Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([OH:21])[C:18](O)=[O:19])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.S(Cl)(Cl)=O.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=1.CCN(CC)CC>C(Cl)Cl>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:16][CH:17]([OH:21])[C:18]([NH:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([O:27][CH3:26])[CH:29]=3)=[O:19])[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: COc1cccc(N)c1
Reactant: O=C(O)C(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1cccc(NC(=O)C(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Temperature: 0 °C
Yield: 47.5 %

Procedure:
3-(3,6-Dibromo-9H-carbazol-9-yl)-2-hydroxypropanoic acid (0.025 g, 0.061 mmol) was suspended in anhydrous CH2Cl2 and cooled to 0° C. Thionyl chloride (0.005 mL, 0.073 mmol) was added dropwise and the reaction was stirred at 0° C. for 1 h. m-Anisidine (0.008 mL, 0.073 mmol) and Et3N (0.010 mL, 0.073 mmol) were added and the reaction was allowed to warm to ambient temperature over 2.5 h. Upon completion, the solution was partitioned between EtOAc and H2O. The aqueous layer was washed 3× with EtOAc, and the combined organics were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by chromatography (SiO2, 0-30% EtOAc/Hexane) to afford the desired product (15 mg, 48%).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16](=[O:18])[C:15]([CH2:19][CH2:20][CH3:21])=[C:14](Cl)[C:13]=2[CH:23]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>C(O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16](=[O:18])[C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([NH:28][CH2:27][CH2:26][O:25][CH3:24])[C:13]=2[CH:23]=1
Reactant: COCCN
Reactant: CCCc1c(Cl)c2cc(Br)ccc2oc1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCc1c(NCCOC)c2cc(Br)ccc2oc1=O

Procedure:
Triethylamine was added to a solution of 6-bromo-4-chloro-3-propyl-2H-1-benzopyran-2-one (0.5 g), in dry ethanol (10 ml) followed by 2-methoxyethylamine (0.16 ml). The mixture was heated at reflux under nitrogen overnight, evaporated and the residue extracted with ethyl acetate and the extract washed with dilute hydrochloric acid, brine, dried and evaporated under reduced pressure. The residue was triturated with ethanol and light petroleum (b.p. 40-60° C.) to give 6-bromo-4-(2-methoxyethylamino)-3-propyl-2H-1-benzopyran-2-one, m.p. 75-7° C. (compound 21).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH:16](OCC)O)=[CH:11][C:10]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24])C1C=CC=CC=1.[CH3:27][C:28]([NH2:37])([CH3:36])[CH2:29][CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1>>[CH3:36][C:28]([NH:37][CH2:16][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:11]=1)[OH:21])([CH3:27])[CH2:29][CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: CC(C)(N)CCn1cncn1
Product: CC(C)(CCn1cncn1)NCC(O)c1ccc(O)c(NS(C)(=O)=O)c1

Procedure:
The target compound is prepared analogously to the methods described for Example 7 from 379 mg (1 mmol) N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 154 mg (1 mmol) 1,1-dimethyl-3-[1,2,4]triazol-1-yl-propylamine. Colourless solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[N:5][CH:4]=1.O.O.O.[C:18]([O-])(=[O:20])[CH3:19].[Na+].C(OC(=O)C)(=O)C>O>[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:18](=[O:20])[CH3:19])[CH2:13][CH2:14]2)[CH:6]=[N:5][CH:4]=1
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCN(c2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Chloro-2-(1-piperazinyl)-pyrazine hydrochloride (15 g, 0.064 mole) is added to a solution of 20 g of sodium acetate trihydrate (0.147 mole) in 250 ml ice water. The vigorously stirred mixture is treated with 15 ml acetic anhydride followed by 100 ml water. The mixture is stirred 3 hours while warming to room temperature and the product, which separates as an oil, is extracted with toluene. The toluene extract is washed with water and concentrated in vacuo to give a crude product which is recrystallized twice from n-butylchloride to give the title compound, mp 106°-107.5° C.
Reaction SMILES: [C:1]([Cl:4])(=O)C.Cl.[C:6]([C@H:9]1[CH2:18][C@H:17]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=2)=[O:21])[C:16]2[C:11](=[CH:12][C:13]([Cl:31])=[CH:14][C:15]=2[Cl:30])[NH:10]1)([OH:8])=[O:7]>CO.Cl.CO>[ClH:4].[ClH:30].[CH3:1][O:7][C:6]([C@H:9]1[CH2:18][C@H:17]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=2)=[O:21])[C:16]2[C:11](=[CH:12][C:13]([Cl:31])=[CH:14][C:15]=2[Cl:30])[NH:10]1)=[O:8]
Reactant: NCc1cccc(C(=O)N[C@H]2C[C@H](C(=O)O)Nc3cc(Cl)cc(Cl)c32)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2cccc(CN)c2)c2c(Cl)cc(Cl)cc2N1
Reaction time: 2 h

