Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[N:22]1([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C1(C)C=C[C:38]([S:41](O)(=[O:43])=[O:42])=CC=1.C(=O)([O-])[O-].[Na+].[Na+].CS(Cl)(=O)=O>O1CCOCC1.O>[CH:17]1([CH:13]([N:11]2[CH:12]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:32][C:31]4[CH:33]=[CH:34][C:28]([N:22]5[CH2:23][CH2:24][N:25]([S:41]([CH3:38])(=[O:43])=[O:42])[CH2:26][CH2:27]5)=[CH:29][CH:30]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:14][C:15]#[N:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N#CCC(C1CCCC1)n1cc(-c2ccnc(Cl)n2)cn1
Reactant: Nc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCN(c2ccc(Nc3nccc(-c4cnn(C(CC#N)C5CCCC5)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (30 mg, 0.1 mmol), 4-(piperazin-1-yl)aniline (28.5 mg, 0.149 mmol), and p-toluenesulfonic acid (14 mg, 0.084 mmol) in dry 1,4-dioxane (0.8 mL) was refluxed overnight, then cooled to room temperature. To the resulting mixture was added 1.0 M sodium carbonate in water (0.8 mL), followed by methanesulfonyl chloride (0.015 mL, 0.20 mmol). The reaction was stirred at room temperature for 30 min and the phases were separated. The organic phase was purified on RP-HPLC at pH 10 to give the desired product as a racemic mixture (33 mg, 63%). LCMS (M+H) 521.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]1[C:18]([C:17]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH3:21])[NH:11][C:12]2=[N:13][NH:14][CH:15]=[C:16]12
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccccc1C=O
Product: CCOC(=O)C1=C(C)Nc2n[nH]cc2C1c1ccccc1OC

Procedure:
The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and ethyl acetoacetate in the same manner as in Example 1.
Reaction SMILES: C1C(CCC(C2C(O)=CC(O)=CC=2O[C@@H:18]2O[C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@H:20](O)[C@H:19]2[OH:28])=O)=CC=C(O)C=1.C([O-])(=[O:34])C.[Na+]>C(OC(=O)C)(=O)C>[CH3:18][C:19]([CH2:20][C:21]([CH2:22][C:24]([OH:34])=[O:25])=[O:26])=[O:28]
Reactant: O=C(CCc1ccc(O)cc1)c1c(O)cc(O)cc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)CC(=O)CC(=O)O
Yield: 181.7 %

Procedure:
1 g of phlorizin, 10 mL of acetic anhydride, and 0.82 g (0.01 mol) of sodium acetate were reacted at 100° C. for 6 hrs. The reaction mixture was cooled and the triacetate derivative of phlorizin precipitated from the solution in the form of a crystalline solid. The crystalline solid was separated by filtration, dissolved in 50 mL of hot methanol, and re-crystallized twice from hot methanol. The reaction yielded 0.6 g of the triacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[C:13]([O-])(=O)C.[NH4+].[N+:18](C)([O-:20])=[O:19]>C(O)(=O)C>[CH3:1][O:2][C:3]1([N+:18]([O-:20])=[O:19])[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:5]([CH:6]=[CH2:13])[CH2:4]1
Reactant: C[N+](=O)[O-]
Reactant: CC(=O)[O-]
Reactant: COc1ccc(C=O)cc1OC
Agent: [NH4+]
Solvent: CC(=O)O
Product: C=CC1=CC=C(OC)C(OC)([N+](=O)[O-])C1

Procedure:
207.0 g of 3,4-dimethoxybenzaldehyde, 100.0 g of ammonium acetate and 125 ml of nitromethane are heated to boiling for 3-4 h in 1.0 l of glacial acetic acid. After cooling in an ice bath, the precipitate is filtered off with suction, rinsed with glacial acetic acid and petroleum ether and dried. M.p.: 140-141° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]([C:15]1[CH:23]=[CH:22][C:18](C(Cl)=O)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].Cl.N1C=CC=C[CH:26]=1>>[C:11]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:22][C:23]=1[C:26]1[O:9][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: Nc1ccccc1C(=O)O
Reactant: c1ccncc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: Cl
Product: CC(C)(C)c1ccccc1-c1nc2ccccc2c(=O)o1
Reaction time: 12 h
Yield: 22 %

