Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)#[N:6]>C(OC(=O)C)(=O)C>[C:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:1]([O-:4])=[O:2])[CH:13]=2)[CH2:8]1)#[N:6]
Reactant: O=[N+]([O-])O
Reactant: N#CC1Cc2ccccc2C1
Solvent: CC(=O)OC(C)=O
Product: N#CC1Cc2ccc([N+](=O)[O-])cc2C1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Fuming nitric acid (40 ml, 1.5 g/ml) was added dropwise with stirring to acetic anhydride (80 ml ) keeping the temperature of the mixture at 0° C. After the addition was complete 2-cyanoindane (11.33 g, 79.5 mmol), (J. Chem. Soc. (B), (1969), 1197) was added dropwise with stirring over 30 minutes maintaining the reaction temperature between -5° and 0° C. The mixture was stirred for a further 15 minutes then poured onto ice. The mixture was extracted with dichloromethane (4×150 ml) and the extracts were washed with saturated aqueous sodium bicarbonate (3×150 ml), dried over magnesium sulphate and the solvent evaporated under reduced pressure. The residue was recrystallised from ethanol to give 2-cyano-5-nitroindane (12.09 g, 81%) as a yellow solid, m.p. 80°-82° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7](=O)[C:8]([CH3:12])([CH3:11])[CH2:9][O:10][C:4]=2[CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:15]=[N:14][C:5]2[NH:6][CH2:7][C:8]([CH3:11])([CH3:12])[CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CC1(C)COc2cc(Br)cnc2NC1=O
Solvent: C1CCOC1
Product: CC1(C)CNc2ncc(Br)cc2OC1
Yield: 44.3 %

Procedure:
To a solution of 3-bromo-7,7-dimethyl-6,7-dihydro-9H-5-oxa-1,9-diaza-benzocyclohepten-8-one (620 mg, 2.28 mmol) in THF (15 mL) was added BH3 (9.1 mL of a 1 M solution in THF, 9.1 mmol), and the mixture was heated to reflux overnight. After cooling, the solvent was removed in vacuo. The residue was dissolved in MeOH (15 mL) and 2 N NaOH (5 mL), and the mixture was heated to reflux for 4 h. Methanol was then removed in vacuo and the resulting precipitate was collected by filtration to give the title compound (260 mg, 44%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=1.8 Hz, 1H), 7.19-7.18 (m, 1H), 4.60 (br s, 1H), 3.83 (s, 2H), 3.10 (d, J=3.9 Hz, 2H), 1.03 (s, 6H); ESI MS m/e 257 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]([NH2:26])([C:20]1[S:24][N:23]=[C:22]([CH3:25])[N:21]=1)[CH3:19]>>[CH3:17][C:18]([NH:26][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:20]1[S:24][N:23]=[C:22]([CH3:25])[N:21]=1)[CH3:19]
Reactant: Cc1nsc(C(C)(C)N)n1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: Cc1nsc(C(C)(C)NC(=O)c2cccc(-c3cccc(Cl)c3)n2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 1-methyl-1-(3-methyl-[1,2,4]thiadiazol-5-yl)-ethylamine as starting materials, MS (LC/MS): 373.0 (M+H).
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC.O>C1(C)C=CC=CC=1>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C
Yield: 82.3 %

Procedure:
11 grams of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 20 grams of powdered potassium hydroxide and 27.96 grams of hexadecyl bromide were stirred in 150 ml toluene and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 40 ml. The reaction mixture was cooled to room temperature, 100 ml water was added, and the reaction mixture was extracted thrice with 75 ml dichloromethane. The combined organic phase was washed with 50 ml water and the solvent was removed under reduced pressure. The residue was dissolved in 200 ml of a mixture of 90:10:5 (volume/volume) methanol:water:concentrated hydrochloric acid, and the resulting solution was refluxed for 2 hours. After cooling to room temperature, 100 ml of water was added. The product was extracted thrice with 100 ml dichloromethane, washed consecutively with 100 ml water, 100 ml saturated aqueous solution of sodium carbonate and again with 100 ml water. The solvent was then removed under reduced pressure, and the product was crystallized from hexane (200 ml) to give 21.69 grams pure (S)-1-hexadecyl-glycerol, which was dried in a desiccator under reduced pressure. The yield was 82%.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6](=[S:28])[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[CH:4][CH:3]=1
Reactant: COc1ccccc1NC(=O)c1ccc(C)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1NC(=S)c1ccc(C)cc1
Temperature: 50 °C
Yield: 108.8 %

