Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:19][O:20][C:21](=[O:45])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32](=[O:44])[N:33]([CH3:43])[C:34](=[O:42])[N:35]([CH3:41])[C:36]=2[C:37]([F:40])([F:39])[F:38])=[CH:27][CH:26]=1)[NH2:23].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:19][O:20][C:21](=[O:45])[C@H:22]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[C:32](=[O:44])[N:33]([CH3:43])[C:34](=[O:42])[N:35]([CH3:41])[C:36]=2[C:37]([F:40])([F:38])[F:39])=[CH:29][CH:30]=1)[NH:23][C:4]([C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)n(C)c(=O)n(C)c2=O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Reaction time: 2 h
Yield: 33.2 %

Procedure:
A solution of 2-chloro-6-methylbenzoic acid (190 mg, 1.14 mmol) in dichloromethane (7 mL) containing DMF (4 drops) was treated with oxalyl chloride (0.42 mL, 4.8 mmol) and the mixture was stirred for 2 h. The mixture was concentrated, azeotroping with toluene to remove traces of oxalyl chloride and the residue was used directly in the next step. A mixture of the above prepared acid chloride, 4-(1,3-dimethyl-2,4-dioxo-6-(trifluoromethyl)-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt (423 mg, 1.003 mmol) in dichloromethane (5 mL) was treated with DIPEA (0.625 mL, 4.46 mmol) and the resulting light brown solution was stirred for 3 days. The mixture was concentrated, diluted with ethyl acetate, washed with 1 N HCl and brine solution and was dried over magnesium sulfate. Filtration and evaporation afforded a residue, which was purified by silica gel chromatography using a Biotage column (40s) to give N-[(2-chloro-6-methylphenyl)carbonyl]-4-[1,3-dimethy-2,4-dioxo-6-(trifluoromethyl)-5-pyrimidinyl]-L-phenylalanine methyl ester as a white foam (179 mg, 33%). ES-HRMS m/e calcd for C25H23ClN3O5 (M+Na) 560.1171, found 560.1172.
Reaction SMILES: [CH2:1]([C:4]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[C:11]([O:15][C:16]([N:18]1[C:22]2=[C:23]([NH2:38])[C:24]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:31]=3[F:37])=[C:25]([CH3:28])[C:26](=[O:27])[N:21]2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(OC(=O)C)C>N1C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[C:22]2=[C:23]([NH:38][S:7]([C:4]3([CH2:1][CH:2]=[CH2:3])[CH2:6][CH2:5]3)(=[O:9])=[O:8])[C:24]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:31]=3[F:37])=[C:25]([CH3:28])[C:26](=[O:27])[N:21]2[CH2:20][CH2:19]1)=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(N)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=CCC1(S(=O)(=O)Nc2c(Nc3ccc(Br)cc3F)c(C)c(=O)n3c2N(C(=O)OC(C)(C)C)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.9 %

Procedure:
1-Allyl-cyclopropanesulfonyl chloride (121 mg, 0.001 mol) was added to a stirred solution of 8-amino-7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (150 mg, 0.0003 mol) in pyridine (3 mL). The resulting mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer concentrated to afford the crude product. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 120 mg of the product (60.6% yield).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 88.9 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetrahydrophthalic anhydride (7.56 g), p-toluenesulfonic acid (0.4 g) and toluene (24 g) was refluxed for 10 hours, during which water was azeotropically removed. The reaction mixture was treated in the same manner as in Example 4 to give the compound (I) (15.6 g).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[C:11]([C:12]([OH:14])=O)=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[CH:9]=[C:8]([CH3:23])[N:7]=1.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][NH2:32])[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[C:21]([C:17]1[CH:16]=[C:15]([C:10]2[CH:9]=[C:8]([CH3:23])[N:7]=[C:6]([CH3:5])[C:11]=2[C:12](=[O:14])[NH:32][CH2:31][CH2:30][N:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[CH:20]=[CH:19][CH:18]=1)#[N:22]
Reactant: NCCN1CCOCC1
Reactant: Cc1cc(-c2cccc(C#N)c2)c(C(=O)O)c(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc(-c2cccc(C#N)c2)c(C(=O)NCCN2CCOCC2)c(C)n1
Reaction time: 1 h
Yield: 45.2 %

