Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>CN(C=O)C>[CH2:36]([N:38]([CH2:39][CH3:40])[C:14](=[O:16])[C:13]1[CH:12]=[C:11]([S:17]([NH2:20])(=[O:19])=[O:18])[C:10]([Cl:21])=[CH:9][C:8]=1[NH:7][CH2:6][C:3]1[O:4][CH:5]=[CH:1][CH:2]=1)[CH3:37]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: CCNCC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCN(CC)C(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1

Procedure:
In a similar manner to Example 7, furosemide can be reacted with EDC, HOBt and diethylamine in DMF to yield N,N-diethyl 5-aminosulfonyl-4-chloro-2-[(2-furanylmethyl)-amino]benzamide.
Reaction SMILES: [ClH:1].FC1C=C(NC(=O)CC(NC2C=CC(F)=CC=2)=O)C=CC=1[O:9][C:10]1[C:15]2=[C:16](C)[C:17](OCCN3CCOCC3)=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1>C(N)=O>[Cl:1][C:16]1[CH:17]=[CH:18][N:14]2[C:15]=1[C:10](=[O:9])[NH:11][CH:12]=[N:13]2
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Reactant: Cl
Solvent: NC=O
Product: O=c1[nH]cnn2ccc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
A solution of methyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate (10.0 g, 57.3 mmol, WO 03/099286: Compound A of Example 9) in formamide (40 mL) was heated at 170° C. for 1 h and then at 190° C. for 1 h. Upon cooling to room temperature, the mixture solidified. The product was purified by recrystallization from ethyl acetate to give the title compound (6.53 g, 67%) as a white solid. 1H NMR (CDCl3) δ 10.24 (br s, 1H), 7.48 (d, 1H, J=3.6 Hz), 7.29 (d, 1H, J=2.8 Hz), 6.47 (d, 1H, J=2.8 Hz); MS(ESI+) m/z 170.1 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[CH2:7][N:6]([CH3:10])[C:5]1=[O:11])([CH3:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH:17]=[C:7]1[N:6]([CH3:10])[C:5](=[O:11])[N:4]([CH:1]([CH3:3])[CH3:2])[C:8]1=[O:9])[CH3:16]
Reactant: CC(C)N1C(=O)CN(C)C1=O
Reactant: COC(OC)N(C)C
Product: CC(C)N1C(=O)C(=CN(C)C)N(C)C1=O
Temperature: 100 °C

Procedure:
A mixture of 13.4 g of 3-isopropyl-1-methyl-imidazolidine-2,4-dione and 13.6 ml dimethylformamide dimethylacetal were heated at 100° C. over the weekend. The reaction mixture was cooled to rt and purified by flash chromatography to give 9.9 g of a golden oil. Mass spectrum (EI) m/z 211 M+.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][CH:28]([F:52])[O:29][C:30]1[CH:51]=[CH:50][C:33]([CH2:34][N:35]2[C:39](=[O:40])[N:38]([C:41]3[S:42][C:43]([C:47](O)=[O:48])=[C:44]([CH3:46])[N:45]=3)[CH:37]=[N:36]2)=[CH:32][CH:31]=1.[N:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][NH2:60])[CH:54]=1>>[F:52][CH:28]([F:27])[O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:34][N:35]2[C:39](=[O:40])[N:38]([C:41]3[S:42][C:43]([C:47]([NH:60][CH2:59][C:55]4[CH:54]=[N:53][CH:58]=[CH:57][CH:56]=4)=[O:48])=[C:44]([CH3:46])[N:45]=3)[CH:37]=[N:36]2)=[CH:50][CH:51]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(-n2cnn(Cc3ccc(OC(F)F)cc3)c2=O)sc1C(=O)O
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(Cc3ccc(OC(F)F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 49 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-(difluoromethoxy)benzyl)-5-oxo-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 49% yield: mp 151-152° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.55 (br s, 2H), 8.23 (s, 1H), 7.72-7.63 (m, 1H), 7.43-7.30 (m, 2H), 7.29-7.20 (m, 1H), 7.12-7.00 (m, 2H), 6.78 (t, J=5.6 Hz, 1H), 6.46 (t, JH-F=73.8 Hz, 1H), 4.94 (s, 2H), 4.57 (d, J=5.6 Hz, 2H), 2.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7, 153.4, 151.1, 150.9, 149.9, 149.2, 148.9, 135.8, 132.2, 130.0, 129.9, 121.7, 119.9, 119.2, 115.7, 112.3, 48.9, 41.6, 17.2; MS (ES+) m/z 473.3 (M+1).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=O)=[CH:15][S:14][C:13]1=[N:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=O)(C)(C)C.[Cl:34][C:35]1[CH:42]=[CH:41]C(CBr)=[CH:37][CH:36]=1.Cl>>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]([CH2:17][O:19][CH2:20][C:21]2[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=2)=[CH:15][S:14][C:13]1=[N:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1csc(=Nc2ccc(OC(F)(F)F)cc2)n1CCCNC(=O)OC(C)(C)C
Reactant: Clc1ccc(CBr)cc1
Agent: Cl
Product: NCCCn1c(COCc2ccc(Cl)cc2)csc1=Nc1ccc(OC(F)(F)F)cc1
Yield: 50.4 %

