Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[C:10]([Cl:16])[CH:9]=1)[O:5][CH3:6].[OH-].[K+].O.Cl>C(O)C>[Cl:14][C:12]1[CH:13]=[C:8]([CH:9]=[C:10]([Cl:16])[C:11]=1[Cl:15])[O:7][CH:4]([O:5][CH3:6])[C:3]([OH:17])=[O:2]
Reactant: COC(=O)C(OC)Oc1cc(Cl)c(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(Oc1cc(Cl)c(Cl)c(Cl)c1)C(=O)O
Temperature: 45 °C

Procedure:
A solution of 35.2 g (0.12 mole) methyl-α-(3,4,5-trichlorophenoxy)-α-methoxyacetate in 50 ml ethanol was added slowly to a solution of 9.2 g (0.14 mole) 85% KOH in 150 ml 2B ethanol. The mixture was heated at 45° C for one-half hour, then cooled to room temperature and poured into 300 ml H2O. The pH of the resulting mixture was adjusted to 2 with dilute HCl. An oil separated which was removed by two 150 ml extractions with chloroform. The chloroform extracts were combined, washed with three 150 ml portions of water, and dried over magnesium sulfate. Removal of the solvent in vacuum left 22.9 g (66.8% crude yield) of a solid which was recrystallized from cyclohexane to give α-(3,4,5-trichlorophenoxy)-α-methoxyacetic acid, m.p. 101°-104° C, characterized by infrared spectroscopy. 20.0 g (0.07 mole) of the acid dissolved in 25 ml tetrahydrofuran was added dropwise to 1.9 g (0.08 mole) sodium hydride in 75 ml tetrahydrofuran. One half hour after addition was complete, the solution was evaporated to leave the sodium salt. This was added by portions to a solution of 8.9 g (0.07 mole) oxalyl chloride in 150 ml benzene to give 15.7 g (73.8% yield) of an oil, α-(3,4,5-trichlorophenoxy)-α-methoxyacetyl chloride. Due to its air sensitivity, 5.2 g (0.02 mole) of this compound was immediately dissolved in 25 ml benzene and added slowly to a solution of 1.7 g (0.02 mole) dimethylpropargylamine and 2.1 g (0.02 mole) triethylamine in 100 ml benzene, with stirring while the solution was being cooled to 10° C in an ice bath. After addition was complete the cold bath was removed and the mixture was allowed to come to room temperature. The mixture was then washed first with 100 ml water, followed by two 100 ml portions of 5% sodium carbonate solution. The organic phase was dried over magnesium sulfate, and the solvent was evaporated to give 5.4 g (77.1% yield) of a solid, which was recrystallized from hexane and characterized by infrared and NMR spectroscopy as in N-dimethylpropynyl-α-methoxy-α-(3,4,5-trichlorophenoxy)acetamide, m.p. 76°-80° C.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].CN(C)C=O.Cl>O>[C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C(=Cc1ccc(-c2ccccc2)cc1)c1ccccc1

