Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[NH2:22][CH2:23][C@H:24]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:4]1[C:3]([CH3:21])=[C:2]([Cl:1])[N:7]=[C:6]([NH:22][CH2:23][C@H:24]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25]2)[C:5]1=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)nc(NC[C@H]2CCN(C(=O)OC(C)(C)C)C2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 97.9 %

Procedure:
A mixture of benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (647 mg, 1.98 mmol), tert-butyl (3R)-3-aminomethyl-1-pyrrolidinecarboxylate (preparation 80), (398 mg, 1.98 mmol) and triethylamine (830 ml, 5.95 mmol) in ethyl acetate (25 ml) was heated under reflux for 18 hrs. The cooled mixture was washed consecutively with water, 1N citric acid solution, brine, then dried over MgSO4, and evaporated under reduced pressure to give the desired compound as a gum, (952 mg, 98%).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.Cl[C:11]1[C:12]([NH2:33])=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[C:21]([S:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=2[CH3:32])[N:16]=1>C1COCC1>[CH3:32][C:18]1[CH:19]=[CH:20][C:21]([S:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)[C:12]([NH2:33])=[N:13][CH:14]=1
Reactant: Nc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1cnc(N)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1cnc(N)c(Nc2cccnc2)n1

Procedure:
A suspension of NaH (60% dispersion in oil) (12 mg, 0.298 mmol) is stirred in THF (3 ml). Pyridine-3-ylamine (28 mg, 0.293 mmol) is added and gas evolved. Once all gas production is stopped 3-Chloro-5-[2-methyl-5-(morpholine-4-sulfonyl)-phenyl]-pyrazin-2-ylamine (Intermediate M) (100 mg, 0.271 mmol) in THF (3 ml) is added. The reaction mixture is microwaved at 120° C. for 10 minutes. More NaH (60%) (33 mg, 0.813 mmol) is added to the reaction mixture and the sample is microwaved at 120° C. for 40 minutes. The reaction is quenched with water (100 ml) and evaporated to dryness in vacuo. The brown residue is purified by reverse phase column chromatography to yield the title compound as a brown glass. 1H NMR (400 MHz, DMSO-d6) δ 9.14 (1H, d), 8.99 (1H, s), 8.38-8.33 (3H, m), 7.81 (1H, s), 7.70 (1H, d), 7.66-7.60 (5H, m), 3.64 (4H, t), 2.88 (4H, t), 2.54 (3H, s); MS m/z 427 [M+H]+
Reaction SMILES: [BH4-].[Na+].[CH:3]1([C:6]2[NH:10][N:9]=[C:8]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([C:19]4[S:23][C:22]([C:24](=[O:26])[CH3:25])=[CH:21][CH:20]=4)[N:13]=3)[CH:7]=2)[CH2:5][CH2:4]1>C1COCC1.CO>[CH:3]1([C:6]2[NH:10][N:9]=[C:8]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([C:19]4[S:23][C:22]([CH:24]([OH:26])[CH3:25])=[CH:21][CH:20]=4)[N:13]=3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: CC(=O)c1ccc(-c2ncc(F)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1ccc(-c2ncc(F)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
NaBH4 (220 mg, 5.82 mmol, 5.0 equiv.) was added to a solution of 1-(5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyrimidin-2-yl)thiophen-2-yl)ethanone (Compound 137) (400 mg, 1.17 mmol, 1.0 equiv.) in dry THF (10 mL) and methanol (10 mL) at 0° C. The mixture was stirred for 1 hour, quenched (crashed ice) and concentrated. The residue was recrystallized with methanol and isopropyl ether to give the racemic 1-(5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyrimidin-2-yl)thiophen-2-yl)ethanol (350 mg, 87%). LC-MS (m/z)=346.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[C:5]=1[NH2:12].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>O>[Cl:11][C:6]1[C:5]([NH:12][S:15]([CH3:14])(=[O:17])=[O:16])=[C:4]([CH:9]=[CH:8][C:7]=1[Cl:10])[C:3]([O:2][CH3:1])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(Cl)c(Cl)c1N
Solvent: O
Product: COC(=O)c1ccc(Cl)c(Cl)c1NS(C)(=O)=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
A mixture of methyl-2-amino-3,4-dichlorobenzoate (2.2 g) and methanesulphonyl chloride (2.86 g) was stirred at 100° C. for 4 hours. A further quantity of methanesulphonyl chloride (2.86 g) was added and the mixture was stirred at 100° C. overnight. The mixture was poured into water then extracted with ethyl acetate. The combined organic extracts were washed with water, dried (magnesium sulphate) and evaporated to yield a brown oil which was crystallised from cyclohexane/ethyl acetate to yield methyl 3,4-dichloro-2-(methylsulphonylamino)benzoate as light brown crystals (1.4 g), m.p. 100-102° C.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH:9]([CH2:13][CH2:14][OH:15])[CH2:10][CH2:11][OH:12]>>[CH2:1]([N:9]([CH2:13][CH2:14][OH:15])[CH2:10][CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC=O
Reactant: OCCNCCO
Product: CCCCCCCN(CCO)CCO

