Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH3:19])[NH:15][C:14]3=[O:20])[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1.BrC[CH2:24][C:25]1[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=1>>[CH2:24]([N:15]1[C:14](=[O:20])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:21])[CH:12]=2)[C:17](=[O:18])[N:16]1[CH3:19])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(C)c2=O)cn1
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)n(C)n(Cc3ccccc3)c2=O)cn1
Yield: 14 %

Procedure:
Prepared as in Example 10-65 from 4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,2,4-triazolidine-3,5-dione (example 10-64) and 1-(2-bromoethyl)-4-fluorobenzene. Yield: 14%. 1H NMR (CDCl3, 400 MHz): δ2.18 (s, 3H), 2.40 (s, 3H), 2.87 (t, J=6.8 Hz, 2H), 3.14 (s, 3H), 3.83 (t, J=7.2 Hz, 2H), 5.03 (s, 2H), 6.95 (t, J=8.4 Hz, 2H), 7.14 (t, J=8 Hz, 2H), 7.77 (s, 1H), 7.95 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.01 μM.
Reaction SMILES: O1C=CC=C1C=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2.C1N2[C:29]3[CH2:40][C:39]4[CH:38]=CC=C[C:34]=4[C:30]=3[NH:31]C(=O)C2=NC=1.[H-].[Na+].N1C=CC(C=O)=CC=1>CS(C)=O>[N:31]1[CH:30]=[CH:34][C:39]([CH:38]=[C:7]2[C:19]3[N:18]4[CH:20]=[CH:21][N:22]=[C:17]4[C:16](=[O:23])[NH:15][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)=[CH:40][CH:29]=1
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3ccco3)c2n2ccnc12
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Agent: O=Cc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1[nH]c2c3ccccc3c(=Cc3ccncc3)c2n2ccnc12

Procedure:
The procedure is performed as in Example 17 for the preparation of 10-(2-furylmethylene)-5H,10H-imidazo[l,2-a]indeno[1,2-e]pyrazin-4-one, but starting with 2 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 40 ml of dimethyl sulphoxide, 0.64 g of sodium hydride and 1.07 g of 4-pyridinecarboxaldehyde. The crude product (1.5 g) is purified by crystallization in 100 ml of dimethylformamide and 50 ml of methanol to give 1.06 g of 10-(4-pyridylmethylene)-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one, in the form of an orange solid melting above 260° C. (Analysis % calculated C: 73.07, H: 3.87, N: 17.94, O: 5.12, % found C: 72.9, H: 3.7, N: 18.2).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([O:12][CH2:13][CH3:14])[C:9]=1[C:10]#[N:11])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].Cl.CN(C)[CH:25]=[O:26]>>[C:1]([NH:4][C:5]1[S:6][C:7]([CH:25]=[O:26])=[C:8]([O:12][CH2:13][CH3:14])[C:9]=1[C:10]#[N:11])(=[O:3])[CH3:2]
Reactant: CCOc1csc(NC(C)=O)c1C#N
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1c(C=O)sc(NC(C)=O)c1C#N
Reaction time: 4 h

Procedure:
210 parts of 2-acetylamino-3-cyano-4-ethoxythiophene (Example 7) are introduced into 1000 parts of dimethylformamide, and 200 parts of phosphoryl trichloride are added dropwise in the course of 4 hours. Stirring is continued for 4 hours at 60° C., after which the resulting crystal slurry is brought into solution by adding 600 parts of ice. This solution is stirred into 2000 parts of 12.5% strength sodium hydroxide solution, and acidified with hydrochloric acid after 6 hours. The precipitated product is filtered off under suction, washed with water and dried to give 201 parts of 2-acetylamino-3-cyano-4-ethoxy-5-formylthiophene. A sample recrystallized from dimethylformamide has a melting point of 276°-277° C. and possesses the following analytical values:
Reaction SMILES: CC1NC(C(OCC)=O)=C(C)C=1.I.C=O.[CH3:16][C:17]1[NH:18][C:19]([C:24](OCC)=O)=[C:20]([CH3:23])[C:21]=1[CH3:22]>CCOCC.C(O)(=O)C>[CH3:16][C:17]1[NH:18][C:19]([CH3:24])=[C:20]([CH3:23])[C:21]=1[CH3:22]
Reactant: CCOC(=O)c1[nH]c(C)c(C)c1C
Agent: C=O
Agent: CCOC(=O)c1[nH]c(C)cc1C
Agent: I
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1[nH]c(C)c(C)c1C

