Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[C:35]([NH:37][NH2:38])=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1.C(OCC)(=O)C>[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[C:35]1[O:8][C:6]([C:5]2[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=2)=[N:38][N:37]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: Nc1ccc(C(=O)O)cn1
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N)nc2)o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 9.2 %

Procedure:
To a suspension of 6-aminonicotinic acid (191 mg, 1.38 mmol) in chlorobenzene (2 mL) was added 1,1′-carbonyl-diimidazole (224 mg, 1.38 mmol) and the resulting mixture stirred for 2 h at 90° C. After the suspension was cooled to ambient temperature 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was added and stirred for 1 h at 90° C. After the reaction mixture was cooled to ambient temperature phosphorous oxychloride (0.84 mL, 9.20 mmol) was added and stirring was continued for 4 h at 90° C. The cooled reaction mixture was poured carefully onto a mixture of ethyl acetate (20 mL) and aqueous sodium carbonate (saturated, 20 mL) and was stirred for 1 h at ambient temperature. The aqueous layer was separated and extracted with ethyl acetate (20 mL) and the combined organic layers were washed with aqueous sodium carbonate (saturated). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5) afforded the title compound (27 mg, 9%) as a white solid. MS: m/e=320.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20](O)=[O:21])[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:57][C:58]([F:70])([F:69])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[C:65]1([NH2:68])[CH2:67][CH2:66]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20]([NH:68][C:65]2([C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=3[C:58]([F:57])([F:69])[F:70])[CH2:67][CH2:66]2)=[O:21])[N:10]=1
Reactant: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)O
Reactant: NC1(c2ccccc2C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)NC1(c2ccccc2C(F)(F)F)CC1
Yield: 16.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoic acid (Intermediate-11, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropyl ethyl amine (1.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[2-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-12, 0.066 g, 0.329 mmol) to afford 0.025 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.26-1.28 (m, 4H), 3.91 (s, 3H), 7.24 (d, J=9.3 Hz, 1H), 7.11-7.48 (m, 6H), 7.98 (t, J=7.5 Hz, 2H), 8.27 (s, 1H), 8.74 (s, 1H), 12.56 (br s, 1H); MS (m/z): 545.31 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[N:5][CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1.Br[C:20]1[N:21]=[C:22]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[Br:25]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:25][C:24]1[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:22]([N:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH2:39]2)=[N:21][C:20]=1[C:7]1[CH:8]=[C:3]([O:2][CH3:1])[C:4]([NH2:18])=[N:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1c(N2CCNCC2)nc(Br)c1Br
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(-c2nc(N3CCNCC3)n(COCC[Si](C)(C)C)c2Br)cnc1N
Temperature: 115 °C

Procedure:
A mixture of 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (56.2 mg, 0.225 mmol) and 1-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperazine (90 mg, 0.204 mmol) in DME (2.1 ml) and 2M aqueous Na2CO3 (0.7 ml) was sparged with Ar for 2 min. Pd(Ph3P)4 (23.6 mg, 0.02 mmol) was added. The mixture was sparged with Argon for an additional 2 min and was heated in a sealed tube in a microwave reactor at 115° C. for 15 min. The reaction mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude materials of both reactions were combined and purified by preparative TLC (SiO2, 1.0 mm, 90:10 DCM-MeOH) to furnish 5-(5-bromo-2-(piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine was isolated as a white solid which was directly used in the next step: LCMS (m/z): 485.2 (MH+), tR=0.56 min.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30]([CH:27]3[CH2:29][CH2:28]3)=[O:31])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)C1CC1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CC1