Procedure:
The n-heptyldiethanolamine is prepared from n-heptanal and diethanolamine (DEoA).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:4][C:3]=1[CH3:13].[CH3:14][Mg]Br>O1CCCC1.O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][CH:11]([OH:12])[CH3:14])=[CH:4][C:3]=1[CH3:13]
Reactant: C[Mg]Br
Reactant: Cc1cc(CCC=O)cc(C)c1Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(CCC(C)O)cc(C)c1Br
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-bromo-3,5-dimethylphenyl)propanal (120 mg) in tetrahydrofurane (2 mL) is added at 0° C. methylmagnesium bromide (800 μL of a 1.4 M solution in tetrahydrofurane/toluene 1:3). After stirring for 30 minutes the mixture is partitioned between saturated aqueous NH4Cl solution and diethylether. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. Yield: 130 mg; LC (method 8): tR=0.37 min; Mass spectrum (ESI+): m/z=274 [M+NH4]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][C:20]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:20]=3[CH3:19])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C)cc3C)CC2)ccc1Cl
Yield: 8 %

Procedure:
The title compound (3 mg, 8%) was prepared analogously to example 8 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 2,4-dimethylbenzoic acid. MS: 401.4 (MH+).
Reaction SMILES: C(S([C:6]1[N:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1)(=O)=O)C.[OH-:16].[Na+].Cl>>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:8]=[N:7][C:6](=[O:16])[NH:11][CH:10]=1
Reactant: CCS(=O)(=O)c1ncc(C(F)(F)F)cn1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=c1ncc(C(F)(F)F)c[nH]1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
2-Ethylsulfonyl-5-trifluoromethylpyrimidine (4.7 mmol) was added to 1M NaOH, the mixture stirred at 5° C. for 10 min, then at room temperature for 10 min and finally the pH was adjusted to 2 with HCl. After filtration the filtrate was evaporated, the residue dried and extracted with benzene, the benzene solution evaporated, the residue extracted with boiling ethyl acetate, (3×40 ml), and the ethyl acetate solution evaporated to yield the product; yield 0.50 g (67%). For final purification the product was sublimed at 110°-120° C./0,01 mmHg; m.p. 154° C., 1H NMR (DMSO-d6): δ 8.50 (H-4, H-6), MS [70 eV; m/z (% rel. int.)] 164 (99, M), 145 (21), 136 (100), 117 (25), 116 (16), 109 (11), 90 (28), 89 (40), 75 (35). IR (KBr): 1690 cm-1 (CO).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]=1[C:15]1[C:16]2[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=2[N:18]=[CH:19][N:20]=1.[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:39][CH2:38][C@@H:37]([NH2:40])[CH2:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:35][CH2:36][C@@H:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH2:3][O:2][CH3:1])[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:38][CH2:39]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A72) and commercially available cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:14]3[CH:24]=[CH:25][C:26]([O:28]C)=[CH:27][C:13]=3[N:12]=2)[CH2:6][CH2:5]1.[BrH:30]>O>[OH2:28].[BrH:30].[BrH:30].[BrH:30].[NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:14]3[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:13]=3[N:12]=2)[CH2:6][CH2:5]1
Reactant: COc1ccc2c(c1)nc(NC1CCN(CCN)CC1)n2Cc1ccc(F)cc1
Agent: Br
Solvent: O
Product: NCCN1CCC(Nc2nc3cc(O)ccc3n2Cc2ccc(F)cc2)CC1
Temperature: 80 °C
Yield: 95.7 %