Procedure:
2,4-Dimethyl-5-carbethoxy-pyrrole (1.64 g), acetic acid (25 ml), aqueous hydriodic acid (25 ml) and paraformaldehyde (0.589g), were heated at 95°-100° C. for three hours under nitrogen with stirring. The work up was the same as that of 2,3,4-trimethyl-5-carbethoxy-pyrrole in Example 4 except the 2 × 75 ml of ether was used and care was taken to avoid exposure of the product to air. It was purified by distillation (10 mm, 60° C.) to give 0.628 g (52%), m.p. 106°-108° C. (lit4 m.p. 111°-112° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([Li])CCC.CI>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([CH3:22])=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: Cc1cccc2c(OCCNC(=O)OC(C)(C)C)noc12
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(C)c2c(OCCNC(=O)OC(C)(C)C)noc12
Temperature: -70 °C
Yield: 80 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-7-methyl-1,2-benzisoxazole (0.15 g) in tetrahydrofuran (5 ml) was added butyl lithium (0.7 ml, 1.6M hexane solution) dropwise with stirring at -70° C. under nitrogen atmosphere, the mixture was stirred at the same temperature for 10 minutes, and then the temperature was raised to 0° C. After cooling the reaction mixture to -70° C., methyl iodide (0.11 g) was added and the temperature was allowed to rise to 0° C. The reaction mixture was poured into ice water (40 ml), extracted with ethyl acetate (twice each with 40 ml) and the combined extracts were dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (9/1) as an eluent, to give the title compound (0.12 g, 80%) as a colorless powder.
Reaction SMILES: [CH2:1]([C:7]1[N:8]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=1)[CH2:11][CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:21]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22]1>C(Cl)Cl>[CH2:1]([C:7]1[N:8]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:14]=1[C:21](=[O:28])[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:11][CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc(-c2ccccc2)c2n1CCC2
Reactant: O=C1CCCC(=O)O1
Solvent: ClCCl
Product: CCCCCCc1c(C(=O)CCCC(=O)O)c(-c2ccccc2)c2n1CCC2