Procedure:
The 4-methyl-2'-methoxybenzanilide (50.0 g) obtained in (1) was dissolved in 200 ml of toluene, and 46.1 g of Lawesson's reagent was added. The mixture was refluxed for 1 hour. After the reaction, the reaction mixture was cooled to about 50° C., and 200 ml of water was added. The mixture was further refluxed for 2 hours. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was evapoated under reduced pressure. The residue was recrystallized from methanol and then cyclohexane to give 31.9 g of 4-methyl-2'-methoxybenzothioanilide. mp 91.0°-93.0° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:16])=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=O>S(Cl)(Cl)=O>[Cl:1][C:2]1[C:3]([NH2:16])=[C:4]([C:5]2[O:11][CH2:10][CH2:9][O:8][N:7]=2)[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)NOCCO
Solvent: O=S(Cl)Cl
Product: Nc1c(Cl)cc(Cl)cc1C1=NOCCO1

Procedure:
At 20° C., 30 ml of thionyl chloride are initially charged and 3 g of 3,5-dichloro-2-amino-N-(2-hydroxyethoxy)benzamide are added in 3 portions with stirring. The mixture is stirred at 70° C. for 12 h. The reaction mixture is then cooled and carefully poured onto ice-water. The mixture is extracted twice with in each case 150 ml of dichloromethane and the extracts are dried with sodium sulphate and evaporated to dryness using a rotary evaporator.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH:24][C:20]1[CH:21]=[N:22][CH:23]=[C:18]([C:16]2[CH:15]=[CH:14][C:10]3[N:11]=[CH:12][N:13]=[C:8]([O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:9]=3[N:17]=2)[CH:19]=1)(=[O:35])=[O:34]
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine (Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773 ml) was slowly added 2,4-dichlorobenzene-1-sulfonyl chloride (0.0460 g, 0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, the reaction mixture was diluted with DCM and quenched with 1N. aq HCl. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc-Hexane to give 2,4-dichloro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (0.0340, 41%) as a purple solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.02-2.11 (2H, m), 2.24-2.29 (2H, m), 3.70-3.75 (2H, m), 4.10-4.16 (2H, m), 5.65-5.71 (1H, m), 7.33 (1H, dd, J=1.8, 8.6 Hz), 7.54 (1H, d, J=2.0 Hz), 8.05 (1H, d, J=8.8 Hz), 8.20 (1H, d, J=9.2 Hz), 8.36 (1H, d, J=8.8 Hz), 8.48-8.55 (2H, m), 8.84 (1H, s), 9.15 (1H, d, J=1.6 Hz). m/z=532.0 [M+1]+.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][O:8]1)(=O)=O.[CH2:12]([NH2:15])[CH2:13][NH2:14].C([O-])([O-])=O.[K+].[K+]>[I-].[Na+].C(OCC)(=O)C>[O:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[CH2:6][NH:14][CH2:13][CH2:12][NH2:15]
Reactant: CS(=O)(=O)OCC1CCCO1
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: NCCNCC1CCCO1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 1.42 g of (tetrahydro-2-furanyl)methyl methanesulfonate, 5 ml of ethylendiamine, 1.53 g of potassium carbonate, anhydrous, and 0.1 g of sodium iodide was stirred at 60° C. for 4 hours. After the completion of reaction, ethyl acetate was added, and insolubles were then removed by filtration. The filtrate was concentrated under a reduced pressure, and the resultant residue was poured into 10 ml of a 6N aqueous solution of sodium hydroxide, followed by extraction with 100 ml of methylene chloride. Next, the extract was dried over sodium sulfate, anhydrous, and then concentrated under a reduced pressure to obtain 1.2 g of N-[(tetrahydro-2-furanyl) methyl]ethylenediamine as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]([O:25]C)=[O:24])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:27](=[O:29])[NH2:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]([OH:25])=[O:24])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:27](=[O:29])[NH2:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1ccccc1
Yield: 72.9 %