Procedure:
To a solution of thionyl chloride (0.29 g) in methylene chloride (5 ml) was added N,N-dimethylformamide (0.18 g) at 10° C. and the mixture was stirred at the same temperature for 1 hour. Thereto was added 2,6-dimethyl-4-(3-cyanophenyl)-3-pyridinecarboxylic acid (0.505 g) at 10° C. and the mixture was stirred at ambient temperature for 1 hour. To the resulting mixture was added dropwise a solution of 2-morpholinoethylamine (0.62 g) in methylene chloride (2 ml) at 10° C. The mixture was stirred at the same temperature for 1.5 hours, diluted with methylene chloride (10 ml) and a saturated aqueous solution of sodium bicarbonate (10 ml). The separated organic layer was washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of chloroform and methanol (25:1 V/V). The fractions containing the desired compound were combined and concentrated in vacuo. The residue was tritulated with diethyl ether to give 4-(3-cyanophenyl)-2,6-dimethyl-3-(2-morpholinoethylcarbamoyl)pyridine (0.33 g).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([OH:11])[CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[H-].[Na+].C(O)(O)CCCC>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:11])[CH:2]=[CH2:3]
Reactant: OCCCCCO
Reactant: C=CCBr
Agent: CCCCC(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOCCCCCO
Reaction time: 8 h
Yield: 22.3 %

Procedure:
Allyl bromide (2.5 mL, 0.029 mol) was added dropwise to the mixture of 1,5-pentanediol (3 g, 0.029 mol) and sodium hydride (1.2 g, 80% dispersion in oil) in dry dimethylformamide. Stirring was continued overnight at room temperature. T.l.c. (2:1-toluene and ethyl acetate) still indicated the presence of some unreacted pentanediol. The unreacted sodium hydride was destroyed by addition of methanol. The mixture was concentrated to 50 mL by evaporation in vacuo. After dilution with methylene chloride (150 mL), the solvents were washed with water (three times), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using a 2:1 mixture of toluene and ethyl acetate as eluant. The appropriate fractions gave compound 229 (0.931 g, 30%). 1H-n.m.r. (CDCl3): 5.83 (m, 1 H, --CH=), 5.20 (m, 2 H, =CH2), 3.95 (dd, 1 H, J=5.5 and 1.0 Hz, allylics), 3.66 and 3.46 (two t, 2 H each, J=6.5 Hz, O--CH2), 1.64 (m, 4 H) and 1.44 (m, 2 H): methylenes); 13C-n.m.r. (CDCl3): 134.7 and 116.6 (ethylenics), 71.6, 70.1 (CH2 --O--CH2), 62.1 (CH2OH) 32.2, 29.2 and 22.2 (methylenes).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH3:11]N(C=O)C.C(Cl)(=O)C(Cl)=O.CO>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(O)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(O)cn1
Reaction time: 1 h

Procedure:
To 5-hydroxypyridine-2-carboxylic acid (5.0 g, 36 mmol) suspended in CH2Cl2 (120 mL) was added DMF (1 mL) followed by oxalyl chloride (4.7 g, 37 mmol). After 1 hour, excess MeOH was added. The resulting mixture was stripped of solvent in vacuo yielding a brown solid that was washed with hot EtOAc. Yielded 4.6 g of product.
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([F:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:22]([CH:24]([CH2:29][C:30]1[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1)[C:25](OC)=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:20][C:15]1[CH:14]=[C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:25]=[C:24]([CH2:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=4)[C:22](=[O:23])[N:21]=3)=[CH:11][CH:10]=2)[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: Cc1ccc(Oc2ccc(CCOC(=N)N)cc2)cc1F
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(C)c(F)c4)cc3)nc2=O)cn1
Temperature: 115 °C
Yield: 6.2 %