Procedure:
A mixture of 24.0 parts of the compound of formula ##STR18## 25.8 parts of p-phenylbenzaldehyde-anile and 50.0 parts of potassium hydroxide powder in 600.0 parts by volume of dimethyl formamide is raised to 60° in 30 minutes with stirring and in the absence of air. It is maintained at this temperature for a further 30 minutes, after which it is cooled to about 10°. At a temperature between 10° and 20° 20 parts of water and then 500.0 parts by volume of 10% hydrochloric acid are added. The precipitated product is filtered off with suction, washed with water until neutral and dried. The 4-(5"-methoxybenzoxazolyl-2")-4'-phenylstilbene of formula (10) is obtained in very good yield. It can be purified as described above.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([C:15]#N)[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:17])[CH3:2].C(O)(=[O:21])C.N1C=CC=CC=1>[Ni].O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([CH:15]=[O:21])[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:17])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)Cc1c(C)oc2ccc(C#N)cc12
Agent: [Ni]
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Cc1c(C)oc2ccc(C=O)cc12
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of (5-cyano-2-methyl-benzofuran-3-yl)-acetic acid ethyl ester (4.31 g, 17.7 mmol), NaPH2O2.H2O (14.99 g, 141 mmol) and Raney nickel (3.06 g, 35.4 mmol) in a mixture of water (50 mL), acetic acid (50 mL) and pyridine (100 mL) is heated for 2 h at 100° C. under an argon atmosphere. After cooling to room temperature the reaction mixture is filtered over hyflo and the filtrate concentrated by rotary evaporation. The residue is partitioned between water and TBME, the layers are separated and the aqueous phase is extracted with TBME. The combined organic layers are washed with a 1 M aqueous HCl solution, a saturated aqueous NaHCO3 solution and brine. After drying over Na2SO4 and evaporation of the solvent in vacuo the crude product is obtained as a brown oil. Further purification by flash column chromatography (silica gel gradient of cyclohexane/EtOAc 100:0 to 6:1) affords the title compound as colorless crystals (2.59 g, 10.5 mmol, 60%). 1H NMR (400 MHz, CDCl3, 298 K): δ=10.08 (s, 1H), 8.07 (s, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.52 (d, J=8.9 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 2.49 (s, 3H), 1.27 (t, J=7.1 Hz, 3H). MS (ES+): 247 (M(C14H14O4)+H)+.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N:14]1([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>CCO>[CH2:23]([O:22][C:20]([N:14]1[CH2:19][CH2:18][N:17]([C:2]2[S:3][C:4]3[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:16][CH2:15]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCN(c2nc3ccc([N+](=O)[O-])cc3s2)CC1
Yield: 60.9 %

Procedure:
A mixture of 2-chloro-6-nitrobenzothiazole (1.00 g, 4.66 mmol), benzyl 1-piperazinecarboxylate (1.03 g, 4.66 mmol), and NaHCO3 (0.783 g, 9.32 mmol) in EtOH was heated at reflux temperature for 2 h, concentrated, and extracted with EtOAc. The combined extracts were dried over Na2SO4 and concentrated in vacuo to provide the title compound (1.13 g, 61%), characterized by NMR and mass spectral analyses.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][CH2:49][C:50](O)=[O:51])=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C1C=CN=CC=1.C(#N)C>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:14]=1)[C:50](=[O:51])[CH2:49][NH:48][C:46]([O:45][CH2:44][CH:42]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:43]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:47])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: COc1cc(-c2cc(CNCCO[Si](C)(C)C(C)(C)C)ccn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)CNC(=O)OCC3c4ccccc4-c4ccccc43)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-[2-(tert-Butyldimethylsilyloxy)ethyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amine (3.40 g), N-(9-fluorenylmethoxycarbonyl)glycine (2.34 g), diisopropylethylamine (1.03 g) and 4-(dimethylamino)pyridine (961 mg) were dissolved in acetonitrile (40 mL), and to the solution HBTU (3.13 g) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to obtain the title compound.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH:23]=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].Br[C:26]([F:33])([F:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1.[Zn]>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH:23]([OH:24])[C:26]([F:33])([F:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
A suspension of 4.38 g (67.0 mmol) of Zn powder in 40 mL of THF was treated with 0.58 mL (6.7 mmol) of 1,2-dibromoethane. The resulting mixture was heated at reflux for 2 min, then cooled to rt. Trimethylsilyl chloride (0.43 mL 3.4 mmol) was then added, the resulting mixture was stirred at ambient temperature for 20 min, the cooled to −5° C. A solution of 2.88 g (13.4 mmol) of 1-(t-butoxycarbonyl)-4-formyl piperidine and 9.52 g (46.9 mmol) of ethyl bromodifluoroacetate in 10 mL of THF was gradually added to the activated Zn. After the resulting exotherm subsided, the cooling bath was removed and the resulting mixture was stirred at rt for 20 h. The reaction was quenched with 50 mL of sat'd NH4Cl and the resulting mixture was partitioned between 300 mL of ether and 100 mL of H2O. The organic layer was separated, washed with 50 mL of sat'd NaHCO3, 50 mL of sat'd NaCl, dried and concentrated. Flash chromatography on 200 g of silica gel using 4:1 v/v, then 2:1 v/v hexanes/EtOAc as the eluants afforded 2.25 g (52%) of the title compound as an oil: 1H NMR (500 MHz, CDCl3) δ 1.31-1.34 (m, 1H), 1.37 (t, J=7.0, 3H), 1.45 (s, 9H), 1.69-1.72 (m, 2H), 1.86-1.92 (m, 2H), 2.40 (d, J=7.0, 1H), 2.68-2.72 (m, 2H), 3.83-3.90 (m, 1H), 4.104.20 (m, 2H), 4.36 (q, J=7.0, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8](=[CH:11]N(C)C)[C:9]#[N:10])=O)=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:39][C:40]([NH2:42])=[NH:41])[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[C:8]([C:9]#[N:10])=[CH:11][N:42]=[C:40]([NH:39][C:29]3[CH:30]=[CH:31][C:32]([N:33]4[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]4)=[C:27]([O:26][CH3:25])[CH:28]=3)[N:41]=2)=[CH:15][CH:16]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)C=C(C#N)C(=O)c1ccc(Cl)cc1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc(C#N)c(-c3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 2-(4-chloro-benzoyl)-3-dimethylamino-acrylonitrile (50 mg, 0.21 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (66 mg, 0.18 mmol) using in analogous manner the procedure described in example 28b). Obtained as a pale-yellow solid (10 mg, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[CH2:10][C:4]=2[CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:10][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C1Cc2cc(Cl)ccc2Oc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CN1CCN(C2=Cc3cc(Cl)ccc3Oc3ccccc32)CC1
Yield: 79.9 %