Procedure:
A solution of the {9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (10.1 mg, 0.025 mM) and 0.025 mL (0.025 mM) of 1 N NaOH in 3 mL of ethanol was stirred for 16 hours at 25° C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 7.1 mg (70%) of the {9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.5-7.05 (m, 11H), 6.55 (d, 1H, J=8 Hz), 5.75 (s, 2H), and 4.3 (s, 2H). IR (KBr, cm−1) 3471, 1657, 1615, 1591, 1496, 1453, 1412, 1330, 1272, and 1151. MS (ES) m/e 373, 375, 397.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.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.Cl[Pd]Cl.[Fe+2]>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([CH2:16][OH:15])=[CH:18][CH:19]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc(CO)cc3)cc12
Temperature: 110 °C
Yield: 15.1 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (200.0 mg, 0.73 mmol), 4-(hydroxymethyl)phenylboronic acid (90.0 mg, 0.59 mmol), 2N aqueous potassium carbonate (1.1 mL, 2.2 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (60.0 mg, 0.073 mmol) in toluene (1.5 mL) and EtOH (2.3 mL) was degassed with N2 for 3 minutes and heated to 110° C. for 5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was acidified to pH 5 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Phenomenex Synergi C18 150×30 mm, 4 μm; 28% MeCN in water (0.225% TFA) to 28% MeCN in water (0.225% TFA) for 12 min; Flow Rate: 30 mL/min) to afford the title compound (27 mg, 11% yield) as a white solid. MS (ES+) 302.9 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 7.76 (s, 1H), 7.45 (m, 4H), 4.69 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH3:13]>>[CH2:12]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[N:7]=[C:6]([NH:19][C:18]3[CH:20]=[CH:21][C:15]([O:14][CH2:12][CH3:13])=[CH:16][CH:17]=3)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)=[CH:17][CH:16]=1)[CH3:13]
Reactant: CCOc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Product: CCOc1ccc(Nc2ncc([N+](=O)[O-])c(Nc3ccc(OCC)cc3)n2)cc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-nitropyrimidine with 4-ethoxyaniline gave N2,N4-bis-(4-ethoxyphenyl)-5-nitro-2,4-pyrimidinediamine. LCMS: ret. time: 35.91 min.; purity: 100%; MS (m/e): 396 (MH+); 1H NMR (CDCl3): δ 10.25 (1H, s), 9.11 (1H, s), 7.44 (2H, d, J=8.6 Hz), 7.37 (2H, d, J=9 Hz), 6.88 (2H, d, J=8.6 Hz), 6.80 (2H, d, J=8.6 Hz), 4.06 (2H, q, J=7.2 Hz), 4.02 (2H, q, J=7.2 Hz), 1.45 (3H, t, J=7.2 Hz), 1.42 (3H, t, J=7.2 Hz).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=[O:5].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].[OH:59][C:60]([C:63]1[CH:64]=[C:65]2[C:70](=[CH:71][CH:72]=1)[C:69](=[O:73])[NH:68][CH2:67][CH2:66]2)([CH3:62])[CH3:61]>O1CCOCC1.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].O>[Br:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:68]2[CH2:67][CH2:66][C:65]3[C:70](=[CH:71][CH:72]=[C:63]([C:60]([OH:59])([CH3:61])[CH3:62])[CH:64]=3)[C:69]2=[O:73])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Br)cccc1Br
Reactant: CC(C)(O)c1ccc2c(c1)CCNC2=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(O)c1ccc2c(c1)CCN(c1cccc(Br)c1C=O)C2=O
Temperature: 25 °C