Procedure:
A mixture of 12 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-5-methoxy-1H-benzimidazol-2-amine and 150 parts of a hydrobromic acid solution 48% in water was stirred and heated for 48 hours at 80° C. The reaction mixture was evaporated and the residue was suspended in 2-propanol. The product was filtered off and dried, yielding 18.5 parts (95.7%) of 2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-5-ol trihydrobromide monohydrate; mp. +250° C. (intermediate 140).
Reaction SMILES: CC(C)([O-])C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH3:30])[CH:28]=2)[C:23]([CH:31]=O)=[CH:22]1.CO>COCCOC>[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH3:30])[CH:28]=2)[C:23]([CH2:31][C:17]#[N:18])=[CH:22]1
Reactant: Cc1ccc2c(C=O)cn(C)c2c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: Cc1ccc2c(CC#N)cn(C)c2c1
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
A suspension of potassium tert-butoxide (KOtBu) (2.21 g, 19.7 mm) in DME (30 mL) was cooled to -30° C., and treated with a solution of TosMIC (1.97 g 10.1 mm). After addition was complete, the mixture was further cooled to -60° C., treated with 1,6-dimethyl-1H-indole-3-carboxaldehyde (5.8 mm) in DME(20 mL), and stirred at that temperature for 1.5 hours. Addition of methanol (15 mL) to the cooled solution, was followed by heating to reflux temperature for 15 minutes, and evaporation of the solvent. The residue was treated with H2O (20 mL) containing acetic acid (HOAc) (0.75 mL), then extracted with CH2Cl2 (50 mL×3). The combined organic fractions were extracted with saturated NaHCO3 solution, dried over MgSO4, filtered and evaporated. Purification by flash column chromatography afforded (1,6-dimethyl-1H-indol-3-yl)-acetonitrile (0.86 g, 81%).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[Na+]>ClCCl>[C:30]([N:13]1[CH2:14][CH2:15][CH2:16][N:10]([CH2:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:12]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(C(CCN2CCCNCC2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCCN(CCC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The resulting 1-(3,3-diphenylpropyl )homopiperazine was dissolved in 3 mL of dichloromethane, followed by adding 107 mg of triethylamine and 140 mg of benzoyl chloride. After the mixture was stirred at room temperature for 6 hours, it was mixed with 20 mL of aqueous 2N sodium hydroxide and extracted with 20 mL×2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, hexane/ethyl acetate 4:6) to obtain 249 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure and the residue was dried to give the hydrochloride salt of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(Nc2ccccc2)c2ccccc2n1