Procedure:
The compound (313 mg) obtained in Example 208 (2) and 4-chlorobenzyl bromide (216 mg) were treated in a similar manner to in Example 208 (3), (4) to give the title compound (152 mg) as hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:24]1[CH:25]=[C:26]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>[Cu]I.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:21][N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[C:19](=[O:22])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(C2CC(=O)N(c3cccc([N+](=O)[O-])c3)C2)cc1OCc1ccccc1
Temperature: 110 °C
Yield: 56.7 %

Procedure:
To a round bottom flask was added 4-(3-benzyloxy-4-methoxyphenyl)-pyrrolidin-2-one (1.76 g, 5.9 mmol), 3-iodonitrobenzene (2.64 g, 10.6 mmol), K3PO4 (2.79 g, 13 mmol), trans-cyclohexanediamine (50 μL), DMF (8 mL) and dioxane (8 mL). The mixture was stirred under N2 for 5 min before the addition of CuI (150 mg). After heating to 110° C. for 20 h, the mixture was cooled to r.t. After filtration, the reaction mixture was diluted with EtOAc (100 mL), washed with saturated NH4Cl, brine and dried over Na2SO4. Concentration and purification by column chromatography on silica gel (EtOAc:hexane=1:3) gave 1.4 g of the desired product. Yield: 57%.
Reaction SMILES: [F:1][C:2]1([F:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[CH:5]=[CH:4][C:3]1([F:14])[F:13].C([Li])(CC)C.[B:21](OC)([O:24]C)[O:22]C.Cl>O1CCCC1.COC(C)(C)C>[F:15][C:2]1([F:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([B:21]([OH:24])[OH:22])[C:10]=2[F:12])[CH:5]=[CH:4][C:3]1([F:13])[F:14]
Reactant: Fc1cccc2c1C(F)(F)C(F)(F)C=C2
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: OB(O)c1ccc2c(c1F)C(F)(F)C(F)(F)C=C2
Reaction time: 3 h

Procedure:
A solution of 4.8 g of 1,1,2,2,8-pentafluoro-1,2-dihydronaphthalene [(Z3) where R1=H] in 75 ml of tetrahydrofuran was mixed with 11 ml of sec-butyllithium (2M in pentane) at a temperature below −75° C. After 3 g of trimethyl borate had been added, the mixture was stirred at the same temperature for 3 hours and subsequently brought to room temperature overnight. After hydrolysis using 10% hydrochloric acid, 150 ml of tert-butyl methyl ether were added, and the organic phase was separated off, washed with water and sodium chloride solution and dried. The 1,1,2,2,8-pentafluoro-1,2-dihydronaphthalene-7-boronic acid obtained was reacted with the equimolar amount of 4-propylbromobenzene, 2 mol-equivalents of sodium carbonate and 1 mol % of tetrakis(triphenylphosphine)palladium(0) in 50 ml of an ethanol/toluene/water 1:2:1 (vol.) mixture by refluxing for one day. After conventional work-up, the organic fraction was subjected to chromatographic purification (silica gel, toluene/heptane 2:1), the product-containing fractions were combined, the solvent mixture was distilled off under reduced pressure, and the residue was recrystallised from acetonitrile, giving 1.6 g of 1,1,2,2,8-pentafluoro-7-(4-propylphenyl)-1,2-dihydronaphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)Cc1ccc(O)c(Cl)c1