Procedure:
Thirty grams of 2-chlorodibenzo[b,f]oxepin-10(11H)-one, prepared in accordance with the procedure of Example 3, 45 grams of N-methylpiperazine and a solution of 8 grams of p-toluenesulfonic acid monohydrate in 150 ml of xylene are refluxed for a period of 22 hours in a reflux apparatus equipped with a Dean-Stark trap in order to remove the water that forms. The reaction mixture is cooled, treated with a solution of sodium bicarbonate, washed with water until the water washings are neutral, dried over anhydrous sodium sulfate and filtered through a column of neutral aluminum oxide. The filtrate is concentrated to dryness in vacuo and the residue, 46 grams, crystallized from ethanol to yield 32 grams of 1-(2-chlorodibenzo[b,f]oxepin-10-yl)-4-methylpiperazine having an m.p. of 119°-121° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C.O>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:19][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: NC1CCCCC1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Solvent: O
Solvent: CC#N
Product: CSc1nc(Cl)c(C=O)c(NC2CCCCC2)n1
Reaction time: 16 h
Yield: 99 %

Procedure:
4,6-Dichloro-2-methylsulfanylpyrimidine-5-carboxaldehyde (4.0 g, 0.018 mol) in acetonitrile (65 mL) was treated with rapid stirring with cyclohexylamine (3.76 g, 4.3 mL, 0.038 mol) over 1 min. Reaction stirred 16 h then diluted with 3 volumes of H2O. The precipitated solid was collected, washed with H2O and dried in vacuo to afford 5.1 g. (99%) of the title compound as a white solid. LC MS (m/e)=286 (MH+). Rt=2.85 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>C1COCC1>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([B:16]([OH:21])[OH:17])[CH:3]=1)#[N:6]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc(C#N)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C#N)cc1B(O)O
Reaction time: 0.25 h
Yield: 27.8 %