Procedure:
To the solution of 2-{4-[(3-fluoro-4-methylphenyl)oxy]phenyl}ethyl imidocarbamate (100 mg, 0.347 mmol) and methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (93 mg, 0.416 mmol) in NMP (1.5 mL), was added K2CO3 (192 mg, 1.387 mmol). The mixture was heated with a microwave reactor at 115° C. for 2 h. Purification via MDAP then afforded the title compound (10 mg, 6.23% yield). LCMS: rt=3.30 min, [M+H+]=463
Reaction SMILES: [CH2:1]=[O:2].[O:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:5].N12CCCN=C1CCCCC2.Cl>>[CH3:8][C:7]([CH:6]([CH2:1][OH:2])[C:4](=[O:3])[CH3:5])=[CH2:9]
Reactant: CC(=O)C=C(C)C
Reactant: C=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(C)C(CO)C(C)=O
Yield: 27.7 %

Procedure:
30 g (1 mol) of paraformaldehyde were added to a mixture of 490 g (5 mols) of mesityl oxide and 15.2 g (0.1 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene over the course of 2 - 3 hours at 30° C. After completion of the addition of formaldehyde, the reaction mixture was stirred for about a further hour, then cooled to 0° C and neutralised with dilute hydrochloric acid. The organic phase was separated off and the aqueous phase was repeatedly extracted with methylene chloride. The combined organic phases were dried with zeolite, filtered off and then freed from methylene chloride. The residue (506 g) was fractionally distilled in a high vacuum at about 0.1 - 1 mm Hg. Thereby, 431 g of mesityl oxide were recovered. As a further fraction, 47 g of crude product of boiling point 45° - 85° C/l mm Hg were obtained. A further fractional distillation of this crude product gave 35.5 g of 2-methyl-3-hydroxymethyl-pent-1-en-4-one of boiling point 50° - 52° C/0.2 mm Hg (yield: 78%, relative to mesityl oxide converted), in the form of a colourless liquid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].N12CCCN=C1CC[CH2:11][CH2:10][CH2:9]2.CC(C)=O.BrCCCBr>CN(C=O)C>[CH3:7][O:6][C:4]([C:3]1([C:1]#[N:2])[CH2:11][CH2:10][CH2:9]1)=[O:5]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=O)CC#N
Agent: BrCCCBr
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)C1(C#N)CCC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
10 g (0.1 mol) of methyl cyanoacetate and 10 mL of anhydrous DMF were mixed under stirring for 10 minutes, followed by adding 33.4 g (0.22 mol) of 1,8-diazabicyclo[5,4,0] undec-7-ene (DBU) at 10-20° C. into the mixture, heating the mixture to 50° C. to allow reaction to take place for 15 minutes, moving the mixture to an ice bath (−5˜−10° C.) of a mixture of liquid nitrogen and acetone, and adding 20.4 g (0.10 mol) of 1,3-dibromopropane dissolved in 10 mL of anhydrous DMF into the mixture to form a reaction solution. The reaction solution was subjected to reaction at 25° C. for 15 minutes, and to further reaction at 70° C. for 30 minutes, followed by evaporating, extracting with CH2Cl2 and deionized water, collecting an organic layer from the extraction, evaporating, purifying using silica column chromatography (eluent: acetone/hexane=8/1), and re-evaporating to obtain a product of 8.74 g (0.063 mol, 62.85%) of 4.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][C@@H:9]([C:21]([NH:23][C@H:24]([C:33]([O:35][CH3:36])=[O:34])[CH2:25][O:26][CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30])=[O:22])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:32][O:31][CH:28]([O:29][CH3:30])[CH2:27][O:26][CH2:25][C@@H:24]([C:33]([O:35][CH3:36])=[O:34])[NH:23][C:21](=[O:22])[C@H:9]([CH2:8][CH2:7][OH:6])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: COC(=O)[C@H](COCC(OC)OC)NC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](COCC(OC)OC)NC(=O)[C@H](CCO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
A solution of N-[O-[(1,1-dimethylethyl)dimethylsilyl]-N-[(phenylmethoxy)carbonyl]-L-homoseryl]-O-(2,2-dimethoxyethyl)-L-serine, methyl ester [5.56 g, 10 mmol, prepared as described in Example 10(h)] in methanol (65 ml) was cooled to 0° C. (ice salt bath), treated with p-toluenesulfonic acid monohydrate (386 mg, 2.0 mmol) and stirred at 0° C. for 1.5 hours. The reaction was quenched with sodium bicarbonate solution (198 mg. in 20 ml water), stirred for 5 minutes then evaporated to remove the methanol. The aqueous phase was extracted with ethyl acetate (2×200 ml) and the combined organic extract was washed with water (110 ml), 5% sodium bicarbonate (80 ml) and brine (80 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuo. The crude product was chromatographed on silica gel column (Merck), eluting the column with ethyl acetate:hexane (2:1) and ethyl acetate:methanol (98:2) to give 3.975 g of title product as a syrup.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[O-:31][CH2:32][CH3:33].[Na+]>C(O)C>[CH2:32]([O:31][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1)[CH3:33]
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a solution of 150 mg (0.337 mmol) of the oxadiazole from Example 23A in 6.25 ml of ethanol were added 229 mg (3.37 mmol) of sodium ethoxide, and then the reaction mixture was stirred at RT for 3 days and at 40° C. for 2 days. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 16.8 mg (11% of theory)
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[C:5]([CH2:7]O)[N:6]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Cl:18][CH2:7][C:5]1[N:6]=[C:2]([CH3:1])[S:3][C:4]=1[C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccc(-c2sc(C)nc2CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2sc(C)nc2CCl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
To a stirred solution of (2-methyl-5-m-tolylthiazol-4-yl)methanol (300 mg, 1.37 mmol) in chloroform (10 mL), thionyl chloride (162 mg, 1.37 mmol) was added dropwise at rt and stirred for 30 min and then refluxed for 1 h. The reaction mixture was cooled to rt and absorbed directly on silicagel (10 g). Subsequent flash column chromatography (eluent: 7% ethyl acetate in hexane) yielded the title compound (40 mg, 12%). [LCMS RtF=1.70 min, [M+H]+=238.0; TLC Rf=0.54 (methanol/chloroform 10:90)].
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1>CN(C=O)C>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:20][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: NC1CCOCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: CN(C)C=O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NC1CCOCC1
Yield: 81.8 %