Procedure:
To a stirred solution of anthranilic acid (34.3 g, 250 mmol) in pyridine (400 mL) was added 4-tert-butylbenzoyl chloride (94 mL, 500 mL) dropwise via an addition funnel. After stirring for 12 h, the solution was poured onto a slurry of ice and 2 N aqueous hydrochloric acid (100 mL). The mixture was extracted with dichloromethane and the organic extract was concentrated in vacuo. The residue was dissolved in fresh dichloromethane, washed once with 2 N aqueous hydrochloric acid, once with saturated aqueous sodium chloride solution, twice with saturated aqueous sodium bicarbonate solution, three times with water, dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was crystallized from ether/hexanes to give an initial crop of 15.2 g (22%) of the title compound as an off-white solid, followed by additional crops totalling 16.9 g (24%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=4)[C:11]=3[CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:25]([O-:30])([N+]([O-])=O)=[O:26].C(O)(=O)C>ClCCl>[N+:25]([C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:24][C:11]=2[C:12]=1[C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=1)([O-:30])=[O:26]
Reactant: O=C(O)c1ccc(-c2coc3ccc(-c4ccccc4)cc23)cc1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2c([N+](=O)[O-])oc3ccc(-c4ccccc4)cc23)cc1

Procedure:
A mixture of 3.2 g. of the product of step D, 2 g. of dinitrogen tetraoxide, 1 ml. of acetic acid and 200 ml. of dichloromethane is stirred at 20° C. for 16 hours, washed with water and evaporated. The residue is treated with cold 5 percent sodium hydroxide solution, then acidified with 6N hydrochloric acid. The solid residue is separated and recrystallized from N,N-dimethylformamide to provide 4-(2-nitro-5-phenylbenzofuran-3-yl)benzoic acid, m.p. 235°-249° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([CH3:36])[CH:23]=1)=[O:9])=[O:4].[CH3:37][NH:38][CH3:39]>>[CH3:37][N:38]([CH3:39])[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([CH3:36])[CH:23]=1)=[O:9])=[O:4]
Reactant: CNC
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)CCl)cc34)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)CN(C)C)cc34)cc2C)cn1
Yield: 50 %

Procedure:
The procedure of Example 62 was repeated except for using 0.08 g of the compound obtained in Example 67 and 0.24 ml of dimethylamine 2 M THF instead of the compound obtained in Example 61 to obtain the title compound (0.04 g, 50%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Cl-].[Cl-].[Cl-].[Al+3].[P:14]([Cl:18])(Cl)(Cl)=[O:15]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][P:14]([Cl:18])(=[O:15])[O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cccc(C)c1OP(=O)(Cl)Oc1c(C)cccc1C