Procedure:
The title compound, white solid (73 mg, 74%), MS (ISP) m/z=395.3 [(M+H)+], mp 204° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and cyclopropanecarboxylic acid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[C:18]3[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.[IH:33]>C(OCC)C>[IH:33].[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)#[N:25]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCCCC#N)CC1
Agent: I
Solvent: ClCCl
Solvent: CCOCC
Product: N#CCCCCn1c(N2CCCNCC2)nc2ccccc21
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(4-cyanobutyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.3 mmol) and dichloromethane (5 mL). Add aqueous 48% hydriodic acid solution (0.6 mmol). Heat to 40° C. After 6 hours, cool to ambient temperature dilute with diethyl ether (20 mL), and collect the solid to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:9]1[S:10][CH:11]=[C:12]([C:14](=[N+]=[N-])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:31]([OH:34])([CH3:33])[CH3:32]>C(Cl)Cl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[C:1]([O:5][C:6]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:9]1[S:10][CH:11]=[C:12]([CH:14]([O:34][CH:31]([CH3:33])[CH3:32])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)C(=[N+]=[N-])c1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Reactant: CC(C)O
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C(OC(C)C)c1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
Ethyl 2-[2-[tert-butoxycarbonyl-[(4-methoxyphenyl)methyl]amino]thiazol-4-yl]-2-diazo-acetate (0.6 g, 1.38 mmol) was dissolved in DCM (10 mL) under argon atmosphere. To this solution, iso-propanol (0.12 mL, 1.66 mmol) was added followed by rhodium (II) acetate dimer (12 mg, 0.028 mmol). Mixture was stirred at room temperature for 30 min. then diluted with DCM (10 mL). Organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography using 20% ethyl acetate in hexane to provide ethyl 2-[2-[tert-butoxycarbonyl-[(4-methoxyphenyl)methyl]amino]thiazol-4-yl]-2-isopropoxy-acetate (0.55 g).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([NH:11][C:12]1[N:41]=[C:15]2[N:16]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[C:17]([CH3:30])=[C:18]([C:28]#[N:29])[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[N:14]2[N:13]=1)=[O:10])(C)(C)C.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[C:28]([C:18]1[C@@H:19]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[N:14]2[N:13]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][NH2:7])[N:41]=[C:15]2[N:16]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=2)[C:17]=1[CH3:30])#[N:29]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)CNC(=O)OC(C)(C)C)nc2N1c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)CN)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 0.67 h

Procedure:
Under an atmosphere of argon protective gas, tert-butyl[2-((7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-ylamino)-2-oxoethyl]carbamate (6.4 mg, 11 μmol) was dissolved in dry dichloromethane (5 ml). At room temperature, trifluoroacetic acid (1 ml) was added, and the mixture was stirred for 40 min. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (˜6 mg, quant.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23].Cl>O1CCCC1.O>[N+:22]([C:13]1[CH:14]=[C:15]([S:18]([NH2:21])(=[O:19])=[O:20])[CH:16]=[CH:17][C:12]=1[O:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)([O-:24])=[O:23]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: OCC1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(Tetrahydro-2H-pyran-4-yl)methanol (2.0 g) in tetrahydrofuran (20 mL) was treated with 60% NaH (1.377 g). The solution was stirred for 20 minutes at the room temperature. To this solution was added 4-fluoro-3-nitrobenzenesulfonamide (2.84 g) portion-wise. The reaction was stirred for another 2 hours. The mixture was poured into water, neutralized with 10% HCl, and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel eluting with 20-60% ethyl acetate in hexanes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:28]([OH:30])=[O:29])[CH2:10][CH2:11][S:12][CH2:13][CH:14]([NH2:27])C(C(OCC1C=CC=CC=1)=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].N>>[C:1]([O:5][C:6]([NH:8][CH:9]([C:28]([OH:30])=[O:29])[CH2:10][CH2:11][S:12][CH2:13][CH2:14][NH2:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CCSCC(N)C(=O)C(=O)OCc1ccccc1)C(=O)O
Agent: N
Agent: [Na]
Product: CC(C)(C)OC(=O)NC(CCSCCN)C(=O)O