Procedure:
5 mmoles of 5-(n-hexyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine 69 are reacted in 20 ml of CH2Cl2 with 5 mmoles (0.5 g) of glutaric acid anhydride and 11 mmoles (1.47 g) of AlCL3 similarly to the procedure for preparing the 5-(diphenyl-2,3-dihydro-1H-pyrrolizinyl)-5-oxovaleric-acids. The product is purified by column chromatography (silica gel, 1st n-hexane/ether 1+1, 2nd ether). After the eluates are concentrated, 71 remains as an oil.
Reaction SMILES: [CH3:1][N:2]([CH2:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:23]([NH:25][C:26](=[N:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:40]=1)OC1C=CC=CC=1)#[N:24]>>[C:23]([NH:25][C:26]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH2:8][CH2:9][CH:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:1])=[N:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]2)[CH:40]=1)#[N:24]
Reactant: CN(CCCCN)CCC(c1ccccc1)c1ccccn1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Product: CN(CCCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccccc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.7 g (2.3 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,4-butanediamine and 0.89 g (2.3 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=596 ([M+H]+ 7), 196 (100).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9](=[O:37])[CH2:10][NH:11][C:12](=[O:36])[C@H:13]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:14][C:15](=[O:28])[C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2C(OC(C)(C)C)=O)=[C:6]([Cl:38])[C:5]([Cl:39])=[C:4]([Cl:40])[C:3]=1[Cl:41]>Cl.C(OCC)(=O)C>[ClH:1].[Cl:38][C:6]1[C:7]([O:8][C:9](=[O:37])[CH2:10][NH:11][C:12](=[O:36])[C@H:13]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:14][C:15](=[O:28])[C@@H:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)=[C:2]([Cl:1])[C:3]([Cl:41])=[C:4]([Cl:40])[C:5]=1[Cl:39]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
N-t-Butoxycarbonyl-prolyl-phenylalanyl-glycine pentachlorophenyl ester in an amount of 36.4 g was dissolved in 410 ml of 2.2 N HCl-ethyl acetate. A precipitate was produced soon. After the reaction at room temperature for 1.5 hours, the precipitate was filtered, washed with ether and recrystallized from 1.2 l of methanol to give crystals of prolyl-phenylalanyl-glycine pentachlorophenyl ester.hydrochloride in yield of 21.5 g (65.2%) having a melting point of 182°-184° C. and Rf=0.78 (TLC, chloroform: methanol: acetic acid=85:5:3 by volume).
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[CH:25][C:26]=1[CH2:27]Cl>O>[CH3:32][O:31][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][C:24]=1[O:29][CH3:30])[CH2:27][N:16]([S:13]([C:10]1[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][CH:11]=1)(=[O:15])=[O:14])[CH2:20]2
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(CCl)c(CCl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(S(=O)(=O)c1ccc(C)cc1)C2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
100 ml of an N,N-dimethylformamide solution containing 34.2 g (0.20 mol) of p-toluenesulfonamide, was dropwise added over a period of 60 minutes under cooling with ice to a suspension comprising 19.7 g (0.41 mol) of 50% oily sodium hydride and 60 ml of N,N-dimethylformamide. The reaction solution was stirred at room temperature for 30 minutes at 60° C., and then 300 ml of an N,N-dimethylformamide solution containing 47 g (0.20 mol) of 4,5-bischloromethyl veratrol was dropwise added over a period of 90 minutes at 60° C. The reaction solution was stirred at room temperature for 3 hours, and then poured into 2000 ml of water. The precipitated crystals were collected and washed with water to obtain 60 g (yield: 90.0%) of the above identified compound.
Reaction SMILES: [NH2:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]1=[NH:17].[CH:18]([O-])([O-])OCC>>[CH2:12]([N:4]1[C:5]2[N:6]=[CH:7][NH:8][C:9]=2[C:10](=[O:11])[N:2]2[N:1]=[CH:18][N:17]=[C:3]12)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCn1c(=N)n(N)c(=O)c2[nH]cnc21
Reactant: CCOC([O-])[O-]
Product: CCCCCn1c2nc[nH]c2c(=O)n2ncnc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 20.3 %