Procedure:
2,6-dimethylphenol (1 g, 8.18 mmol) and aluminum trichloride (109 mg, 0.818 mmol, 0.1 eq) were added to a microwave vial. Phosphorus oxychloride (0.375 mL, 4.09 mmol, 0.5 eq) was added, the vial was sealed and subsequently heated in the microwave for 1 h. Reaction progress was monitored by TLC, and the reaction was quenched before going to completion. The reaction mixture was diluted with dicholoromethane, washed with water and brine, dried over MgSO4, and filtered through celite. The filtrate was concentrated under reduced pressure providing an oily residue that was taken directly to the next step without further purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:25]=1[Cl:26].[N:36]1([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:39]2[CH2:40][CH2:41][N:36]([CH2:42][CH2:43][OH:44])[CH2:37][CH2:38]2)=[O:18])[N:8]([C:6]([C:30]2[CH:29]=[CH:28][C:27]([C:22]3[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=3)=[CH:32][CH:31]=2)=[O:7])[CH2:12]1
Reactant: OCCN1CCNCC1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)c2ccc(-c3ccc(Cl)c(Cl)c3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 3′,4′-dichloro[1,1′-biphenyl]-4carboxylic acid, and 2-(1-piperazinyl)ethanol, the title compound was obtained in 86% purity by HPLC. MS(ESI+): m/z =520.
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:23])([CH3:22])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][N:16]2[N:20]=[C:19]([NH2:21])[CH:18]=[N:17]2)[N:14]=1)([CH3:6])([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.[CH:33]1[CH:38]=[C:37]([CH2:39][O:40][C:41](Cl)=[O:42])[C:36]([Cl:44])=[CH:35][CH:34]=1>C(Cl)Cl.O>[Cl:44][C:36]1[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=1[CH2:39][O:40][C:41](=[O:42])[NH:21][C:19]1[CH:18]=[N:17][N:16]([CH2:15][C:13]2[N:14]=[C:10]([C:9]([CH3:23])([CH3:22])[O:8][SiH2:7][C:3]([CH3:6])([CH3:4])[CH3:5])[O:11][CH:12]=2)[N:20]=1
Reactant: O=C(Cl)OCc1ccccc1Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(Cn2ncc(N)n2)co1
Agent: N#N
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[SiH2]OC(C)(C)c1nc(Cn2ncc(NC(=O)OCc3ccccc3Cl)n2)co1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-ylmethyl]-2H-[1,2,3]triazol-4-ylamine (93 mg, 0.30 mmol) in CH2Cl2 (5.0 mL) was treated with DIPEA (0.08 mL, 0.48 mmol) followed by 2-chlorobenzylchloroformate (0.06 mL, 0.39 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and water (5.0 mL) was added. The layers were separated and the aq. layer extracted with CH2Cl2 (2×10 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (9:1 to 1:1 hept-EA) gave the title compound as an orange solid. TLC:rf (1:1 hept-EA)=0.27. LC-MS-conditions 01: tR=1.11 min; [M+H]+=478.01.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]1([CH:20]2[CH2:26][C:25](=O)[O:24][C:22](=[O:23])[CH2:21]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.[Cl:28]CCl>Cl.O1CCOCC1>[ClH:28].[I:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:25]([CH2:26][CH:20]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)[CH2:21][C:22]([OH:24])=[O:23])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(I)cc1N
Reactant: O=C1CC(c2cccc3ccccc23)CC(=O)O1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CC(Cc1nc2ccc(I)cc2[nH]1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Iodo-1,2-phenylenediamine (0.47 g) and 3-(1-naphthyl)glutaric anhydride (0.48 g) were dissolved in dichloromethane (6 ml) with heating. The dark solution was stirred at rt for 1 h. The precipitate formed was collected by suction filtration, washed with dichloromethane, and dried in vacuo to give a mixture of regioisomeric amides (0.69 g) as beige coloured solid. This solid was dissolved in 4M HCl in 1,4-dioxane (3 ml) and the dark solution was heated to reflux for 1 h. All volatiles were removed at the water aspirator and the amorphous residue is crystallised from acetone/methanol to provide 4-(5-iodo-2-benzimidazolyl)-3-(1-naphthyl)butanoic acid HCl (0.54 g) as light grey solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:21]([NH2:24])[CH2:22][CH3:23].O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:24][CH2:21][CH2:22][CH3:23])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCNc1cc(Br)ccc1[N+](=O)[O-]
Reaction time: 14 h
Yield: 95.2 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (0.5 g, 2.29 mmol) and diisopropyl ethyl amine (1.38 mL, 3.44 mmol) in NMP (5 mL) was added propylamine (0.22 mL, 2.7 mmol). The solution was stirred for 14 h to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 2 mL of water, subjected to high vacuum for drying for 14 h to furnish 5-bromo-2-nitro-N-propylbenzenamine (520 mg, 2.18 mmol), 92% yield, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[Cl:11][O-].[Ca+2].Cl[O-]>CC(C)=O.O.C(O)(=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: [O-]Cl
Reactant: COc1ccccc1C=O
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(Cl)cc1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxybenzaldehyde (2g) in acetone (20 ml), water (40 ml) and acetic acid (4 ml) were added. Under ice cooling, calcium hypochlorite (5.25 g) was added, and then the mixture was stirred at that temperature for 1 hour and at room temperature for 2 hours. The reaction solution was extracted with methyl tert-butyl ether (20 ml×2), and the organic layer was washed with an aqueous sodium thiosulfate solution, then dried over magnesium sulfate. The solvent was distilled off in vacuo and the obtained residue was purified by slurry in heptane. The precipitated crystals were collected by filtration and dried in vacuo to obtain the title compound in an amount of 2.2 g as a colorless crystal.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[NH:10]1[C:15]2[CH:16]=[CH:17][S:18][C:14]=2[C:13](=[O:19])[NH:12][C:11]1=[O:20]>>[N+:6]([C:17]1[S:18][C:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[NH:10][C:15]=2[CH:16]=1)([O-:9])=[O:7]
Reactant: O=c1[nH]c(=O)c2sccc2[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]c(=O)c2sc([N+](=O)[O-])cc2[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61 %