Procedure:
To a stirred solution of 3-bromo-4-methylbenzonitrile (3.5 g, 17.86 mmol) in dry THF at −78° C. was added n-BuLi (2N, 10.71 mL) dropwise. The mixture was stirred for 15 min., and added triisopropyl borate (6.71 g, 35.71 mmol). The reaction flask was kept in the cooling bath for 30 min., and at room temperature for 3 hours. The solvent was removed, and the residue was dissolved in ether. The organic phase was washed with 1N HCl solution and water, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was crystallized from a mixture of CH2Cl2 and hexane to give 5-cyano-2-methylphenylboronic acid (800 mg, 20%). 1H-NMR (CDCl3 400 MHz): δ7.50-7.78 (m, 2H), 7.30 (d, 1H), 2.42 (s, 3H).
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[O:1]([CH:8]([CH3:12])[C:9]([O:11][CH2:18][CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CC(Oc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)Oc1ccccc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Phenoxypropionic acid (6.64 g, 0.04 mol) is mixed with excess ethanol (10 ml) and concentrated sulfuric acid (0.5 ml) is added. The reaction mixture is refluxed for 3 hours, cooled to room temperature and concentrated. The residue is washed with 1N NaOH and brine, dried (Na2SO4), and concentrated to yield 7.32 g (94.3% yield) of the ester which can be used directly for the subsequent reaction without further purification. 1H nmr (CDCl3) δ: 7.22-7.29 (overlap 2H, phenyl H), 6.88-6.966 (overlap 3H, phenyl H), 4.10-4.20 (overlap 4H, 2CH2O), 2.73 (t, 2H. J=6.4 Hz, CH2), 1.23 (t, 3H, J=7.1 Hz, CH3); 13C nmr (CDCl3) δ: 170.7, 158.7, 129.4(2C), 120.9 114.6(2C), 63.4, 60.5, 34.5, 14.1.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH:19][C@@H:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:21])[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:29][OH:30]>C(O)C>[NH2:18]/[C:17](=[N:29]\[OH:30])/[C:14]1[CH:13]=[CH:12][C:11]([CH:10]([NH:19][C@@H:20]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH3:21])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:16][CH:15]=1
Reactant: NO
Reactant: C[C@@H](NC(CO[Si](C)(C)C(C)(C)C)c1ccc(C#N)cc1)C(=O)OC(C)(C)C
Solvent: CCO
Product: C[C@@H](NC(CO[Si](C)(C)C(C)(C)C)c1ccc(/C(N)=N/O)cc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 93.3 %

Procedure:
To a solution of tert-butyl N-[2-{[tert-butyl(dimethyl)silyl]oxy}-1-(4-cyanophenyl)ethyl]-D-alaninate (2 g, 0.0049 mol) in Ethanol (40 ml) was added 50% aqueous Hydroxylamine (1.63 ml, 0.0247 mol) at RT. The reaction mixture was heated at 70° C. for 6 h, cooled to RT and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, brine, dried over Na2SO4 and evaporated to afford (2 g, 90%) of the title compound as brown oil. 1H NMR: (DMSO-d6, 400 MHz) δ 9.57 (s, 1H), 7.61-7.59 (d, J=8.3 Hz, 2H), 7.30-7.28 (d, J=8.3 Hz, 2H), 5.76-5.74 (d, J=5.00 Hz, 2H), 4.77-4.74 (m, 1H), 3.21-3.19 (m, 1H), 2.69-2.59 (m, 1H), 1.95-1.72 (m, 1H), 1.39 (s, 9H), 1.10-1.06 (m, 3H), 0.86-0.82 (m, 9H), 0.03 (s, 3H), −0.12 (s, 3H). LC/MS (Method A): 438.3 (M+H)+. HPLC (Method A) Rt 3.82 min. (Purity: 71.1%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([NH2:17])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:27]2)=CC=1.O1CCCC1>C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15](=[S:27])[NH2:17]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCC(N)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CCC(N)=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 120 %