Procedure:
The mixture of 1-amino-2-imino-3-pentyl-1,2,3,7-tetrahydro-6H-purin-6-one (0.10 g, 0.4 mmol) and ethyl orthoformate (5 mL, 30 mmol) was stirred at 100° C. for 6 hours. The reaction mixture was concentrated and purified by preparative LCMS to yield the desired product (20 mg, 20%). LCMS calculated for C11H15N6O(M+H): 247.1; found: 247.1.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:31])([F:32])[F:33])=[C:23]([C:24]([N:10]2[CH2:9][CH2:8][C:7]3[C:12](=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=[CH:5][CH:6]=3)[CH2:11]2)=[O:25])[CH:27]=1)(=[O:18])=[O:17]
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1cccc2c1CNCC2
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cccc(C(F)(F)F)c2C1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.2). MS (m/e): MS (m/e): 496.4 (M+H+).
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]([C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)#[CH:10].[N:16]([C:19]1[S:20][C:21]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[C:22]([CH3:24])[N:23]=1)=[N+:17]=[N-:18]>>[CH2:28]([NH:27][C:25]([C:21]1[S:20][C:19]([N:16]2[CH:10]=[C:9]([C:11]3[CH:15]=[CH:14][S:13][CH:12]=3)[N:18]=[N:17]2)=[N:23][C:22]=1[CH3:24])=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: C#Cc1ccsc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(-c3ccsc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 66 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 3-ethynylthiophene to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 66% yield: mp 123-126° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 7.82-7.81 (m, 1H), 7.51-7.32 (m, 7H), 6.11 (br s, 1H), 4.63 (d, J=6.0 Hz, 2H), 2.71 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 155.4, 153.3, 144.8, 137.4, 130.3, 128.9, 127.9, 127.9, 126.8, 125.7, 124.4, 122.6, 116.4, 44.3, 17.4; MS (ES+) m/z 382.3 (M+1).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].BrC[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.O>CN(C=O)C.C(OCC)(=O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:3][CH2:2]2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cccc2c1NCCC2
Reactant: Clc1ccc(CCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc2c1N(Cc1ccc(Cl)cc1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
To a mixture of ethyl 1,2,3,4-tetrahydroquinoline-8-carboxylate (1.1 g) and DMF (9.0 mL) was added sodium hydride (55% dispersion in paraffin liquid, 280 mg) at 0° C., followed by stirring at room temperature for 30 minutes. To the reaction mixture was added a solution of 1-(bromoethyl)-4-chlorobenzene (1.2 g) in DMF (2.0 mL) under ice-cooling, followed by stirring at room temperature for 3 days. To the reaction mixture was added sodium hydride (55% dispersion in paraffin liquid, 280 mg), followed by stirring for 1 day. To the reaction mixture were added water and ethyl acetate, and a liquid-separation operation was carried out. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoline-8-carboxylate (510 mg).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:21]2[CH:28]=[CH:27][S:26][C:22]=2[N:23]=[CH:24][N:25]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[C:21]3[CH:28]=[CH:27][S:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Reactant: Clc1ncnc2sccc12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2sccc12)c1nc2ccccc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
Into a 10-mL sealed tube was placed (1S)-1-(1-phenyl-1H-1,3-benzodiazol-2-yl)ethan-1-amine from Example 4 (300 mg, 1.26 mmol, 1.00 equiv), 4-chlorothieno[2,3-d]pyrimidine (250 mg, 1.47 mmol, 1.16 equiv), N-ethyl-N-isopropylpropan-2-amine (322 mg) and BuOH (5 mL). The resulting solution was stirred for 1 overnight at 120° C. and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (0:100-80:20) to afford 260 mg (55%) of 143 as a light yellow solid. LC-MS (ES, m/z): 372 [M+H]+. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.19 (s, 1H), 7.70 (d, 1H), 7.68-7.08 (m, 10H), 5.74-5.67 (m, 1H), 1.73 (d, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]([OH:15])=O.[Cl-].[Al+3].[Cl-].[Cl-]>S(Cl)(Cl)=O.O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[C:5]2[C:4]=1[CH2:11][CH2:12][C:13]2=[O:15]
Reactant: COc1c(C)cc(C)cc1CCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: COc1c(C)cc(C)c2c1CCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
A solution of 3-(2-methoxy-3,5-dimethylphenyl)propionic acid (8.80 g, 42.2 mmol) in thionyl chloride (80 mL) was refluxed for 1.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 1,2-dichloroethane (100 mL). To this solution was added anhydrous aluminum chloride (5.80 g, 43.5 mmol) gradually at 0° C. and the mixture was stirred at room temperature for 1.0 hour. After completion of the reaction, the reaction mixture was poured in iced water and extracted with 1,2-dichloroethane. The organic layer was washed serially with 1N-hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 6.90 g of the title compound. Yield 86%. Oil.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([C:8]1[NH:13][CH2:12][C:11]2=[C:14]([CH3:20])[N:15]=[C:16]([CH2:17][CH2:18][CH3:19])[N:10]2[N:9]=1)[C:5](=O)[CH3:6])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>COCCOCCOC.[Pd].CC1C=CC(C(C)C)=CC=1>[ClH:1].[CH2:5]([N:4]([CH2:2][CH3:3])[C:8]1[N:13]=[CH:12][C:11]2=[C:14]([CH3:20])[N:15]=[C:16]([CH2:17][CH2:18][CH3:19])[N:10]2[N:9]=1)[CH3:6]
Reactant: CCCc1nc(C)c2n1N=C(N(CC)C(C)=O)NC2
Agent: [Pd]
Agent: Cl
Agent: [Al+3]
Solvent: O
Solvent: COCCOCCOC
Solvent: Cc1ccc(C(C)C)cc1
Product: CCCc1nc(C)c2cnc(N(CC)CC)nn12