Procedure:
To a mixture of 2,6-dibromo-benzaldehyde (1.60 g, 6.06 mmol), Pd2(dba)3 (222 mg, 0.243 mmol), xantphos (210 mg, 0.364 mmol), and Cs2CO3 (2.77 g, 8.49 mmol) in dioxane (60 ml) under argon was added 6-(1-hydroxy-1-methyl-ethyl)-3,4-dihydro-2H-isoquinolin-1-one (US2009/0306041) (995 mg, 4.85 mmol). The resulting mixture was refluxed overnight. After cooling down to r.t., water was added, and the mixture was extracted three times with EtOAc. The combined organic layers were dried, filtered, and evaporated to dryness. The crude product was purified by flash chromatography (silica gel, cyclohexane/EtOAC gradient) to yield Intermediate 42.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](Cl)=[N:5][C:6]([Cl:10])=[N:7][C:8]=1[Cl:9].C(O)=O.[S-:15][C:16]#[N:17].[K+]>O>[Cl:10][C:6]1[N:7]=[C:8]([Cl:9])[C:3]([S:2][CH3:1])=[C:4]([S:15][C:16]#[N:17])[N:5]=1
Reactant: CSc1c(Cl)nc(Cl)nc1Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: O=CO
Solvent: O
Product: CSc1c(Cl)nc(Cl)nc1SC#N
Temperature: 25 °C
Yield: 92.8 %

Procedure:
In a 50-ml four-necked flask equipped with a thermometer, reflux condenser and stirrer, were charged 2.30 g (0.010 mole) of 5-methylthio-2,4,6-trichloropyrimidine and 15 ml of formic acid. While stirring the contents at room temperature, 1.07 g (0.011 mole) of potassium thiocyanate was added. Then, the resulting mixture was heated and was then stirred at 50° C. for 1 hour. After cooling the reaction mixture, it was poured into a great deal of water. The precipitated solid was collected by filtration and dried to obtain 2.34 g of crude crystals (yield: 92.9%). A portion of the crude crystals was recrystallized from ethyl acetate, thereby obtaining a purified product. m.p. 143°-144.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH:11]C(C2C=CC=CC=2)C)[CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1)=[O:4]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH2:11])[CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1NC(C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1N
Reaction time: 19 h
Yield: 76 %

Procedure:
A mixture of 4-(1-phenyl-ethylamino)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2.4 g, 6.62 mmol) and 20% palladium hydroxide on carbon (1 g) in methanol (20 mL) was stirred under a hydrogen balloon for 19 h. The mixture was then filtered through a thin pad of celite and concentrated to provide 4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a colorless oil (1.3 g, 81.2%) MS: 259 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[NH2:6].[C:23]([S:26][CH2:27][CH:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29](O)=[O:30])(=[O:25])[CH3:24]>CO>[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)[NH:6][C:29](=[O:30])[CH:28]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:27][S:26][C:23](=[O:25])[CH3:24]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React O-benzyl-L-tyrosine methyl ester hydrochloride (2.77 g) and 3-acetylthio-2-benzylpropionic acid (2.05 g) in a manner similar to that described in Example 1, Step 1 to give a yellow-orange oil. Chromatograph this oil on a column of silica gel (2.5L) and elute with CH2Cl2 : ethyl acetate 98:2 to give Isomer A, a white solid (0.84 g) m.p. 108°-109°; [α]D26 =-39.8° (MeOH); overlap Isomer A and Isomer B (0.80 g); and Isomer B, white solid (0.45 g), m.p. 92°-93°, [α]D26 =+19.2° (MeOH).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.[H-].[Na+].[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)CCCC>[CH3:10][C:7]1[CH2:8][CH2:9][C:4]([C:2]([CH3:11])([S:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:1])([OH:3])[CH2:5][CH:6]=1
Reactant: Sc1ccccc1
Reactant: CC1=CCC2(CC1)OC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCO
Product: CC1=CCC(O)(C(C)(C)Sc2ccccc2)CC1
Yield: 52.7 %