Procedure:
N-t-Butoxycarbonyl-S-(2-carbobenzyloxycarbonyl aminoethyl)-D,L-homocysteine (1.0 g) is treated with sodium in liquid ammonia according to the procedure described in Example 2. After the ammonia has evaporated off, the residue is extracted with ethanol. Inorganic salts (0.4 g) is removed by filtration. After removal of ethanol, the residue is taken up in 5 ml of water. The aqueous solution is extracted with ether, and then acidified to pH 4 with 4M hydrochloric acid. The solution is concentrated to a volume of 2 ml. Excess ether is added. The product crystallizes out as a white solid (0.32 g). The NMR spectrum (in MeOH-d4 and NaOD) shows a triplet at 3.7, complex absorption between 2.1 and 2.6, a multiplet between 1.5 and 1.9, and a singlet at 1.2.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[ClH:6].[CH3:7][C:8]1[CH:9]=[C:10]([CH:26](O)[CH2:27][NH+:28]=[C:29]([NH2:31])[NH2:30])[CH:11]=[C:12]([CH3:25])[C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C.CCOCC>[ClH:3].[Cl:6][CH:26]([C:10]1[CH:9]=[C:8]([CH3:7])[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[C:12]([CH3:25])[CH:11]=1)[CH2:27][NH:28][C:29]([NH2:31])=[NH2+:30]
Reactant: Cc1cc(C(O)C[NH+]=C(N)N)cc(C)c1OCc1ccccc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(C(Cl)CNC(N)=[NH2+])cc(C)c1OCc1ccccc1[N+](=O)[O-]
Reaction time: 24 h
Yield: 75.3 %

Procedure:
Phosphoryl Chloride (3.3 mL,3.54 mmol) was added to a solution of 14 (40.2 mg, 0.10 mmol) in DMF (1 ml). Following stirring under N2 for 24 hrs, the cmde product was isolated by diluting with Et2O. The product was then purified by recrystillization from CHCl3Et2O/EtOH. Giving pure compound 15 (31.2 mg, 74%) as an off-white solid: 1H NMR (270 MHz, MeCN d3) δ8.14(d, 1H, I=8.2 Hz, ArNO2), 8.07(d, J=8.2 Hz, 1H, ArNO2), 7.81 (t, J=8.2 Hz, 1H, ArNO2), 7.59(t, J=8.2 Hz, 1H, ArNO2), 7.49(t, J=5.2 Hz, 1H, RCH2NH), 7.19(s, 2H, Ar-H), 5.20.(s, 2H, ArOCH2 Ar(NO2)), 5.04(m, 1H, ArCH(OH)), 3.71(m, 2H, CH2—NH), 2.24(s, 6H, ArCH) 13C NMR (67.5 MHz, MeOHd4) δ157.4, 156.1, 147.4, 134.1, 133.7, 133.4, 131.5, 128.8, 128.5, 127.9, 124.5, 70.1, 60.3, 48.3, 15.2;
Reaction SMILES: [BH4-].[Na+].[CH:3]1[N:7]2[C:8]3[C:19](=[O:20])[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:9]=3[NH:10][C:11](=[O:12])[C:6]2=[N:5][CH:4]=1.C>CO.CN(C)C=O>[OH:20][CH:19]1[C:8]2[N:7]3[CH:3]=[CH:4][N:5]=[C:6]3[C:11](=[O:12])[NH:10][C:9]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]1=2
Reactant: O=C1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(n3ccnc13)C(O)c1ccccc1-2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
0.86 g of sodium borohydride is added over 5 minutes to a stirred suspension of 2.4 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4,10-dione in 75 ml of methanol at a temperature between 25° C. and 35° C. After stirring for 30 minutes at 20° C., the insoluble material is isolated by filtration, washed with 10 ml of methanol and dried under reduced pressure (15 mmHg; 2 kPa) at 20° C. The product obtained (2.3 g) is dissolved in 100 ml of dimethylformamide and, after addition of 0.1 g of decolorizing charcoal, the solution is filtered and the filter is then washed with 20 ml of dimethylformamide. The filtrate and the washings are combined and 240 ml of distilled water are added. The solid is filtered off, washed twice with 40 ml in total of distilled water and with 20 ml of acetone and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 1.9 g of 10-hydroxy-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one are thus obtained, melting at 290° C. (decomposition) [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): 5.65 (d, J=8.5 Hz, 1H: CH--O--); 6.17 (d, J=8.5 Hz, 1H: --OH); 7.33 and 7.41 (2dt, J=7.5 and 1 Hz, 1H each: --H7 and --H8); 7.57 and 7.77 (2dd, J=7.5 and 1 Hz, 1H each: --H6 and --H9); 7.58 and 7.93 (2s broad, 1H each: --H of the imidazole); 12.40 (cplx, 1H: --NH--)].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[CH3:11][CH:12]([C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[C:13]#[CH:14]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:14]#[C:13][CH:12]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH3:11])=[C:4]([CH3:10])[N:3]=1
Reactant: C#CC(C)c1cc(OC)c(OC)c(OC)c1
Reactant: Cc1nc(N)nc(N)c1I
Product: COc1cc(C(C)C#Cc2c(C)nc(N)nc2N)cc(OC)c1OC
Yield: 85.9 %

