Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.OS([O-])=O.[Na+]>C(Cl)Cl>[Br:17][CH:10]([C:9](=[O:16])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(Br)C(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 250 mL round bottomed flask were placed ethyl 4-(4-chlorophenyl)-3-oxobutanoate (4.04 g, 16.8 mmol) and methylene chloride (100 mL). To the solution was added N-bromosuccinimide (3.13 g, 17.6 mmol) and the mixture was stirred for 3 h at rt. To the mixture was added a freshly prepared 10% aqueous solution of NaHSO3 (5 g NaHSO3 dissolved in 50 mL water) and the resulting biphasic mixture was vigorously stirred for 15 min at rt. The organic phase was separated and the aqueous phase was extracted with DCM (30 mL). The organic phases were combined and washed with a saturated aqueous solution of NaHCO3 (50 mL) and dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residual yellow oil was essentially pure and was used in the next step without further purification. LC/MS (FA) ES− 319.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]([N:15](C(C)C)CC)(C)C.CN>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (5 g, 26 mmol) in THF (50 mL) was added diisopropylethylamine (3.36 g, 26 mmol) at −78° C., followed by the dropwise addition of methylamine (13 mL, 2 mol/L in methanol, 26 mmol). After the addition, the mixture was warmed to RT and stirred for 3 h. The reaction mixture was then diluted with ethyl acetate and washed with brine (50 mL*3). The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (4.4 g, 100%) as a yellow solid. MS (ES+) C5H5ClN4O2 requires: 188, 190. Found: 189, 191 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.CN(C1C=CC=CN=1)C.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:26]([O:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:13][CH2:12]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccccc1
Reactant: COc1ccc(CN2CCC(O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCC(OC(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.4 %

Procedure:
0.52 g (0.0023 mol) of 1-(4-methoxy-benzyl)-piperidin-4-ol was dissolved in 25 ml of dimethylformamide and treated with 0.14 g (0.0012 mol) of dimethylaminopyridine and 0.28 g (0.0023 mol) of benzoic acid. The mixture was cooled to 0° and 0.490 g (0.0025 mol) of N-ethyl-N'-(3-dimethylamino-propyl)-carbodiimide hydrochloride was added. The mixture was warmed to room temperature and stirred for 18 hrs. The solvent was distilled off and the residue was taken up in ethyl acetate and treated with silica gel. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane (1:3→1:2) as the eluent. 0.16 g (21%) of 1-(4-methoxy-benzyl)-piperidin-4-yl benzoate was obtained as a yellow oil. MS: me/e=326 (C20H24 NO3+).
Reaction SMILES: [F:1][S:2]([F:17])([F:16])([F:15])([F:14])[C:3]1[CH:4]=[C:5]([NH:9]S(C)(=O)=O)[CH:6]=[CH:7][CH:8]=1.F[C:19]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH3:33])[CH:20]=1>CN1C(=O)CCC1.CC(=O)OCC>[CH3:32][S:29]([C:28]1[C:19]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([S:2]([F:1])([F:14])([F:15])([F:16])[F:17])[CH:4]=2)=[CH:20][C:21]([CH3:33])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:30])=[O:31]
Reactant: CS(=O)(=O)Nc1cccc(S(F)(F)(F)(F)F)c1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(Nc2cccc(S(F)(F)(F)(F)F)c2)cc1C
Temperature: 150 °C
Reaction time: 7 h
Yield: 25.6 %

Procedure:
1.0 g of N-(3-pentafluorosulfanylphenyl)methanesulfonamide, 0.8 g of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate and 1.4 ml of TBTMG were dissolved in 10 ml of NMP (anhydrous) and stirred at 150° C. for 7 h. The mixture was then diluted with 100 ml of EA and washed firstly 3 times with 30 ml of a saturated aqueous Na2CO3 solution each time and then 3 times with 30 ml of a saturated aqueous NaHSO4 solution each time. The residue after drying over MgSO4 and removal of the solvent in vacuo was chromatographed on silica gel with DIP. 370 mg of a resinous solid were obtained.
Reaction SMILES: [H-].[Na+].[F:3][CH2:4][CH2:5][CH2:6][OH:7].Cl[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=1.[OH-].[Na+]>CN(C)C=O.C(O)C>[F:3][CH2:4][CH2:5][CH2:6][O:7][C:9]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OCCCF
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCCCF)nc1
Reaction time: 0.42 h

