Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:12][C:13]1[CH:14]=[C:15]([C:21]#[N:22])[C:16](=[CH:19][CH:20]=1)[C:17]#[N:18])([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:6].C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:5]([NH:12][C:13]1[CH:14]=[C:15]([C:21]#[N:22])[C:16](=[CH:19][C:20]=1[N+:1]([O-:4])=[O:2])[C:17]#[N:18])([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:6]
Reactant: CCOC(=O)C(=O)Nc1ccc(C#N)c(C#N)c1
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)Nc1cc(C#N)c(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
To 50 ml ice-cooled 100% nitric acid was added gradually 2.0 g (8.2 mmol) 4-ethoxalylaminophthalonitrile. Stirring was continued at 25° C. for 48 h. The reaction mixture was poured into 300 ml ice-water to give 1.6 g crude product. Column chromatography (200 g kiselgel; eluents: toluene containing ethyl acetate) gave 0.7 g (30%) 4-ethoxalylamino-5-nitrophthalonitrile. M.p. 140°-141° C. 1H-NMR (DMSO-d6): 11.7 (1H, s), 8.97 (1H, s), 8.70 (1H, s), 4.4 (2H, q), 1.4 (3H, t), and 0.75 g (32%) 4-ethoxalylamino-3-nitrophthalonitrile. M.p. 140-141° C. 1H-NMR (DMSO-d6) 11.7 (1H, s), 8.4 (2H, dd, J=9Hz), 4,4 (2H, q), 1.4 (3H, t).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH3:25])[N:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[Cl:26].[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[C:5]([Cl:26])[CH:6]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:25])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(-c2ncnc(C)c2C#Cc2ccc(N)nc2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncnc(-c2ccc(C(=O)O)c(Cl)c2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 13.8 g (36.4 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-2-chloro-benzoic acid methyl ester using 7.64 g (182 mmoL) LiOH in 200 mL water and 400 mL THF. The reaction mixture is stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5-6 is reached. The precipitated product is filtered off and washed with water and MeOH. After drying 12.1 g of the desired product is obtained, which is used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[N:4]([CH2:15][C:16]2[CH:17]=[C:18]([Cl:29])[CH:19]=[C:20]3[C:24]=2[N:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[N:22]=[CH:21]3)[N:3]=1.[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)OC>[Cl:29][C:18]1[CH:19]=[C:20]2[C:24](=[C:16]([CH2:15][N:4]3[C:5]4[C:10](=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=4)[C:2]([NH:1][CH3:30])=[N:3]3)[CH:17]=1)[N:23]([CH2:25][CH:26]([CH3:27])[CH3:28])[N:22]=[CH:21]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1ccc2c(c1)c(N)nn2Cc1cc(Cl)cc2cnn(CC(C)C)c12
Solvent: COC(OC)OC
Product: CNc1nn(Cc2cc(Cl)cc3cnn(CC(C)C)c23)c2ccc(C(=O)OC)cc12
Temperature: 60 °C

Procedure:
A mixture of compound 67 (0.054 g, 0.13 mmol), p-toluenesulphonic acid (0.003 g, 0.013 mmol), in trimethylorthoformate (3 mL) was heated at 100° C. in a closed vessel for 16 h. Then, the reaction was concentrated to dryness under vaccum. The residue was dissolved in tetrahydrofuran (4 mL), sodium borohydride was added (0.015 g, 0.395 mmol) and the resulting mixture was heated at 60° C. for 5 h.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C@@H:24]1[CH2:27][CH2:26][N:25]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C@@H:24]1[CH2:27][CH2:26][N:25]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CON
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Yield: 82.5 %

Procedure:
Following a procedure analogous to Example 45, from the carboxylic acid (6b, 553 mg, 2.00 mmol) of Example 9 or 16 and (S)-tert-butyl 2-((aminooxy)methyl)azetidine-1-carboxylate (578 mg) described in Reference Example 21, 760.1 mg of the title compound was afforded (yield 83%).
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[NH:12][CH3:13]>C(Cl)Cl>[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[N:12]([CH3:13])[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(=O)Cl
Reactant: CNc1ccccc1F
Solvent: ClCCl
Product: COC(=O)CC(=O)N(C)c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-chloro-3-oxopropanoate (1.75 mL, 15.99 mmol) in dry DCM (32 ml) was added 2-fluoro-N-methylaniline (2 g, 15.99 mmol) and the reaction mixture was stirred at 0° C. for 1 h, evaporated then redissolved in EtOAc, washed with dilute NaHCO3, and brine. The organic phase was dried over sodium sulfate, and concentrated under reduced pressure to afford methyl 3-((2-fluorophenyl)(methyl)amino)-3-oxopropanoate as yellow oil which was used without further purification (3.3 g, 16 mmol, 97%, crude). To a solution of this material (3.3 g, 16 mmol) in THF (16 ml) and water (16 ml) was added LiOHH2O (1.35 g, 31.5 mmol) and the reaction mixture was stirred overnight, evaporated (to remove the THF) and then extracted with EtOAc. The aqueous phase was acidified to pH˜1 by addition of 1N HCl and extracted with EtOAc. The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound 245 as a brown solid, which was used without further purification (2.75 g, 13.03 mmol, 81% yield). MS (m/z): (M+1) 218.0 (88%), (2M+Li) 429.0 (100%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].F[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[C:20](#[N:24])[CH:21]([CH3:23])[CH3:22].Cl>O1CCCC1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:21]([CH3:23])([CH3:22])[C:20]#[N:24])=[CH:13][CH:14]=1
Reactant: CC(C)C#N
Reactant: COc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)C#N)cc1
Yield: 52 %