Procedure:
A stirred mixture of concentrated sulphuric acid (98%, 270 ml) and fuming nitric acid (270 ml) at 0° C. was treated portionwise with Example 1 (90 g, 530 mmol). Upon complete dissolution, stirring was continued at room temperature for a further 20 min. The solution was added slowly to vigorously stirred ice/water (2000 ml). After 30 min stirring at room temperature, a yellow solid was filtered, washed with water and dried in vacuo at 40° C. to give the title compound in 61% yield, >95% purity. LC-MS m/z=251.0 [M+H]+; RT=2.92; LC-MS method 1. 1H NMR: δH (400 MHz, D6-DMSO) 7.66 (1H, s), 11.71 (1H, b), 11.79 (1H, b).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].C(N(C(C)C)C(C)C)C.[Cl:21][C:22]1[N:27]=[C:26]([Cl:28])[C:25]([C:29]#[N:30])=[CH:24][N:23]=1>COCCOC>[Cl:21][C:22]1[N:27]=[C:26]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([NH:7][CH3:8])=[O:6])[C:25]([C:29]#[N:30])=[CH:24][N:23]=1.[Cl:28][C:26]1[C:25]([C:29]#[N:30])=[CH:24][N:23]=[C:22]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([NH:7][CH3:8])=[O:6])[N:27]=1
Reactant: N#Cc1cnc(Cl)nc1Cl
Reactant: CNC(=O)c1cccc(N)c1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(Nc2nc(Cl)ncc2C#N)c1
Product: CNC(=O)c1cccc(Nc2ncc(C#N)c(Cl)n2)c1
Temperature: 25 °C
Yield: 51.1 %

Procedure:
To 3-amino-N-methylbenzamide (353 mg, 2.351 mmol) in DME (8 mL) at 0° C. was added N-ethyl-N-isopropylpropan-2-amine (1.024 mL, 5.88 mmol) followed by 2,4-dichloropyrimidine-5-carbonitrile (450.0 mg, 2.59 mmol). The resulting reaction mixture was allowed to warm to RT (ice melt) over 3 h, concentrated, purified using MPLC (25 g cartridge, 40 g column, 0 to 100% EtOAc-hexanes). Separation of 2- and 4-substitution products was not achieved. Fractions with both products were combined and concentrated giving about a 3:1 mixture of 3-(2-chloro-5-cyanopyrimidin-4-ylamino)-N-methylbenzamide and 3-(4-chloro-5-cyanopyrimidin-2-ylamino)-N-methylbenzamide (172.7 mg).
Reaction SMILES: N1CCCCC1.FC(F)OC1C(OC)=CC(C=O)=CC=1OC.C(CC(N[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=O)(O)=O>C1(C)C=CC=CC=1>[C:32]([OH:34])(=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:30]=1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: COc1cc(C=O)cc(OC)c1OC(F)F
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Yield: 163.8 %

Procedure:
Piperidine (110 μL, 1.10 mmol) was added to a suspension of 4-(difluoromethoxy)-3,5-dimethoxybenzaldehyde (200 mg, 1.10 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (233 mg, 1.05 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 30 min. The reaction was then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (4 mL) and water (2 mL) and the solution was acidified with 20% aqueous AcOH. The crude product was collected by filtration and recrystallised from EtOH/water and filtered to afford (E)-2-[[4-(difluoromethoxy)-3,5-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (210 mg, 51%) as a pale yellow crystalline solid; mp 211-215° C.; δH (400 MHz, DMSO-d6) 3.87 (s, 6H, OCH3), 6.87 (t, J=75 Hz, 1H, OCHF2), 6.98 (d, J=15.6 Hz, 1H, CH═CHCO), 7.17 (s, 2H, H2′, H6′), 7.18 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.61 (d, J=15.6 Hz, 1H, CH═CHCO), 7.62 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 8.00 (d, J5,6=8.0 Hz, 1H, H6), 8.61 (d, J3,4=8.0 Hz, 1H, H3), 11.33 (s, 1H, NH), 13.60 (s, 1H, CO2H); δC (100 MHz, DMSO-d6) 56.4, 105.5, 116.8 117.2 (t, J=259 Hz), 120.4, 122.9, 123.1, 129.6, 131.1, 132.9, 134.0, 140.8, 141.1, 152.6, 163.7, 169.4; νmax 1153, 1113, 1224, 1506, 1593, 1694, 2602, 2946 cm−1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]2[N:12]=[C:11]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[S:10][C:6]=2[N:7]=[CH:8][N:9]=1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][C:24]=1[C:31]([F:34])([F:33])[F:32].C(N(CC)CC)C.[OH2:42]>C(Cl)Cl>[CH3:2][O:3][C:4]1[C:5]2[N:12]=[C:11]([NH:13][C:14]([N:16]3[CH2:17][CH2:18][N:19]([C:27](=[O:42])[C:26]4[CH:29]=[CH:30][C:23]([F:22])=[C:24]([C:31]([F:34])([F:33])[F:32])[CH:25]=4)[CH2:20][CH2:21]3)=[O:15])[S:10][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: COc1ncnc2sc(NC(=O)N3CCNCC3)nc12
Reactant: Fc1ccc(CCl)cc1C(F)(F)F
Reactant: O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncnc2sc(NC(=O)N3CCN(C(=O)c4ccc(F)c(C(F)(F)F)c4)CC3)nc12
Yield: 30.5 %