Procedure:
Sodium hydride (0.220 g, 5.50 mmol) was added to a solution of 3-fluoropropan-1-ol (0.390 g, 5 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred under an atmosphere of nitrogen for 25 min and added a solution of ethyl 6-chloronicotinate (0.928 g, 5.00 mmol) in N,N-dimethylformamide (2.5 mL). The reaction mixture was stirred for 35 min and then quenched with water. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. Purification by column chromatography using a gradient of ethyl acetate in heptane yielded an oil. The crude was dissolved in 1M sodium hydroxide, (16.50 mL, 16.50 mmol) and ethanol (20 mL) and heated to 50° C. for 1.5 h. The organic solvent was removed in vacuo, and the residual aqueous solution was cooled on ice. 2 M hydrochloric acid was added until an acidic pH was reached. The obtained precipitate was filtered off, washed with ice-water, and dried in vacuo affording the title compound, 0.53 g (81%) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (dd, 1 H), 8.14 (dd, 1 H), 6.90 (dd, 1 H), 4.65 (t, 1 H), 4.54 (t, 1 H), 4.43 (t, 2 H), 2.05-2.19 (m, 2 H); MS (APPI/APCI) m/z 228[M+H+].
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]12[C:20]([CH3:27])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][C:17](=NN)[CH:16]1[CH2:15][N:14]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:13]2)=[O:11].[I:37]I.C(OCC)(=O)C>O1CCCC1>[CH3:8][O:9][C:10]([C:12]12[C:20]([CH3:27])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH:18]=[C:17]([I:37])[CH:16]1[CH2:15][N:14]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:13]2)=[O:11]
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=NN)CCC2(C)c1ccccc1
Reactant: II
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2(C)c1ccccc1
Yield: 70.3 %

Procedure:
2.95 cm3 of triethylamine were added to a solution of 2.8 g (7 mmol) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-methyl-4-phenyloctahydroisoindole-3a-carboxylate in 80 cm3 of tetrahydrofuran and a solution of 3.6 g (14.1 mmol) of iodine in 40 cm3 of tetrahydrofuran was run in dropwise. After addition of ethyl acetate, the organic phases were washed with two times 50 cm3 of a saturated aqueous sodium hydrogencarbonate solution, washed with two times 50 cm3 of a saturated aqueous sodium thiosulphate solution, then dried over magnesium sulphate and concentrated under reduced pressure. After purification by chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (85/15 by volume) mixture, 2.4 g (69%) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-methyl-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were obtained in the form of a yellow oil, the characteristic of which was as follows:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]([NH2:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:27][C:28]1[S:32][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:30][CH:29]=1>C(Cl)Cl.CCOC(C)=O>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]([NH:19][S:33]([C:31]1[S:32][C:28]([Cl:27])=[CH:29][CH:30]=1)(=[O:35])=[O:34])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CCC(CC)C(N)c1nccn1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1nccn1Cc1ccccc1
Reaction time: 3.5 h
Yield: 59 %

Procedure:
To a stirred solution of [1-(1-benzyl-1H-imidazol-2-yl)-2-ethylbutyl]amine (448 mg, 1.74 mmol) in CH2Cl2 (15 mL) was added triethylamine (0.36 mL, 2.6 mmol) and 5-chlorothiophene-2-sulfonylchloride (453 mg, 2.09 mmol). The mixture was stirred for 3.5 h and then diluted with EtOAc, washed twice with 1N HCl, dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was purified by column chromatography (SiO2, CHCl3, then 1% MeOH/CHCl3 to 2% MeOH/CHCl3) to yield a white solid in 59% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([O:12][CH3:13])[CH:6]=1.[C-:14]#[N:15].[K+]>CC(C)=O.CCO.O>[CH3:13][O:12][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:14]#[N:15])[CH:10]=[CH:9][C:8]=1[CH3:11]
Reactant: COc1cc(CCCBr)ccc1C
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(CCCC#N)ccc1C
Yield: 99.9 %

Procedure:
A solution of 8.68 g (35.7 mmol) of 4-(3-bromopropyl)-2-methoxy-1-methylbenzene in 50 mL of acetone and 50 mL of EtOH was treated with a solution of 2.8 g (42.8 mmol) of KCN in 20 mL of H2O and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed with H2O, then saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 6.75 g (100% yield) of the product as an oil. The structure was confirmed by NMR and IR spectroscopy.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].C(N(CC)CC)C.[CH2:36]([O:43][C:44]([NH:46][C@H:47]([C:55](O)=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O.O1CCCC1>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:55](=[O:56])[C@H:47]([CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[NH:46][C:44]([O:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O)OCc1ccccc1
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (384 mg) prepared in Example 1 and triethylamine (0.19 ml) in water (10 ml) was added a solution of N-hydroxysuccinimide ester of N-benzyloxycarbonyl-L-phenylalanine (635 mg) in tetrahydrofuran (10 ml) at room temperature under stirring, which was continued overnight. The mixture was evaporated to remove tetrahydrofuran, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated to dryness. The residue was triturated in diethyl ether to give 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-L-phenylalanylamino)-β-D-ribofuranuronic acid (521 mg), mp. 145°-150° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][OH:14])[CH2:7][CH2:6]2.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][O:14][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(CO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCC(COS(=O)(=O)c1ccc(C)cc1)C2
Yield: 80.9 %