Procedure:
Add potassium bis(trimethylsilyl)amide (39.90 g, 200 mmol) to a stirred solution of 4-fluoroanisole (15.0 mL, 133 mmol), isobutyronitrile (49.0 mL, 539 mmol) and anhydrous tetrahydrofuran (150 mL). Heat the reaction to reflux under nitrogen for 72 h. Cool the reaction to room temperature, pour it into 1 N hydrochloric acid (300 mL), and extract with diethyl ether (3×100 mL). Wash the diethyl ether extracts with brine (100 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 10% ethyl acetate/hexanes to yield 12.13 g (52%) of 2-(4-methoxy-phenyl)-2-methyl-propionitrile: TLC: Rf in 10% ethyl acetate/hexanes: 0.30; 1H NMR (CDCl3): 7.40-7.37 (m, 2H), 6.92-6.90 (m, 2H), 3.81 (s, 3H), 1.70 (s, 6H).
Reaction SMILES: C([O:4][C:5]([C:7]1[O:14][C:13]2[C:12]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)=[N:11][N:10](C(OCC)=O)[C:9]=2[CH:8]=1)=[O:6])CC.[OH-].[Na+]>CO>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:12]1[NH:11][N:10]=[C:9]2[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[O:14][C:13]=12)=[O:26]
Reactant: CCCOC(=O)c1cc2c(o1)c(NC(=O)c1ccccc1[N+](=O)[O-])nn2C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccccc1C(=O)Nc1[nH]nc2cc(C(=O)O)oc12
Yield: 129 %

Procedure:
To a solution of 3-(2-Nitro-benzoylamino)-furo[3,2-c]pyrazole-1,5-dicarboxylic acid 1-ethyl ester 5-propyl ester (7.6 g, 0.0176 mol) in methanol (100 mL), NaOH 2N (44.1 mL, 0.0882 mmol) was added. The mixture was gently refluxed for 8 hours, then the solvent was evaporated under vacuum, and the residual aqueous solution was diluted with water and ice. Hydrochloric acid (12 N) was added until pH 2. The yellowish solid that precipitated was collected, washed with water and dried under vacuum at 60° C. 6.5 g of the title compound was so obtained.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[CH:22][C:23]5[O:27][C:26]([C:28](OC)=[O:29])=[CH:25][C:24]=5[CH:32]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.[OH:33][CH2:34][CH2:35][NH2:36]>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[CH:22][C:23]5[O:27][C:26]([C:28]([NH:36][CH2:35][CH2:34][OH:33])=[O:29])=[CH:25][C:24]=5[CH:32]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1
Reactant: NCCO
Product: O=C(NCCO)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1

Procedure:
In like manner to preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, the reaction of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine with 2-hydroxyethylamine yielded N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]1[CH2:26]Cl>CN(C)C=O>[CH3:17][N:18]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]1[CH2:26][O:10][C:4]1[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([CH3:1])[CH:3]=1
Reactant: CSc1ccc(O)cc1C
Reactant: Cn1c([N+](=O)[O-])cnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc(OCc2ncc([N+](=O)[O-])n2C)cc1C
Temperature: 25 °C

Procedure:
To a solution of 15.4 g (0.1 mol) of 3-methyl-4-methylmercaptophenol in 30 ml of dimethylformamide, 13.8 g (0.1 mol) of potassium carbonate powder are added, and then a solution of 17.6 g (0.1 mol) of 1-methyl-2-chloromethyl-5-nitro-imidazole in 40 ml of dimethylformamide is added dropwise while stirring at 25° C. The temperature of the faintly exothermal reaction is adjusted to at most 35° C. by cooling with ice water. The mixture is then stirred for another hour at 25° C., poured onto ice/water, the precipitate is suction-filtered, washed with water and recrystallized from methanol with an addition of charcoal to yield 21.7 g (74% of the theoretical yield) of 1-methyl-2-(3-methyl-4-methylthiophenyl-oxymethyl)-5-nitro-imidazole in the form of yellow crystals, m.p. 108° C.
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:13]Br)[CH:3]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][C:11]=1[F:12])[C:6](=[O:8])[N:18]([CH:15]([CH3:17])[CH3:16])[CH2:13]2
Reactant: COC(=O)c1cc(F)c(Br)cc1CBr
Reactant: CC(C)N
Product: CC(C)N1Cc2cc(Br)c(F)cc2C1=O