Procedure:
A solution of hydrogen chloride in methanol was prepared by the cautious addition of acetyl chloride (6 ml) to ice-cooled methanol (25 ml). Trans-2-carboxy-5,7-dichloro-4-(3-aminomethylphenyl)carbonylamino-1,2,3,4-tetrahydroquinoline hydrochloride (87 mg, 0.202 mmol) (Example 81) was dissolved in the HCl/methanol solution and the resulting mixture was stirred in a stoppered flask for 2 h. The methanol and excess hydrogen chloride were removed in vacuo and the product recrystallised from methanol/ether to give the title compound as a colourless crystalline solid (80 mg) m.p. 173° C. (dec). δ (DMSO, 360 MHz) 1.94 (1H, ddd, J=13.7, 13.4 and 3.8 Hz, CHACHBHCCHD), 2.51 (1H, dm J=13.7 Hz, CHACHBHCCHD), 3.81 (3H, s, CH3), 4.10 (1H, dd, J=12.6 and 2.7 Hz, CHACHBHCCHD), 4.23 (2H, s, CH2NH2), 5.36 (1H, m, CHACHBHCCHD), 6.81 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.91 (1H, d, J=2.0 Hz, 6-H or 8-H), 7.56 (1H, t, J=7.7 Hz, Ar-H), 7.65 (1H, d, J=7.8 Hz, Ar-H), 7.77 (2H, m, Ar-H); m/e (FAB+), 408 (M+1), 93 (100%); Found C, 49.05; H, 4.43; N, 8.94; C19H19Cl2N3O3. 1.5HCl requires C, 49.29; H, 4.46; N, 9.08%.
Reaction SMILES: [N+:1]([C:4]1[C:9](F)=[CH:8][CH:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])([O-])=O.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:31]2[CH2:30][CH2:29][N:28]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:33][CH2:32]2)=[CH:6][C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1c(F)cccc1NS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 29.5 %

Procedure:
A mixture of N-(2-nitro-3-fluorophenyl)-benzenesulfonamide (4.68 g, 15.7 mmol), Boc-piperazine (3.5 g, 18.9 mmol) and K2CO3 (3.8 g, 27.8 mmol) in DMF was stirred at 70° C. for 24 h. The mixture was filtered and purified by column chromatography (SiO2, CH2Cl2/MeOH/heptane/NH3 4:1:5:0.2%) to give 2.0 g of desired product. 1H-NMR δ 7.98 (d, 1H), 7.89-7.84 (m, 2H), 7.63-7.50 (m, 3H), 7.00 (d, 1H), 6.68 (dd, 1H), 3.59-3.45 (m, 8H), 1.49 (s, 9H); MS (posES-FIA) m/z=found: 485.0 (M++Na+). The product (1.85 g, 4.00 mmol) was dissolved in EtOH:THF (4:1) followed by addition of Raney-Ni and hydrazine (1.0 mL, 20 mmol). The reaction was stirred at room temperature for 3 h until the yellow color disappeared. Filtration through wet Celite, followed by removal of the solvent afforded 1.26 g of N-(2-amino-5-(4-tert-butoxycarbonyl-1-piperazinyl)-phenyl)-benzenesulfonamide which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:17]#[N:18].[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)#[N:18]
Reactant: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Cl
Reactant: Nc1ccc2ncccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1ccc2ncccc2c1
Reaction time: 20 h
Yield: 115.7 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-cyclopropylpropanamide (80 mg, 0.301 mmol), 6-aminoquinoline (60 mg, 0.416 mmol), K2CO3 (65 mg, 0.471 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give a crude (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (130 mg). The crude (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (130 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (35 mg). MS 392.2 (M+H); UV 203.6, 266.4, 299.0, 358.5 nm; t 0.406 min.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:27]O>O>[C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([O:21][CH3:27])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Yield: 72 %