Procedure:
A mixture of 67 g (0.38 moles) of 3-chloro-4-hydroxyphenylacetic acid, 1.5 g of p-toluenesulfonic acid, and 250 ml of methanol was refluxed overnight, i.e., about 18 hours. The excess methanol was removed by vacuum to give a thick tawny oil. This oil was dissolved in ether, twice washed with water, and dried over anhydrous sodium sulphate. The ethereal solution was filtered, the ether removed and a tawny oil remained. Using as solvent 2.5% v/v methanol in chloroform and a silica gel matrix, thin-layer chromotography showed that the oil was essentially homogeneous, there being only a trace impurity present at the origin, which is believed to be unreacted acid. This oil was satisfactory for use as the starting material for forming the ether of Example 1B.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.O>CN(C)C=O>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[CH:15][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:21]
Reactant: Nc1ncnc2ccccc12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ncnc2ccccc12)C(=O)OCC
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
A mixture of 4-aminoquinazoline (11.6 g) and diethyl ethoxymethylenepropanedioate (19.0 g) in N,N-dimethylformamide (40 ml) was stirred for 1 hour and 20 minutes at 160° C. and then cooled to 0° C. to precipirate crystals. To the mixture was added small volume of water with stirring. The crystals were separated by filtration, washed with water, dried overnight under reduced pressure and dissolved in ethyl acetate. The resultant solution was dried over anhydrous magnesium sulfate and recrystallized from a mixture of ethyl acetate and hexane to give crystalline diethyl[(4-quinazolinylamino)methylene]propanedioate (22.7 g).
Reaction SMILES: COC1C(=O)C(=O)C=1[NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([C:19]2[S:20][CH:21]=[CH:22][C:23]=2[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[O:18])[CH:13]=[CH:14][CH:15]=1.N>CS(C)=O.CO>[NH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([C:19]2[S:20][CH:21]=[CH:22][C:23]=2[NH:24][CH2:25][C:26]2[C:27]3[C:28](=[CH:11][CH:10]=[CH:15][CH:14]=3)[N:29]=[CH:30][CH:31]=2)=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: COc1c(Nc2cccc(NC(=O)c3sccc3NCc3ccncc3)c2)c(=O)c1=O
Agent: N
Solvent: CS(C)=O
Solvent: CO
Product: Nc1cccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)c1
Reaction time: 6 h

Procedure:
To a solution of N-{3-[(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino]phenyl}-3-[(pyridin-4-ylmethyl)amino]thiophene-2-carboxamide (EXAMPLE 1) (50 mg, 0.01 mmol) in DMSO (150 μL) was added a 2M solution of ammonia in methanol (650 μL). The reaction was left for 6 h at rt. The reaction was then purified by reverse phase HPLC using a gradient of 5→65% MeCN/H2O over 15 min at 15 mL/min. Removal of the solvent provided EXAMPLE 3 as a white solid. MS (ES): m/z 469.9 [MH+]. 1H NMR (DMSO-d6, 400 MHz): δ=5.06 (d, J=6.0 Hz, 2H), 6.82 (d, J=5.6 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.25 (t, J=8.4 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.39 (d, J=4.4 Hz, 1H), 7.61 (d, J=5.2 Hz, 1H), 7.64-7.68 (m, 2H), 7.78 (t, J=7.2 Hz, 1H), 8.02-8.06 (m, 2H), 8.21 (d, J=8.4 Hz, 1H), 8.83 (d, J=4.4 Hz, 1H), 9.48 (s, 1H), 9.78 (s, 1H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[OH:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CCOC(C)=O>[CH3:10][S:11]([O:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])(=[O:13])=[O:12]
Reactant: O=S(=O)(NCCO)c1ccc(I)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCNS(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.3 %