Procedure:
2,4-Diamino-5-iodo-6-methylpyrimidine (250 mg) was allowed to react with 5-(But-3-yn-2-yl)-1,2,3-trimethoxybenzene (440 mg) as per the general procedure to afford 2,4-Diamino-5-(3-(3,4,5-trimethoxyphenyl)but-1-ynyl)-6-methylpyrimidine as a white powder (294 mg, 86%): Rf=0.29 (9:1, CHCl3:MeOH); mp=191-193° C.; 1H NMR (DMSO-d6) δ 6.76 (s, 2H), 6.19 (s, 2H), 4.02 (q, J) 7.1 Hz, 1H), 3.77 (s, 6H), 3.63 (s, 3H), 2.21 (s, 3H), 1.51 (d, J) 7.1 Hz, 3H); 13C NMR (DMSO-d6) δ 167.0, 164.1, 161.0, 152.8, 139.4, 136.0, 104.0, 100.8, 88.6, 76.4, 60.0, 55.8, 32.5, 24.6, 22.5; Anal. (C18H22N4O3) C, H, N.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1.[N:21]1([CH2:27][CH2:28][OH:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl>[N+:18]([C:5]1[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]2)=[CH:7][C:2]([O:29][CH2:28][CH2:27][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3][CH:4]=1)([O-:20])=[O:19]
Reactant: OCCN1CCCCC1
Reactant: NC(=O)[C@H]1CC[C@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: NC(=O)[C@H]1CC[C@H](Nc2cc(OCCN3CCCCC3)ncc2[N+](=O)[O-])CC1
Temperature: 80 °C

Procedure:
Trans-4-(2-Chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxamide (3.00 g, 10.04 mmol) was suspended in toluene (30 mL). 1-Piperidine ethanol (6.62 mL, 50.2 mmol), 18-crown-6 (3.98 g, 15.06 mmol) and cesium carbonate (9.82 g, 30.1 mmol) were then added to the reaction. The resulting reaction mixture was heated at 80° C. overnight followed by additional heating at 90° C. for 8 hours. The reaction mixture was diluted with DCM and washed with water and brine. The organic layer was concentrated under vacuum to yield 6.43 g of crude material as a yellow oil/residue. The sample was purified by flash chromatography, eluting with 0-100% 90:10:1 dichloromethane/methanol/NH4OH:dichloromethane to afford 1.62 g of trans-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide (41.2% yield) as a yellow solid. Mass cal'd: 391.2; MS (ESI pos. ion) m/z: 392.2 [M+H].
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[Cl:36][C:37]1[N:38]=[N:39][C:40](I)=[CH:41][CH:42]=1>>[Cl:36][C:37]1[N:38]=[N:39][C:40]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:14][CH:15]=2)=[CH:41][CH:42]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Clc1ccc(I)nn1
Product: C[C@@H](c1ccc(-c2ccc(Cl)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 62 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 3-chloro-6-iodo-pyridazine following a procedure analogous to that described in Example 1. Yield: 62% of theory; LC (method 1): tR=1.88 min; Mass spectrum (ESI+): m/z=466/468 (Cl) [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1.Cl[C:10]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]([CH3:18])[N:11]=1.[F-].[K+].O>CS(C)=O.CCN(C(C)C)C(C)C>[CH3:18][N:12]1[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:10]([N:2]2[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]2)=[N:11]1
Reactant: C1=CCCNCC1
Reactant: Cn1cc([N+](=O)[O-])c(Cl)n1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1cc([N+](=O)[O-])c(N2CCC=CCC2)n1
Temperature: 75 °C
Yield: 99186 %