Procedure:
To a stirred solution of 76 g of 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene in 300 ml of n-pentanol were added 2.0 g of 60% sodium hydride and 60 g of thiophenol. After 18 hours reflux, the mixture was vacuum concentrated at 90°-95° C. The residue was dissolved in methylene chloride and washed twice with 2N sodium hydroxide. The dried solution was Claisen-distilled to give 106 g of crude product, b.p. 120°-125° C. (0.1 mm). Recrystallization from 250 ml of hexane gave 69.1 g of the desired product, m.p. 73°-74° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6].C(N(CC)CC)C.[Br:15][C:16]1[C:17](Cl)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1>C(#N)C.C(OCC)(=O)C>[Br:15][C:16]1[C:17]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6])=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1
Reactant: CC(=O)NCCN
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NCCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
0.14 ml (1.42 mmol) of N-(2-aminoethyl)acetamide and 0.22 ml (1.60 mmol) of triethylamine are added to a solution of 300 mg (1.32 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 4.2 ml of acetonitrile at room temperature. The mixture is stirred at room temperature for 24 hours and then diluted with ethyl acetate. It is washed with saturated NaCl solution, 10% strength citric acid solution and saturated NaHCO3 solution. The organic phase is dried (Na2SO4), filtered and concentrated. The resulting residue is recrystallized from ethyl acetate. 294 mg (1.00 mmol; yield: 75%) of the product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH3:21])[N:15]=[N:14]1.[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH2:8][C:6]1[C:5]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:4][C:3]([N:13]2[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH3:21])[N:15]=[N:14]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCn1nnn(-c2cc(OC(C)C)c(C)cc2Cl)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCn1nnn(-c2cc(OC(C)C)c(CBr)cc2Cl)c1=O
Temperature: 25 °C
Yield: 49.5 %

Procedure:
Under a dry nitrogen atmosphere, a stirred solution of 4.4 g (0.014 mole) of 1-(2-chloro-4-methyl-5-isopropoxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one (compound 91), 2.5 g (0.014 mole) of N-bromosuccinimide, and 0.06 g (0.00025 mole) of benzoyl peroxide in 80 mL of carbon tetrachloride was heated at reflux temperature for two days. The reaction mixture was allowed to cool to room temperature, filtered, and the filtrate washed with a saturated aqueous sodium chloride solution. The washed filtrate was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to leave an oil. The oil was crystallized from petroleum ether to yield 2.7 g of 1-(4-bromomethyl-2-chloro-5-isopropoxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one, mp 68°-70° C.
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[NH:6][C:7]([C:9]3[C:14]4[O:15][CH2:16][CH2:17][NH:18][C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[I-].[K+].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[NH:6][C:7]([C:9]3[C:14]4[O:15][CH2:16][CH2:17][N:18]([CH2:23][CH2:24][N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Clc1cc2nc(-c3cccc4c3OCCN4)[nH]c2cc1Cl
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc2nc(-c3cccc4c3OCCN4CCN3CCOCC3)[nH]c2cc1Cl
Yield: 92.3 %

Procedure:
4.5 g (14 mmol) of 8-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (compound 1a) obtained in Example 5 was dissolved in 100 mL of dimethylformamide. 1.3 g (7 mmol) of 4-(2-chloroethyl)morpholine, 0.58 g (3.5 mmol) of potassium iodide and 0.97 g (7 mmol) of K2CO3 were added thereto, followed by irradiation of microwave at 110° C. for 10 min. The reaction mixture was concentrated under reduced pressure, followed by dilution with ethyl acetate. The resulting product was washed with distilled water and saturated sodium chloride solution, followed by drying over magnesium sulfate and concentrating under reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate/hexane=1/1) to obtain the title compound (2.8 g, yield: 91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20]Br>CN(C=O)C>[F:1][C:2]1[C:9]2[O:10][CH2:19][CH2:20][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1cc(O)c(O)c(F)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(F)c2c(c1)OCCO2
Yield: 95.4 %

Procedure:
To a solution of 3-fluoro-4,5-dihydroxybenzaldehyde (0.66 g, 4.2 mmol) in DMF (30 ml) was added potassium carbonate (1.15 g, 8.3 mmol) and 1,2-dibromoethane (0.72 ml, 8.3 mmol) and the resultant mixture was heated to 80° C. for 18 h before the solvent was removed under reduced pressure. The reaction mixture was then treated with dichloromethane and water. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried and the solvent was removed under reduced pressure to give the desired compound as a cream solid (0.73 g, 95%).