Procedure:
A solution of piperazine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide hydrochloride (as prepared in Example 1, 300 mg, 0.91 mmol), 4-fluoro-3-(trifluoromethyl)benzyl chloride (140 mL, 0.92 mmol) and triethylamine (3.4 mL, 2.27 mmol) in methylene chloride (15 mL) was stirred overnight at 25° C. At this time, the reaction was poured into water and was extracted into ethyl acetate. The combined organics were washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solids were recrystallized twice from 2:1:1 methanol/dimethylsulfoxide/dioxane to afford 4-(4-fluoro-3-trifluoromethyl-benzoyl)-piperazine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (134 mg, 30.5%) as white solid; ES-HRMS m/e calcd for C19H16F4N6O3S (M+H)+ 485.1014, found 485.1014.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[C:8]([C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)=[CH:7][N:6]=1.[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])([O-:26])=[O:25].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CC(N(C)C)=O.C(OCC)(=O)C>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[C:8]([C:19]3[NH:23][CH:22]=[CH:21][N:20]=3)=[CH:7][N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=3)=[O:31])[N:10]=2)=[CH:12][CH:13]=1)#[N:18]
Reactant: N#Cc1ccc(-c2nc(NCCN)ncc2-c2ncc[nH]2)cc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2nc(NCCNC(=O)c3cccc([N+](=O)[O-])c3)ncc2-c2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.9 %

Procedure:
A mixture of 4-{2-[(2-aminoethyl)amino]-5-imidazolylpyrimidin-4-yl}benzene-carbonitrile (30 mg, 0.098 mmol), 3-nitrobenzoic acid (17 mg, 0.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (19 mg, 0.1 mmol), 1-bydroxybenzotriazole hydrate (HOBT) (14 mg, 0.1 mmol), and 4-dimethylaminopyridine (DMAP) (12 mg, 0.1 mmol) in DMA (500 uL) were stirred at room temperature. After 12 hours, the reaction was diluted with ethyl acetate (10 ml) and extracted with sat. aq. NaHCO3 (2×5 ml), water (3×5 ml), brine (5 ml), dried with Na2SO4, filtered, and concentrated. The resulting product, N-(2-{[4-(4-cyanophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)(3-nitrophenyl)carboxamide weighing 32 mg (70% yield) was approximately 95% pure by LCMS and HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:24])=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[C:3]([CH3:24])=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Cc1c(N)cccc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2C)n(C)n1
Yield: 81.5 %

Procedure:
Using N-[6-(3-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (130 mg, 0.402 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (83 mg, 0.523 mmol), triethylamine (122 mg, 1.21 mmol) and tetrahydrofuran (5.0 mL) as starting materials and in the same manner as in Example 96, the title compound (146 mg, 82%) was obtained as a white powder.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.[Cu]Cl>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([N:22]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=[C:10]2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:20][CH:19]=1
Reactant: C(C#Cc1ccccc1)#Cc1ccccc1
Reactant: Nc1ccc(Br)cc1
Agent: Cl[Cu]
Solvent: ClC(Cl)Cl
Product: Brc1ccc(-n2c(-c3ccccc3)ccc2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
Under an argon atmosphere, 15 g (74 mmol) of 1,4-di-phenylbutadiyne, 12.76 g (74 mmol) of p-bromoaniline and 1.84 g (18 mmol) copper(I) chloride were put into 500 ml round-bottomed flask, and the resulting mixture was reacted at 150° C. for 5 hours while stirring. After the reaction was completed, the reaction mixture was cooled down to room temperature, dissolved in chloroform and then washed with 5% hydrochloric acid several times. The combined organic extract was washed with water several times and then dried with anhydrous magnesium sulfate. The solvent was removed to obtain solid, which was recrystallized from ethyl acetate to give 20.4 g (73.5%) white solid having a melting point of 218-219° C.