Procedure:
A mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propanamide (10.44 g), 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide (14.64 g) and tetrahydrofuran (300 mL) was stirred at room temperature for 2 hrs. To the reaction mixture was added ethyl acetate, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (10.7 g, 96%) of 3-(5-methyl-2-phenyl-4-oxazolyl)propanethioamide from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 167-168° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[N:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[N:34]1[CH2:40][CH2:39][CH2:38][N:37]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:36][CH2:35]1
Reactant: Fc1ccc(N2CCCNCC2)c(F)c1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCN2CCCN(c3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title A compound, 1-(2,4-difluorophenyl)-1,4-diazepane (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography using a 95/5.0/0.5-mixture of DCM/MeOH/NH4OH as eluent to give 7-(2-(4-(2,4-difluorophenyl)-1,4-diazepan-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=479.01). 1H NMR (DMSO-d6, 400 MHz) δ 1.82 (m, 2H), 2.71 (m, 2H), 2.82 (m, 2H), 2.88 (t, 2H, J=6.4 Hz), 3.24 (m, 4H), 4.22 (t, 2H, J=6.4 Hz), 6.57 (d, 1H, J=3.6 Hz), 6.71 (m, 1H), 6.85-6.94 (m, 2H), 7.09 (m, 1H), 7.14 (d, 1H, J=3.6 Hz), 7.19 (d, 1H, J=3.2 Hz), 7.51 (br s, 2H, NH2), 7.92 (s, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([Cl:17])[CH:14]=[N:13]1.[CH3:23]O>>[CH3:23][O:20][C:19](=[O:21])[CH:18]([C:8]1[CH:9]=[CH:10][C:11]([N:12]2[CH:16]=[C:15]([Cl:17])[CH:14]=[N:13]2)=[C:6]([Cl:5])[CH:7]=1)[CH3:22]
Reactant: CC(C(=O)O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Yield: 86.9 %

Procedure:
100 ml of thionyl chloride are added to 28.51 g (0.1 mole) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid and heated to the boil for half an hour. The solution is concentrated in a vacuum, and 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid chloride is thus obtained. 500 ml of absolute methanol are added; and, again, heating to the boil for half an hour and concentrating are effected, followed by taking up in benzene, washing with water and sodium hydrogen carbonate solution, drying of the organic solution and distilling to produce 26 g (86.9% of theory) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid methyl ester (b.p. 126° to 127° C./10-2 mm Hg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([O:11]C)=O.[CH3:17][P:18](=[O:23])([O:21][CH3:22])[O:19][CH3:20]>>[CH3:20][O:19][P:18]([CH2:17][C:9](=[O:11])[CH:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:13][CH2:14][CH2:15][CH3:16])(=[O:23])[O:21][CH3:22]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(OC1CCCCO1)C(=O)OC
Product: CCCCC(OC1CCCCO1)C(=O)CP(=O)(OC)OC

Procedure:
Prepared from methyl 2-(2-tetrahydropyranyl)oxycaproate and dimethyl methylphosphonate according to the known method. (Yield 48%).
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]([CH2:21][C:22](OCC)=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[C:13]([CH2:21][C:22]([NH:6][C:5]1[CH:7]=[C:8]([Cl:9])[C:2]([Cl:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: O=C(CC(=O)c1ccccc1)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 180 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
A mixture of 4,5-dichloro-2-nitroaniline (2.07 g, 10 mmol) and ethyl benzoylacetate (technical, 5 mL, approximately 22 mmol) was heated at 180° C. for 16 h under stirring. It was cooled to 150° C. and kept at this temperature under aspirator vacuum for 5 h, then cooled to room temperature. Chloroform (50 mL) was added and the mixture was evaporated, then diluted with ether (200 mL) and cooled to -10° C. Precipitate was filtered and washed with ether (5×50 mL) to give 2.12 g (60%) of the title compound as an orange solid: mp 177°-179° C. (from EtOH); IR (KBr) 3330, 1693, 1670, 1561, 1472, 1340, 1233, and 764 cm-1 ; 1H NMR (DMSO-d6) δ4.24 (s, 2H), 7.53 (m, 2H), 7.65 (m, 1H), 7.77 (d, 1H, J=7.6 Hz), 7.97 (d, 1H, J=7.6 Hz), 8.11 (s, 1H), 8.23 (s, 1H), 10.70 (s, 1H, N--H). HRMS Calcd for C15H10N2O4Cl2 : 352.0018. Found: 352.0020.