Procedure:
A solution of 2,4-dichloro-quinazoline (15 g), N,N-diisopropyl-ethylamine (24.9 ml) and aniline (7.5 ml) in isopropanol (75 ml) is heated to reflux for 45 min. The cold reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is crystallized from diethylether- toluene (1:1) to give 2-chloro-4-phenylamino-quinazoline, m.p. 194-196° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][S:8][C:9]([CH3:38])([CH3:37])[C:10]([NH:12][CH2:13][CH2:14][N:15]([CH2:34][CH2:35][NH2:36])[CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]([CH3:32])([S:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH3:21])=[O:11])=[CH:5][CH:4]=1.[C:41](Cl)(Cl)=[S:42]>ClCCl>[CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][S:8][C:9]([CH3:38])([CH3:37])[C:10]([NH:12][CH2:13][CH2:14][N:15]([CH2:34][CH2:35][N:36]=[C:41]=[S:42])[CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]([CH3:32])([S:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH3:21])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CSC(C)(C)C(=O)NCCN(CCN)CCNC(=O)C(C)(C)SCc2ccc(OC)cc2)cc1
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CSC(C)(C)C(=O)NCCN(CCN=C=S)CCNC(=O)C(C)(C)SCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a round bottom flask containing the aniline 24 (28.8 mg, 0.0487 mmol) and dichloromethane (10 mL) was added 0.2211 M solution of thiophosgene (0.22 mL, 0.0509 mmol) in dichloromethane. The heterogeneous reaction mixture was stirred at room temperature for 1 hour and the solvent was removed in vacuo. Flash chromatography of this crude product using 100% EtOAc gave the isothiocyanate 25 as a clear oil (18.9 mg, 61.3% yield). 1H NMR (in CDCl3): δ7.17 (d,j=8.5 Hz,4H,2H3 &H5 --Ar--OCH3), 7.07 (m,2H,2NH--CO), 6.82 (d,j=8.5 Hz,4H,2H2 &H6 --Ar--OCH3), 3.78 (s,6H, 2CH3O), 3.70 (s,4H,2S--CH2 --Ar), 3.49 (t,j=5.9 Hz,2H,N--CH2CH2 -NCS ), 3.21 (q,j=6.2 Hz,4H,2N--CH2CH2 --NHCO), 2.78 (t,j=5.9 Hz,2H,N--CH2CH2 --NCS), 2.58 (t,j=6.4 Hz,4H, 2N--CH2CH2 --NHCO), 1.54 (s,12H,4CH3 --C--S) ppm. MS (m/z,CI): 633(25, MH+). IR (CDCl3): 3370, 2950, 2920, 2850, 2100, 1720, 1655, 1610, 1510, 1245, 1170, 1030, 830 cm-1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.CCOC(C)=O>[N:13]([CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2)=[N+:14]=[N-:15]
Reactant: ClCc1cccc2cnccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cccc2cnccc12
Reaction time: 3 h

Procedure:
To a solution of 0.0415 g (0.23 mmol) 16 in 3 mL DMF was added 0.0169 g (0.26 mmol) sodium azide. After a 3 h, an additional 0.0033g (0.05 mmol) portion of sodium azide was added. After 24 h at room temperature, the reaction mixture was diluted with 50 mL EtOAc and washed with 20 mL brine. The aqueous layer was extracted with 10 mL EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (10×175 mm silica gel, linear gradient 5-20% EtOAc:hexane) produced 17. 1H NMR (CDCl3, 400 MHz) δ 9.318 (s, 1H, ArH); 8.637 (d, 1H, J=6.10 Hz, ArH); 8.010 (d, 1H, J=7.94 Hz, ArH); 7.822 (d, 1H, J=6.10 Hz, ArH); 7.713 (d, 1H, J=7.02 Hz, ArH); 7.617 (dd, 1H, J=7.17, 8.09 Hz, ArH); 4.774 (s, 1H, ArH); MS (Electrospray): m/z 185.0 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH:18]1([CH:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[NH2:22])[CH2:20][CH2:19]1>>[CH:18]1([CH:21]([NH:22][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:19][CH2:20]1
Reactant: Cc1nc(C(N)C2CC2)no1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: Cc1nc(C(NC(=O)c2cnc(C3CC3)c(OCC3CC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and α-cyclopropyl-5-methyl-1,2,4-oxadiazole-3-methanamine (CAN 1291557-80-6) as starting materials, and isolated (95 mg, 86%) as light yellow solid; LC-MS (UV peak area, ESI) 100%, 370.1876 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1.I[CH:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:19]([CH3:21])[CH3:20])[CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CC(C)I
Reactant: Oc1cccc(-c2nc3ccc(Br)cc3o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
To a solution of 3-(6-bromobenzoxazol-2-yl)phenol (Compound of Example 272) (1.02 g) in N,N-dimethyl formamide (6 ml) were added 2-iodopropane (0.68 g) and potassium carbonate (0.63 g) at 50° C., and the mixture was stirred at 50° C. for 1.5 hour. To the mixture were further added 2-iodopropane (0.34 g) and potassium carbonate (0.31 g), and the mixture was further stirred at 50° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:20 to 1:6, v/v) was concentrated under reduced pressure to isolate 6-bromo-2-(3-isopropoxyphenyl)benzoxazole (896 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[O:9][C:7](=[O:8])[CH:6]([C:10]([CH3:12])=[O:11])[C:4](=[O:5])[CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O.N1CCCCC1>C1C=CC=CC=1>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=[CH:12][C:10]([CH:6]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:9][C:7]1=[O:8])=[O:11]
Reactant: CC(=O)C1C(=O)C=C(C)OC1=O
Reactant: O=Cc1cccs1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC1=CC(=O)C(C(=O)C=Cc2cccs2)C(=O)O1
Temperature: 50 °C
Reaction time: 7 h
Yield: 57.2 %