Procedure:
To a solution of (Z)-2,3,6,7-tetrahydro-1H-azepine hydrochloride (32.3 g, 0.24 mmol) in DMSO (650 mL) was added 3-chloro-1-methyl-4-nitro-1H-pyrazole (37.2 g, 0.23 mmol) followed by DIPEA (64 mL, 0.36 mmol) and potassium fluoride (56.2 g, 0.96 mmol). The reaction mixture was heated at 75° C. for 25 hr before being cooled to room temperature, poured into water (1.5 L) and extracted with EtOAc (4×500 mL). The combined organic layers were washed with water (400 mL) and brine (300 mL), separated, dried over MgSO4 and concentrated under reduced pressure to give (Z)-1-(1-methyl-4-nitro-1H-pyrazol-3-yl)-2,3,6,7-tetrahydro-1H-azepine as a light brown solid (50.7 g). To a solution of this solid (1.80 g, 8.1 mmol) in ethanol (80 mL) and water (8 mL) was added ammonium chloride (2.15 g, 40.1 mmol) and iron powder (1.77 g, 31.8 mmol). The reaction mixture was heated at 80° C. for 1.5 hr, before being cooled to room temperature, filtered through Celite® and concentrated under reduced pressure. The residue was dissolved in DCM (200 mL) and washed with water (200 mL). The aqueous layer was extracted with DCM (100 mL) and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give (Z)-1-methyl-3-(2,3,6,7-tetrahydro-1H-azepin-1-yl)-1H-pyrazol-4-amine as a brown oil (1.36 g, 87%). A solution of HATU (3.22 g, 8.47 mmol), 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (2.52 g, 7.07 mmol), (Z)-1-methyl-3-(2,3,6,7-tetrahydro-1H-azepin-1-yl)-1H-pyrazol-4-amine (1.36 g, 7.07 mmol) and DIPEA (2.48 mL, 14.2 mmol) in DMF (30 mL) was stirred at room temperature for 18 hr. The reaction mixture was diluted with DCM (50 mL) and washed with water (100 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification of the residue via silica gel column chromatography (5-80% 10% MeOH in DCM/DCM) gave (Z)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(2,3,6,7-tetrahydro-1H-azepin-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a brown solid (2.71 g, 72% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 8.82 (s, 1H), 7.85 (s, 1H), 7.40-7.30 (m, 1H), 7.08-6.99 (m, 2H), 5.93-5.84 (m, 2H), 3.77 (s, 3H), 3.19 (t, J=5.1 Hz, 4H), 2.42-2.37 (m, 4H), 1.58-1.48 (m, 9H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].FC1(F)C2C(=C(F)C(F)=C(F)C=2F)C(=O)[O:19]1.ClC1C=C(Cl)C=CC=1C(O)=O>>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Agent: O=C(O)c1ccc(Cl)cc1Cl
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 62.5 %

Procedure:
Into a 200 ml glass reactor equipped with a reflux condenser and a stirrer, 50 g (0.207 mol) of the mixture (1:1) of the 3,4,5,6-tetrafluorophthaloyldifluoride and the 3,3,4,5,6,7-hexafluoro-1-[3H]-isobenzofuranone of Example 2, and 79.0 g (0.414 mol) of 2,4-dichlorobenzoic acid were charged, and the mixture was reacted at 150° C. for 6 hours with vigorous stirring. Then, the reaction mixture was separated by distillation to obtain 28.5 g of tetrafluorophthalic anhydride. The yield was 62.5%.