Procedure:
Diisopropylethylamine (585 μl, 3.36 mmol) followed by methane sulphonyl chloride (260 μl, 3.36 mmol) was added to a stirred solution of N-(2-hydroxyethyl)-4-iodobenzenesulphonamide (Method 45; 1 g, 3.06 mmol) in EtOAc (25 ml) at 5° C., under nitrogen. The reaction was allowed to warm to ambient temperature and stirred for 24 hours. The reaction mixture was washed with 1M hydrochloric acid (3×25 ml), saturated aqueous sodium hydrogen carbonate solution (3×25 ml), brine (2×25 ml), an then dried. The volatiles were removed by evaporation and the residue purified by chromatography on silica, eluting with DCM/MeOH (100:0 increasing in polarity to 99:1) to give the title compound (562 mg, 45%) as a white solid. NMR: 3.08 (m, 2H), 3.12 (s, 3H), 4.08 (t, 2H), 7.55 (d, 2H), 7.98 (d, 2H), 8.03 (t, 1H); m/z 405.
Reaction SMILES: [CH:1]1([C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=2)(O)[CH3:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:23][S:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>ClCCl>[CH:1]1([C:4]([C:31]2[C:30]3[C:34](=[C:26]([CH2:25][S:24][CH3:23])[CH:27]=[CH:28][CH:29]=3)[NH:33][CH:32]=2)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: COc1ccc(C(C)(O)C2CC2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(C)(c2c[nH]c3c(CSC)cccc23)C2CC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mg (0.48 mmol) of the compound from Example 140A and 0.04 ml (0.57 mmol) of trifluoroacetic acid were added to 84 mg (0.48 mmol) of the compound from Example 8A in 2.5 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, and the crude product was then purified directly by preparative HPLC (mobile phase: acetonitrile/water gradient). 63 mg (361% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:25])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[Cl:25][C:6]1[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(C2CCOC2)cc(=O)[nH]1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: Nc1nc(Cl)cc(C2CCOC2)n1
Temperature: 110 °C
Yield: 41.1 %

Procedure:
A suspension of 2-amino-6-(tetrahydro-furan-3-yl)-3H-pyrimidin-4-one (1.5 g, 8.28 mmol), tetraethyl ammonium chloride (2.7 g 16.3 mmol) and dimethylaniline (1.4 mL, 11.1 mmol) in acetonitrile (15 mL) was treated with phosphorous oxychloride (2.4 mL, 26.2 mmol) and heated at 110° C. for 20 min. The resulting solution was cooled to rt and concentrated to minimum volume and pipetted onto ice chips. The aqueous portion was extracted with EtOAc (3×50 mL). The combined organic layers were basified with satd. aq. NaHCO3 solution to pH ˜7. The organic portion was separated, dried, and concentrated. The crude material was chromatographed (MeOH/CH2Cl2) to yield 680 mg (42%) of product as a light orange foam. 1H NMR (CDCl3): 6.59 (s, 1H), 5.16 (br s, 2H), 4.00-4.10 (m, 2H), 3.85-3.91 (m, 2H), 3.28-3.35 (m, 1H), 2.25-2.34 (m, 1H), 2.08-2.18 (m, 1H).
Reaction SMILES: [N:1]([CH:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[CH2:7][CH2:6][CH:5]1[OH:19])=[N+:2]=[N-:3].[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]([CH:4]1[CH:5]([O:19][Si:24]([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25])[CH2:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])=[CH:9]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1C=C(c2ccncc2[N+](=O)[O-])CCC1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(c2ccncc2[N+](=O)[O-])=CC1N=[N+]=[N-]
Reaction time: 18 h
Yield: 60 %

Procedure:
To a solution of (+/−)-2-azido-4-(3-nitropyridin-4-yl)cyclohex-3-enol (1.0 equiv.) in DCM (0.15 M) was added TBSCl (2.0 equiv.), imidazole (2.0 equiv.) and DMAP (0.1 equiv.) at room temperature. After 18 h, water was added, the organics were dried with brine, then Na2SO4, and concentrated. The crude material was loaded to silica gel and purified via column chromatography (ISCO) eluting with ethyl acetate and hexanes (20%). Obtained (+/−)-4-(3-azido-4-(tert-butyldimethylsilyloxy)cyclohex-1-enyl)-3-nitropyridine as a yellow oil in 60% yield. LCMS (m/z): 376.3 (MH+), LC Rt=5.848 min.
Reaction SMILES: [NH2:1][C:2]1[C:3](/[C:9](=[N:15]\[H])/[NH:10][O:11][C:12](=O)[CH3:13])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.CC(O)=O.C([O-])(O)=O.[Na+]>O>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[N:15]=[C:12]([CH3:13])[O:11][N:10]=2)[C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: [H]/N=C(/NOC(C)=O)c1nc(Br)cnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(-c2nc(Br)cnc2N)no1
Temperature: 70 °C
Yield: 66 %