Procedure:
N-Ethyl-N-(3,4-dihydro-5-methyl-7-propylimidazo [5,1-f]-as-triazin-2-yl)acetamide, hydrochloride (Example 7) (4.1 g.) and lithium aluminium hydride (3.3 g.) in a mixture of dimethyl digol (130 ml.) and diethyl digol (150 ml.) were heated under reflux for 24 hours and cooled. Water (3.37 ml.) was added followed by aqueous sodium hydroxide (3.3 ml.) and water (9.8 ml.). The solid was filtered off and the filtrate was evaporated. The residue was chromatographed on active alumina (300 g.) using ethyl acetate as eluent. The first 400 ml. of eluate was discarded and a fraction (900 ml.) then collected was evaporated to give an oil. This oil (1.1 g.) and palladium on charcoal catalyst (1 g., 10%) in p-cymene (60 ml.) were heated under reflux for 30 minutes, cooled and filtered. The filtrate was shaken with 2N hydrochloric acid (3 × 25 ml.) and the aqueous acid solution was separated and neutralised by addition of potassium carbonate. The mixture was extracted with ethyl acetate and the extracts were dried over magnesium sulphate, filtered and evaporated. The residue in ether was treated with a solution of hydrogen chloride in anhydrous ether. The solid crystallised from a mixture of ethyl acetate and ether to give the product, m.p. 83°-84°.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[C:13]([OH:32])[CH:12]=1.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[F:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]2[N:18]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:23][CH2:24]3)[C:34](=[O:36])[O:32][C:13]=2[CH:12]=1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(O)cc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cc1F)oc(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 276.3 %

Procedure:
Hünig's base (0.5 mL, 2.86 mmol) was added to a solution of 1,1-dimethylethyl 4-[(4-fluoro-2-hydroxy-5-methylphenyl)amino]-1-piperidinecarboxylate (D1, 593 mg, 1.34 mmol) in dichloromethane (10 mL) at rt under argon. The reaction was cooled to 0° C. and the triphosgene (167 mg, 0.564 mmol) was added. The reaction was then stirred for 1.5 h at 0° C. and quenched with saturated aqueous NaHCO3 (10 mL) before being partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×) and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give an orange oil. The residue was purified via chromatography (silica, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give 1,1-dimethylethyl 4-(6-fluoro-5-methyl-2-oxo-1,3-benzoxazol-3(2H)-yl)-1-piperidine carboxylate (D2, 546 mg, 73% purity, 85% yield) as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[OH:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29]>>[OH:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:39])([F:35])([F:36])([F:37])[F:38])[CH:33]=1)[C:28]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:29]
Reactant: O=C(O)c1cc(CO)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: Cc1ccc(NC(=O)c2cc(CO)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
62 mg (0.21 mmol) of the compound of Example 6A and 60 mg (0.21 mmol) of the compound of Example 37A were reacted and worked up analogously to the procedure of Example 16. The product obtained in this manner was re-purified by preparative HPLC (Method 15). The product-containing fractions were combined and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed successively with saturated potassium carbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Drying of the residue gave 40 mg (48% of theory) of the title compound.
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][CH2:20][C:21]([NH:23][C@H:24]([P:26](=[O:29])([OH:28])[OH:27])[CH3:25])=[O:22])=O)C1C=CC=CC=1>>[NH2:19][CH2:20][C:21]([NH:23][C@H:24]([P:26](=[O:27])([OH:29])[OH:28])[CH3:25])=[O:22]
Reactant: C[C@H](NC(=O)CNC(=O)OCc1ccccc1)P(=O)(O)O
Solvent: NCc1ccccc1
Product: C[C@H](NC(=O)CN)P(=O)(O)O

Procedure:
In a manner analogous to that given in Example 1 (b), from the benzylamine salt of (1R)-1-[(benzyloxycarbonyl-glycyl)amino] -ethylphosphonic acid there was obtained (1R)-1 -glycylamino-ethylphosphonic acid of melting point 279°-281° C (decomposition); [α]D20 =- 69.4°(c = 1% in water).