Procedure:
[2-(1-Cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetic acid (1.42 g) and conc. sulfuric acid (0.2 ml) were dded to methanol (30 ml) and the mixture was refluxed for 3 hours. Then, water was added. The mixture was extracted with ethyl acetate and the extracted layer was washed and dried. Ethyl acetate was distilled off under reduced pressure and the residue was recrystallized from hexane-ethyl acetate to obtain the title compound, m.p. 137°-138° C., yield 72%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.[OH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[N:27]([CH3:35])[C:26]=1[CH3:36])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>>[OH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([O:34][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:31][CH:32]=2)[N:27]([CH3:35])[C:26]=1[CH3:36])=[O:24]
Reactant: Cc1c(C(=O)NCCCO)c2ccc(O)cc2n1C
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)NCCCO)c2ccc(Oc3ccnc4cc(C(=O)N5CCCC5)sc34)cc2n1C

Procedure:
This material was prepared from the reaction of (7-chloro-thieno[3,2-b]pyridin-2-yl)-pyrrolidin-1-yl-methanone with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid (3-hydroxy-propyl)-amide 63b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ8.44 (1H, d, J=5.5 Hz), 7.85 (1H, s), 7.83 (1H, d, J=10.0 Hz), 7.35 (1H, d, J=1.9 Hz), 7.01 (1H, dd, J=1.9, 8.5 Hz), 6.66 (1H, d, J=5.5 Hz), 3.88 (2H, m), 3.67 (7H, m), 3.54 (2H, m), 2.63 (3H, s), 1.83-2.10 (6H, m). LCMS (ESI+) [M+H]/z Calc'd 493, found 493.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5](=[CH:7][CH2:8][CH2:9][CH:10]([CH2:12][CH:13]=[O:14])[CH3:11])[CH3:6].[Cl-].[NH4+]>CCOCC>[CH3:11][CH:10]([CH2:9][CH2:8][CH:7]=[C:5]([CH3:6])[CH3:4])[CH2:12][CH:13]([OH:14])[CH3:1]
Reactant: CC(C)=CCCC(C)CC=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)=CCCC(C)CC(C)O

Procedure:
Eighty ml. of a 3M solution of methylmagnesium bromide in ether is added slowly to 31 g. of citronellal in 250 ml. of dry ether. The mixture is heated at reflux for about 1 hour, cooled to 0° and treated with saturated aqueous ammonium chloride until reaction subsides. The organic layer is separated and the aqueous layer extracted with ether. The organic layer and ether extracts are combined, washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent gives 4,8-dimethylnon-7-en-2-ol.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=1.C(N(CC)CC)C>O>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](=[CH:14][C:13]2[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=2)[C:26]([OH:28])=[O:27])=[CH:23][CH:24]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CSc1ccc(C=C(C(=O)O)c2ccc(Br)cc2)cc1
Temperature: 90 °C
Yield: 44.4 %

Procedure:
A mixture of acetic anhydride (100 mL), 4-(methylthio)benzaldehyde (12.61 g, 82.8 mmol), 4-bromophenylacetic acid (17.79 g, 82.7 mmol), and triethylamine (8.48 g, 83.8 mmol) was heated to reflux for 4.25 hours. The reaction was cooled to 90° C., and water (100 mL) was added through an addition funnel. A yellow solid separated from the solution and was isolated by filtration and air dried and recrystallized from a mixture of ethyl acetate and isooctane to afford the acid (12.83 g, 44%): mp 187°-190° C. 1H NMR (acetone d6) 300 MHz 7.83 (s,1H), 7.57 (d, J=8.5Hz, 1H), 7.20 (d, J=8.5Hz, 2H), 7.10 (d, J=8.1Hz, 2H), 7.08 (d, J=8.1Hz, 1H), 2.46 (s, 3H). Mass spectrum M+ +H=350.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:3]=1.[C:17](#[N:19])[CH3:18].Cl.C(O)(=O)C>C(Cl)(Cl)Cl.[NH4+].[OH-].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:17]([NH2:19])[CH3:18])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1Cc1ccccc1F
Reactant: CC#N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)=Nc1ccc(Cl)cc1Cc1ccccc1F
Reaction time: 1 h