Procedure:
A mixture of (E)-3-amino-6-bromo-N-(ethanoyloxy)pyrazine-2-carboximidamide (8.405 g, 22.71 mmol) and AcOH (30 mL) was heated to 70° C. for 2 hours. The reaction mixture was allowed to cool, diluted with water and then neutralised with solid NaHCO3. The resultant dark coloured precipitate was filtered off (3.83 g, 66% Yield). 1H NMR (400.0 MHz, DMSO) d 2.68 (s, 3H), 7.31 (br s, 2H) and 8.34 (s, 1H) ppm; MS (ES+) 258.80
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C@@H:18]([NH2:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([NH:20][C@H:18]([C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=3[N:10]=2)[CH3:19])[N:25]=[CH:24][N:23]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1Cc1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1Cc1ccccc1
Temperature: 90 °C
Yield: 35.6 %

Procedure:
A mixture of (S)-1-(1-benzyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (320 mg, 1.19 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (184 mg, 1.19 mmol) and DIPEA (1.06 mL, 5.95 mmol) in IPA (5 mL) was heated at 90° C. in a sealed vial overnight. The resultant mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient 0-10% [2M NH3 in MeOH] in DCM) to afford 394 as a white solid (164 mg, 36%). LCMS (Method K): RT 3.58 min [M+H]+ 388.1 1H NMR (DMSO-d6, 400 MHz): δ 7.94 (1H, s), 7.69 (1H, d, J=7.9 Hz), 7.61 (1H, dd, J=8.9, 4.5 Hz), 7.13-7.28 (5H, m), 6.95-7.05 (3H, m), 5.65 (1H, qn, J=7.9 Hz), 5.46 (2H, q, J=9.91, 5.5 Hz), 3.12 (1H, d, J=5.5 Hz), 1.49 (3H, d, J=6.77 Hz)
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[C:5]#[CH:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[C:5]#[CH:6])=[CH:13][CH:12]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C#CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CC(C)(C)C(=O)COc1ccc(Cl)cc1
Yield: 94 %

Procedure:
A solution of 98 g (0.67 mole) of 1-chloro-3,3-dimethyl-pent-4-in-2-one is added dropwise, with stirring, to a boiling mixture of 86.1 g (0.67 mole) of 4-chlorophenol and 92.5 g (0.67 mole) of potassium carbonate powder in 500 ml of acetone. After five hours the mixture is filtered, the filtrate is evaporated, the residue is taken up in 250 ml of methylene chloride and this solution is washed with 200 ml of 1N sodium hydroxide solution and 200 ml of water. After the solvent has been distilled off, 149 g (that is to say 94% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-pent-4-in-2-one are obtained as a colorless viscous oil, which upon standing solidifies to crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH:23]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)/[CH:23]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1cc(Cl)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(Cl)cc(C(F)(F)F)c1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 0.404 mmol) in toluene 5 mL was added 3-chloro-5-(trifluoromethyl)benzaldehyde 48 (84.4 mg, 0.404 mmol). PTSA (153.9 mg, 0.809 mmol) was added to the reaction mass, then stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 49, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-2-(3-chloro-5-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 49 was eluted at 35% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:19]([O:20][CH2:21][C:22]([O:24]C)=[O:23])=[C:18]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl>O1CCOCC1.O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[C:26]([C:28]([CH3:30])([CH3:29])[CH3:31])[C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:18]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)COc1c(C(C)(C)C)cc(C(=O)CN2CCN(c3ccncc3)CC2)cc1C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1cc(C(=O)CN2CCN(c3ccncc3)CC2)cc(C(C)(C)C)c1OCC(=O)O
Temperature: 100 °C

Procedure:
A solution of methyl 4-(2-[4-(4-pyridyl)piperazin-1-yl]acetyl)-2,6-di-tert-butylphenoxyacetate (241 mg) in dioxane (2.0 ml) was treated with 1N hydrochloric acid and the mixture heated at 100° C. for 20 hours. The mixture was cooled, diluted with water, filtered and the filtrate freeze-dried. The solid residue was purified by flash chromatography on silica eluting with toluene/ethyl acetate/0.880 ammonia/ethanol (60:20:10:35 v/v/v/v). The fractions containing the desired product were evaporated, the residue treated with dioxane, filtered and the filtrate diluted with water and freeze dried to give a white foam, which on drying at 55° C. gave the title compound, 90 mg: NMR (d6DMSO)δ8.16(2H,d), 7.97(2H,s), 6.84(2H,d), 4.22(2H,s), 3.86(2H,s), 3.37(4H,t), 2.64(4H,t), 1.39(18H,s); m/e 468 (M+H)+ ; calculated for C27H37 N3O4.2H2O: C, 64.4; H, 8.2; N, 8.3. found C, 64.6; H, 7.9; N, 7.9%.