Procedure:
To a solution of 65.0 g (0.39 mole) of dehydroacetic acid and 47.0 g (0.42 mole) of thiophene-2-aldehyde in 370 ml of benzene was added dropwise 6.8 g of piperidine with cooling in an ice-water bath. After termination of the dropwise addition, the mixture was stirred at 50° C. for 7 hours. After the reaction, the solvent was concentrated under a reduced pressure. The precipitated crystal was collected by filtration and recrystallized from toluene to obtain 58.5 g (yield: 58%) of 3-(2-thienylacryloyl)-6-methyl-2H-pyran-2,4(3H)-dione in the form of a light crystal, m.p. 162°-164° C.
Reaction SMILES: [CH:1]1([CH2:5][C:6]2([CH3:38])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27]C(=O)OC(C)(C)C)=[CH:26][C:20]=4[S:19](=[O:36])(=[O:35])[N:18]=3)[C:7]2=[O:37])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:17]([C:8]3[C:7](=[O:37])[C:6]([CH2:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)([CH3:38])[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:18][S:19](=[O:36])(=[O:35])[C:20]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CC3CCC3)C1=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CC2CCC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 55H (0.105 g, 0.195 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (2 mL) at room temperature for 1 hour. After concentrating in. vacuo, the resulting oil was partitioned between ethyl acetate and NaHCO3(aq), the organic layer was removed and the bicarb layer extracted 3× with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in. vacuo. to yield a solid that was used without further purification. 1H NMR (300 MHz, DMSO-d6): δ ppm 1.22 m, 3 H) 1.47 m, 3 H) 1.57 (s, 3 H) 1.71 m, 2 H) 2.18 m, 1 H) 2.32 (m, 1 H) 7.01 (m, 2 H) 7.45 (d, J=8.46 Hz, 1 H) 7.54 (t, J=7.17 Hz, 1 H) 7.76 m, 2 H) 8.15 (d, J=7.72 Hz, 1 H) 13.54 m, 1 H). MS (ESI+) m/z=438 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[C:21]([Cl:37])=[CH:20][N:19]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)ccc2C1
Temperature: 100 °C

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine (0.105 g, 0.000407 mol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (0.140 g, 0.000403 mol), 10-camphorsulfonic acid (0.237 g, 0.0010 mol) and isopropyl alcohol (4 mL). The mixture was heated in a microwave at 100° C. for 20 min. After evaporation of the solvent, the residue was treated with a 10% sodium carbonate solution/DCM, separated, washed, dried and evaporated to give a solid. This material was chromatographed on a silica gel prep plate with DCM/10% ammonia/methanol (10-1) giving the product as a tan solid (0.084 g, 39%). Mp 88-91° C. LCMS (m/e) 530 (M); 1H-NMR (DMSO, 400 MHz) δ 9.41 (s, 1H), 9.31 (s, 1H), 8.68-8.56 (m, 1H), 7.82-7.80 (d, 1H, J=7.80 Hz), 7.70-7.66 (t, 1H, J=8.84 Hz), 7.37-7.33 (t, 1H, J=7.58 Hz), 7.14 (s, 2H), 7.00-6.98 (d, 1H, J=8.60 Hz), 3.59-3.42 (br, 2H), 3.06-2.89 (m, 5H), 2.76-2.68 (m, 2H), 2.65 (s, 4H), 2.47-2.38 (m, 4H), 1.09-1.03 (m, 6H).