Procedure:
A mixture of 5.1 g of 2-fluoro-5-nitrobenzoic acid and 6.21 g of tetrahydro-2H-pyran-4-amine in 5 ml of DMF is irradiated in a microwave field for 15 minutes at 100° C. The mixture is irradiated a second time for 15 minutes at 100° C. The same reaction is repeated on identical amounts of reagents. All the reaction mixtures are pooled and the solvent is evaporated off under reduced pressure. The residue is recrystallized from EtOAc to give 6 g of expected product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16](=[N:23][O:24][CH3:25])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.CC1[N:32]=C(C#CC2CC3(C4C(=CC=CC=4)C(=O)C3)ON=2)C=CC=1>>[CH3:25][O:24][N:23]=[C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2([O:12][N:11]=[C:10]([C:9]#[C:8][C:4]3[CH:3]=[CH:2][CH:7]=[C:6]([CH3:5])[N:32]=3)[CH2:14]2)[CH2:15]1
Reactant: Cc1cccc(C#CC2=NOC3(CC(=O)c4ccccc43)C2)n1
Reactant: CON=C1CC2(CC(C#Cc3cccc(Cl)c3)=NO2)c2ccccc21
Product: CON=C1CC2(CC(C#Cc3cccc(C)n3)=NO2)c2ccccc21
Yield: 82 %