Procedure:
In 500 ml three-necked flask fitted with a stirrer, gas inlet tube, and a double condenser is placed 13.65 g (50 mmoles) of 4-chloro-2[(2-fluorophenyl)methyl]benzenamine and 200 ml of acetonitrile. Hydrogen chloride gas is bubbled into this stirred suspension. The temperature rises to ca. 38° C. and a solution is formed in about 10 min. The reaction mixture is then heated to gentle reflux while maintaining a stream of hydrogen chloride throught the reaction mixture. After 1 hr TLC of an aliquent using 2% acetic acid, 10% MeOH in CHCl3 or 1% NH4OH/20% MeOH in CHCl3 on fluorescent silica plates shows only a trace of starting material. The reaction mixture is then concentrated in vacuo to a pale semi-solid. This is partitioned between 100 ml of methylene chloride and ca 30 ml of 3 N sodium hydroxide. The aqueous phase is back extracted with 100 ml of methylene chloride. The organic phases are combined, washed with 50 ml of brine, dried over potassium carbonate and concentrated in vacuo to pale yellow oil. This oil is crystallized from hexane with a little methylene chloride to give end product of m.p. 115°-119° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[N:4]=[C:5]([NH2:7])[S:6][C:2]=2[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:9][CH:10]=1
Reactant: Nc1nc(-c2ccc(F)cc2)c(Br)s1
Reactant: C1COCCN1
Product: Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1

Procedure:
5-Bromo-4-(4-fluoro-phenyl)-thiazole-2-ylamine and morpholine (6 eq) were stirred for 30 minutes at 120 C, under microwave heat. Triturated with ethyl acetate/n-Heptane solvent mixture (1:2 ratio) to afford the title compound pure. LCMS Method A Rt=1.14 (M+1=280.0, M−1=278.1). 1H NMR (400 MHz, DMSO-D6) 2.67-2.75 (m, 4H) 3.67-3.74 (m, 4H) 6.87 (s, 2H) 7.14-7.20 (m, 2H) 8.11 (ddd, J=12.41, 5.53, 3.03 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:28]OC(=O)C(C)(C)C)[C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[C:10](=[O:36])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:42])(=[O:41])[CH2:39][OH:40].Cl.C(O)C>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:28][O:40][CH2:39][C:38]([OH:42])=[O:41])[C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:27]=3)=[CH:17][CH:16]=2)[C:10](=[O:36])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Reactant: O=C(O)CO
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)COCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Yield: 52.7 %

