recrystallised from ethanol (with charcoal) to yield a crude product (0.47 g) which was recrystallised from ethanol to yield the title compound, 0.29 g, m.p. 261°-262° C.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=[O:14].[Na+].OOS([O-])=O.[K+].O>C(#N)C.O>[C:1]1([C:7]23[O:14][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2ccccc2)CCCC1
Reactant: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: c1ccc(C23CCCCC2O3)cc1
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of phenyl cyclohexene (79 mg, 0.5 mmol) in a mixture of acetonitrile (4.5 ml) and water (2 drops) were added first finely crushed NaHCO3 (168 mg, 2 mmol) and oxone (307 mg, 0.5 mmol) then the catalyst (0.05 mmol). The resulting yellow suspension was allowed to react at RT, under good stirring. TLC was used to follow the reaction which indicated that the reaction was finished in 2 h. Water (3 ml) was added to the reaction mixture followed by extraction into methylene dichloride. The organic extracts were combined and dried over anhydrous sodium sulphate. Concentration on a rotary evaporator gave a material which was purified on a column using 2% ethyl acetate:petrol mixture as eluent to give the desired compound as a colourless oil. (72 mg, 83% yield, 70% e.e).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[F:14])=O)C.[CH3:16][NH:17][C:18]([NH2:20])=[S:19].N12CCCN=C1CCCCC2.CS(O)(=O)=O>C1(C)C=CC=CC=1.O>[F:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:20]=[C:18]([SH:19])[N:17]([CH3:16])[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1F
Reactant: CNC(N)=S
Agent: CS(=O)(=O)O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cn1c(S)nc(-c2ccncc2F)cc1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A suspension of 3-(3-fluoropyridin-4-yl)-3-oxo-propionic acid ethyl ester (60.3 g, 286 mmol), N-methylthiourea (88 g, 976 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (48 g, 315 mmol) in toluene (600 ml) was heated at 100° C. for 5 hour. After addition of water (2000 ml) and methanesulfonic acid (30.3 g, 315 mmol) at room temperature and stirring for one hour, resulting precipitate was collected by filtration and dried to afford 6-(3-fluoropyridin-4-yl)-2-mercapto-3-methyl-3H-pyrimidin-4-one (46.3 g, 195 mmol, 68%) as white crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[C:5]([OH:7])=[O:6].[CH3:10][N:11]([CH2:13][C:14]1[C:22]([OH:23])=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][N:18]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH3:12].I[CH2:34][CH3:35].O>CN(C=O)C>[F:3][C:4]([F:9])([F:8])[C:5]([OH:7])=[O:6].[CH2:34]([O:23][C:22]1[C:14]([CH2:13][N:11]([CH3:10])[CH3:12])=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:25])=[O:26])[CH:17]=[CH:16]2)[CH3:35]
Reactant: CCI
Reactant: CN(C)Cc1c(O)ccc2c1ccn2S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1CN(C)C

Procedure:
NaH (95%) (101 mg, 4.23 mmol), was added to a solution of 4-[(dimethylamino)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol (700 mg, 2.11 mmol; Example 131) in DMF (20 ml) at ambient temperature. The mixture was stirred for 15 min before iodoethane (0.203 ml, 2.54 mmol) was added. After 1 h water was added and the mixture extracted with Et2O. A small portion was purified on Gilson HPLC using 20-50% MeCN in 0.1% TFA. Yield: 65 mg; colorless oil. MS (ESI+) for C19H22N2O3S m/z 359 (M+H)+.