Procedure:
This compound was prepared using procedures analogous to those described for the synthesis of Example 52, Step 6 starting from methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate and isopropylamine. LC/MS: (M+H)+=271.9/273.9.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[C:7]([F:32])=[C:8]([CH:20]=[CH:21][C:22]=1[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1)[O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][CH3:19])[N:11]=1.Cl.O>O1CCCC1>[F:32][C:7]1[C:6]([CH:2]=[O:1])=[C:22]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)[CH:21]=[CH:20][C:8]=1[O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][CH3:19])[N:11]=1
Reactant: COc1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C3OCCO3)c2F)ccc1C#N
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2F)ccc1C#N
Temperature: 25 °C
Yield: 73.9 %

Procedure:
A solution of 6-(3-(1,3-dioxolan-2-yl)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-methoxynicotinonitrile (2.18 g, 4.93 mmol) in tetrahydrofuran (6 mL) was added 3 M HCl (3 mL). The solution was refluxed for four hours. The solution was cooled to room temperature and water was added. The solution was extracted with ethyl acetate. The organic layer was washed with water, then washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure to give 6-(2-fluoro-3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-methoxynicotinonitrile (1.45 g, 74% yield).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1>CCOC(C)=O>[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])([CH3:1])[CH3:18])=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccc(-c2ccccc2Br)cc1
Reactant: C[Mg]Br
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc(-c2ccccc2Br)cc1

Procedure:
Prepared according to the general procedure Cer-1 using methyl magnesium bromide and ketone from step 1 as starting material. Flash chromatography (Hex:EtOAc; 90:10) afforded the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[Cl:10])#[N:2].BrN1C(=[O:17])CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:10][C:4]1[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:9]=[O:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C#N)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cccc(C=O)c1Cl
Yield: 107.5 %

Procedure:
To a solution of 2-chloro-3-methylbenzaldehyde (19.4 g) in ethanol (45 ml) was added an aqueous hydroxylamine hydrochloride (9.7 g) solution (12 ml), and an aqueous sodium hydroxide (6.9 g) solution (10 ml) was added. The mixture was stirred at room temperature for 1.5 hours. Water (500 ml) was added and the precipitated crystals were collected by filtration. The obtained white crystals (16.1 g) were dissolved in acetic anhydride (50 ml) and the mixture was heated under reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (5:1)) to give 2-cyano-6-methylchlorobenzene (10.9 g) as a white solid. A suspension of 2-cyano-6-methylchlorobenzene (10.9 g), N-bromosuccinimide (12.8 g) and benzoyl peroxide (523 mg) in carbon tetrachloride (100 ml) was heated under reflux for 3.5 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (20:1)) to give 2-chloro-3-cyanobenzaldehyde (12.8 g) as a colorless oil. Subsequently, the title compound was prepared from 2-chloro-3-cyanobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]2>C(Cl)Cl>[C:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:8]=[O:7])[CH:18]=[CH:17]2)([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc2cc(CO)ccc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(C=O)ccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A mixture of 5 mL (61.8 mmol) of pyridine and 70 mL of CH2Cl2 was cooled to 0° C. Then 3.0 g (30 mmol) of CrO3 was added in several portions. The mixture was stirred at 0° C. for 15 min before a solution of 0.69 g (3.19 mmol) of methyl 6-hydroxymethyl-2-naphthoate in 10 mL of CH2Cl2 was added. The mixture was stirred at room temperature for 2 hr and then filtered through Florisil (500 mL CH2Cl2 rinse). The filtrate and washings were concentrated and filtered through 50 g of silica gel with 50% EtOAc/hexane to give 0.66 g (96% yield) of the pure aldehyde as a white solid. The analytical sample was recrystallized from EtOAc/hexane: mp 132°-134° C.; IR (mull) 1740, 1700, 1350, 1310, 1270, 1220, 1180, 1140, 1110, 990, 920, 830, 780, 760 cm- 1 ; 1H NMR (CDCl3) δ4.00 (s, 3, CO2CH3), 8.0-8.7 (m, 6, ArH), 10.23 (s, 1, CHO); MS calcd for C13H10O3 214.0630, found 214.0627.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:21][CH2:22]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Yield: 98.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-methylbenzoic acid (5 g) and 1-(2,4-dimethylphenyl)piperazine (4.6 g), the title compound (8.9 g) was obtained.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:11]([C:12]2[S:13][C:14]([Br:17])=[N:15][N:16]=2)[N:10]=[C:9]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[S:8]1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:17][C:14]1[S:13][C:12]([N:11]2[N:10]=[C:9]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[S:8][C:7]2([CH2:6][CH2:5][CH2:4][NH2:1])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:16][N:15]=1
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nnc(Br)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nnc(Br)s1
Temperature: 23 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-bromo-1,3,4-thiadiazole (0.006 g, 0.011 mol) was dissolved in 0.25 mL THF, followed by addition of water (0.015 g, 15 μL) and triphenylphosphine (0.015 g, 0.057 mmol), and the reaction mixture was stirred at 23° C. overnight. The crude mixture was purified by directly loading onto a preparative TLC plate and eluting first with 12:1 (DCM:MeOH), followed by a second elution with 10:1 (DCM:MeOH) (both with NH4OH present), to afford the desired product (0.003 g, 53%). MS ESI (+) m/z 495/497 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.52 (m, 3H), 7.35 (t, 2H, J=7.6 Hz), 7.30 (d, 1H, J=7.2 Hz), 7.12 (m, 2H), 3.46 (m, 1H), 2.65 (m, 6H), 2.05 (m, 1H), 1.61 (m, 1H).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].Cl[C:11](=[CH2:14])[C:12]#[N:13].Cl>O>[C:12]([C:11]1[N:3]=[N:2][N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:14]=1)#[N:13]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C=C(Cl)C#N
Agent: Cl
Solvent: O
Product: CCOC(=O)Cn1cc(C#N)nn1
Temperature: 25 °C