Procedure:
In 30 ml of ethyl acetate was dissolved 1 g of 1-benzyl-4-{4-[N-pivaloyloxymethyl-N-(2-pyrimidinyl)-amino]benzyl}-2,3-dioxopiperazine, and 1 g of glycolic acid and 0.02 ml of N hydrogen chloride-ethanol solution were added, after which the resulting mixture was subjected to reaction at room temperature for 3 hours with stirring. After the completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was extracted with 100 ml of methylene chloride. The methylene chloride layer was washed with 30 ml of water and then 30 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (Wakogel C-200, eluted with chloroformethanol), and recrystallized from ethyl acetate-diisopropyl ether, to obtain 0.5 g (52.8% yield) of 1-benzyl-4-{4-[N-carboxymethoxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine having a melting point of 85° to 90° C.
Reaction SMILES: CN1CCC(=C2C3C(=CC=CC=3)C=CC3C2=CC=CC=3)CC1.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([C@H:33]([N:36]2[CH2:40][CH2:39][C@H:38]([O:41][CH2:42][O:43][CH3:44])[CH2:37]2)[CH2:34][OH:35])[CH:30]=[CH:31][CH:32]=1.[CH3:45][O:46][CH2:47][O:48][C:49]1[CH:50]=[C:51]([C@@H:55]([OH:66])[CH2:56][N:57]2[CH2:61][CH2:60][C@H:59]([O:62][CH2:63][O:64][CH3:65])[CH2:58]2)[CH:52]=[CH:53][CH:54]=1.[CH3:67][NH:68][C:69]1[CH:78]=[CH:77][C:72]([C:73]([O:75][CH3:76])=[O:74])=[CH:71][CH:70]=1>>[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([C@H:33]([N:36]2[CH2:40][CH2:39][C@H:38]([O:41][CH2:42][O:43][CH3:44])[CH2:37]2)[CH2:34][OH:35])[CH:30]=[CH:31][CH:32]=1.[CH3:45][O:46][CH2:47][O:48][C:49]1[CH:50]=[C:51]([C@@H:55]([OH:66])[CH2:56][N:57]2[CH2:61][CH2:60][C@H:59]([O:62][CH2:63][O:64][CH3:65])[CH2:58]2)[CH:52]=[CH:53][CH:54]=1.[CH3:45][O:46][CH2:47][O:48][C:49]1[CH:50]=[C:51]([C@@H:55]([N:68]([C:69]2[CH:78]=[CH:77][C:72]([C:73]([O:75][CH3:76])=[O:74])=[CH:71][CH:70]=2)[CH3:67])[CH2:56][N:57]2[CH2:61][CH2:60][C@H:59]([O:62][CH2:63][O:64][CH3:65])[CH2:58]2)[CH:52]=[CH:53][CH:54]=1
Reactant: CNc1ccc(C(=O)OC)cc1
Agent: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: COCOc1cccc([C@@H](CO)N2CC[C@H](OCOC)C2)c1
Agent: COCOc1cccc([C@@H](O)CN2CC[C@H](OCOC)C2)c1
Product: COCOc1cccc([C@H](CN2CC[C@H](OCOC)C2)N(C)c2ccc(C(=O)OC)cc2)c1

Procedure:
2-(S)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and 1-(R)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol were prepared from (R)-1-(3-methoxymethoxyphenyl)-1,2-ethanediol-2-tosylate in 58% yield as a mixture according to the procedures similar to those described in Preparation 3. Title compound was prepared by reactin, the mixture of 2-(S)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and 1-(R)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol wth methyl 4-methylaminobenzoate in 54% yield according to the procedures similar to those described in Example 1 (i).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Si:21]([O:28][C@H:29]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[CH:36][C:37](Cl)=[N:38][CH:39]=2)[CH2:30]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>>[Si:21]([O:28][C@H:29]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[CH:36][C:37]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[C:8]5[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]=5[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:10]=4[N:11]=3)=[N:38][CH:39]=2)[CH2:30]1)([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22]
Reactant: Nc1ncc2c3ccnc(F)c3n(C3CCCC3)c2n1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(c2ccc(Cl)nc2)C1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)C1

Procedure:
Compound 280 was prepared from compound 245 and (S)-5-(3-(tert-butyldimethylsilyloxy)-pyrrolidin-1-yl)-2-chloropyridine using methods described in Example 186a.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH:10]([CH3:23])[N:9]=1.[CH2:24]([N:27]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]1=2)[C:25]#[CH:26].C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][N:27]3[C:40](=[O:41])[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]3=4)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH:10]([CH3:23])[N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2C
Reactant: C#CCn1c(=O)c2ccccc2c2ccccc21
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc2n1-c1sc(C#CCn3c(=O)c4ccccc4c4ccccc43)cc1C(c1ccccc1Cl)=NC2C

Procedure:
This compound was prepared by reacting rac-4-(2-chloro-phenyl)-2-iodo-6,9-dimethyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3a][4,1]diazepine (from example 108) with 5-(2-propynyl)-6(5H) phenanthridinone under the conditions described in example 37. The product was isolated by chromatography over the 50 -fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The product was crystallized from ethanol to give yellowish crystals of the title compound with mp, 182°-186° with foaming. These crystals contained according to analytical data molar amounts of water.