Procedure:
The title product was obtained the method described for the compound of Example 84 starting from the Compound of example 93 instead of the compound of Example 83. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 1:1) to give the title compound as a yellowish oil. Yield: 82%.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH3:9].Br[C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2>C1(C)C=CC=CC=1.CCOCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:8]([O:10][P:11]([C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([C:27]([F:29])([F:30])[F:28])=[CH:22][CH:21]=2)(=[O:15])[O:12][CH2:13][CH3:14])[CH3:9]
Reactant: FC(F)(F)c1ccc2ncc(Br)cc2c1
Reactant: CCOP([O-])OCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1cnc2ccc(C(F)(F)F)cc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
1.44 g of tetrakis-(triphenylphosphine)-palladium(O) are introduced in 16 ml of toluene, 3.8 ml of triethylamine and 3.6 ml of diethylphosphite at room temperature under nitrogen and mixed with 6.90 g of 3-bromo-6-trifluoromethyl-quinoline. It is stirred for two hours at 90° C. bath temperature. The mixture is diluted with ether, suctioned off and the filtrate is concentrated by evaporation. After column chromatography, 8.3 g of 6-trifluoromethyl-quinoline-3-phosphonic acid diethyl ester of melting point 69° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7]OS(C)(=O)=O)[CH:3]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[N:34]=[C:21]2[N:22]=[C:23]([NH:27][CH2:28][CH:29]3[CH2:33][CH2:32][CH2:31][NH:30]3)[N:24]=[C:25]([NH2:26])[N:20]2[N:19]=1.[CH3:35]CN(CC)CC>CC#N>[CH3:7][C:4]1[C:3]([CH2:35][N:30]2[CH2:31][CH2:32][CH2:33][CH:29]2[CH2:28][NH:27][C:23]2[N:24]=[C:25]([NH2:26])[N:20]3[N:19]=[C:18]([C:14]4[O:13][CH:17]=[CH:16][CH:15]=4)[N:34]=[C:21]3[N:22]=2)=[C:2]([CH3:1])[O:6][N:5]=1
Reactant: Cc1cc(COS(C)(=O)=O)no1
Reactant: CCN(CC)CC
Reactant: Nc1nc(NCC2CCCN2)nc2nc(-c3ccco3)nn12
Solvent: CC#N
Product: Cc1noc(C)c1CN1CCCC1CNc1nc(N)n2nc(-c3ccco3)nc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulfonic acid 5-methyl-isoxazol-3-ylmethyl ester (48 mg, 0.25 mmol; see Example 2(a) above) was added to a solution of 2-furan-2-yl-N5-pyrrolidin-2-ylmethyl-[1,2,4]-triazolo[1,5-a][1,3,5]triazine-5,7-diamine (0.24 mmol; see Example 6(a) and (b) above) and Et3N (0.30 mmol) in 2 mL of CH3CN. The resulting reaction mixture was stirred at room temperature for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 3.8 (br s, 2H), 2.2-3.2 (m, 8H), 1.6 (br s, 6H). MS: m/z: 410 [M+H]+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH3:37])[N:17]2[N:38]=[CH:39][N:40]=[C:16]2[N:15]1[CH:41]1[CH2:46][CH2:45][N:44]([C:47]([CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[O:48])[CH2:43][CH2:42]1>C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([CH:41]4[CH2:46][CH2:45][N:44]([C:47]([CH:49]5[CH2:54][CH2:53][O:52][CH2:51][CH2:50]5)=[O:48])[CH2:43][CH2:42]4)[C:16]4[N:17]([N:38]=[CH:39][N:40]=4)[C:18]=3[CH2:35][CH2:36][CH3:37])=[CH:22][CH:23]=2)[NH:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(C(=O)C3CCOCC3)CC2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCN(C(=O)C3CCOCC3)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
A mixture of hydroxylammonium chloride (967 mg), sodium hydrogen carbonate (1.68 g) and dimethyl sulfoxide (9 mL) was stirred at 60° C. for 30 min, 4′-({5-oxo-7-propyl-4-[1-(tetrahydro-2H-pyran-4-ylcarbonyl)piperidin-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (518 mg, dimethyl sulfoxide (3 mL) solution) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (6 mL). N,N′-Carbonyldiimidazole (178 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (167 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=5/95→30/70 (volume ratio)] and crystallized from acetonitrile to give the title compound as colorless crystals (253 mg, 44%).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C(O)C>[CH:13](=[N:3][NH:2][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1ccccc1C(=O)O
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccccc1NN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 2-hydrazino-benzoic acid mono hydrochloric acid salt (13.66 g, 72.42 mmol) dissolved in water (580 mL) and ethanol (125 mL) was added a solution of benzaldehyde (7.35 mL, 72.42 mmol) in ethanol (20 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for an additional 3 hours. The resulting solid was collected by filtration and dried in a vacuum oven to provide 12.0 g (69%) of 2-(N′-benzylidene-hydrazino)-benzoic acid as a yellow solid.