Procedure:
4.1 g (31.9 mmol) of ethyl azidoacetate and 2.8 g (31.9 mmol) of 2-chloroacrylonitrile are stirred in 32 ml of water at a bath temperature of 80° C. for 16 h. After cooling to RT, the solution is acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure. 50 ml of ethanol and 10 drops of concentrated sulphuric acid are added to the residue, and the mixture is stirred under reflux for 16 h. For work-up, the reaction mixture is concentrated under reduced pressure, ethyl acetate is added to the residue, the suspension is washed with semiconcentrated sodium bicarbonate solution and the organic phase is dried over sodium sulphate. The solvent is removed completely on a rotary evaporator and the solid is dried under reduced pressure. Yield: 1.5 g (25% of theory)
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:20][NH:21][CH3:22].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:20][N:21]([CH3:22])[S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N(C)C)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (110 mg; 0.33 mmol; 1 eq), is dissolved in DMF (10 ml). Dimethylamine (0.1 ml; 1.65 mmol; 5 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added. After one hour, the solvents are evaporated to dryness. The crude product is re-dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is precipitated in a mixture of DCM and diethyl ether, affording after filtration, Compound (18) as a yellow powder (52 mg; 46%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]1[S:18][C:17]([N:19]2[C:23]([C:24](O)=[O:25])=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[N:20]2)=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:32]([NH:39][C:24]([C:23]1[N:19]([C:17]2[S:18][C:14]([CH2:13][NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:31])=[CH:15][CH:16]=2)[N:20]=[C:21]([C:27]([F:28])([F:30])[F:29])[CH:22]=1)=[O:25])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2C(=O)O)s1
Reactant: NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2C(=O)NCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
To a stirred solution of 25 (45 mg, 0.097 mmol) in CH2Cl2 (0.65 mL) were added benzylamine (0.016 mL, 0.146 mmol), EDC (37.3 mg, 0.195 mmol) followed by DMAP (4.76 mg, 0.039 mmol). The mixture was stirred for 16 h at room temperature. The mixture was quenched with a saturated sodium carbonate solution and extracted with ethyl acetate, washed with brine, dried (MgSO4) filtered and concentrated. The residue was purified by silica gel column chromatography with gradient of EtOAc (20-60%) in hexanes to afford 26a (24 mg, 45%) as a white solid. LRMS (ESI): calc. 551.2; found 574.6 (MNa)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2O)=[C:4]([O:13][CH3:14])[CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[C:10]2[C:5](=[C:4]([O:13][CH3:14])[CH:3]=[C:2]([F:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(F)cc2c(O)nccc12
Product: COc1cc(F)cc2c(Cl)nccc12
Yield: 95.1 %

Procedure:
A solution of 7-fluoro-5-methoxyisoquinolin-1-ol (383 mg, 1.983 mmol) in POCl3 (2772 μl, 29.7 mmol) was refluxed (90° C.) for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum to give 1-chloro-7-fluoro-5-methoxyisoquinoline (399 mg, 95% yield).