Procedure:
(RS)-(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-methanol (939 mg, 4.88 mmol), p-toluenesulfonyl chloride (934 mg, 4.9 mmol), triethylamine (1.12 ml, 7.88 mmol) and N,N-dimethyl aminopyridine (10 mg) in CH2Cl2 (10 ml) was stirred together at ambient temperature for 24 hr. Acidification with 1N HCl (pH 1-2), extraction of the aqueous phase with CH2Cl2 (2×20 ml), drying (Na2SO4) filtration and evaporation afforded the crude product which wag chomatographed over SiO2 (Merck 230-400 mesh) eluting with EtOAc-n-Hexane (1:3) to afford the title compound as a colourless oil (1.37 g, 3.95 mmol, 81%), MS m/e=346.1 (M+).
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9][CH2:10]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC(N)=[S:14].[OH-].[K+].Cl>C(O)C.CO>[O:7]([CH2:8][CH2:9][CH2:10][SH:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCOc1ccccc1
Reactant: NC(N)=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: SCCCOc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
160 g of 3-bromopropyl phenyl ether and 63 g of thiourea were dissolved in 300 ml of ethanol and the solution was refluxed with heating for 3 hours. A methanol solution containing 194 g of potassium hydroxide was added to the reaction solution and the mixture was stirred at 50° C. for 2 hours. The mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate followed by distillation under reduced pressure to obtain 76.5 g of 3-phenoxypropanethiol. A boiling point was 135° to 138° C. at 17 mm Hg.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:9]2[CH:18]=[C:19]([F:21])[CH:20]=[C:8]2[C:7]=1[OH:22])=O)C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=1[S:31]([NH2:34])(=[O:33])=[O:32].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[F:21][C:19]1[CH:20]=[C:8]2[C:7]([OH:22])=[C:6]([C:4]3[NH:23][C:24]4[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=4[S:31](=[O:33])(=[O:32])[N:34]=3)[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[N:9]2[CH:18]=1
Reactant: Nc1ccc(I)cc1S(N)(=O)=O
Reactant: CCOC(=O)c1c(O)c2cc(F)cn2n(CCC(C)C)c1=O
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cc(F)cn21
Temperature: 120 °C
Yield: 19.5 %

Procedure:
6-Fluoro-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 14i, 136.7 mg, 0.441 mmol) and 2-amino-5-iodo-benzenesulfonamide (Example 4a, 131.3 mg, 0.441 mmol) were mixed in anhydrous pyridine (2 mL) and heated at 120° C. for 3 h. 1,8-Diazabicyclo[5.4.0]undec-7-ene (200 μL) was added and the mixture was heated at 120° C. for 16 h. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm, 20% ethyl acetate in hexanes) afforded the desired product, 6-fluoro-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (0.047 g, 0.086 mmol, 19.5% yield) as a dark purple solid. LC-MS (ESI) calcd for C19H18FIN4O4S 544.01. found 544.97 [M+H+].
Reaction SMILES: [N-:1]=[C:2]=[O:3].[Na+].[C:5]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:26]3[NH:30][CH2:29][CH2:28][S:27]3)[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[C:5]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:26]3[N:30]([C:2]([NH2:1])=[O:3])[CH2:29][CH2:28][S:27]3)[CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(N2CCN(CCOc3ccccc3C3NCCS3)CC2)cc1
Reactant: [N-]=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: NC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A solution of 1.07 g of sodium isocyanate in 20 ml of water is added to a solution of 3.03 g of 2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine in 40 ml of ethanol, and 2.46 g of acetic acid are added thereto. The mixture is stirred at room temperature for 2 hours. 200 ml of water are added to the mixture, and the aqueous mixture is made alkaline with potassium carbonate. The aqueous mixture is extracted with ethyl acetate and chloroform, successively. The extracts are combined, washed with water, dried and then concentrated under reduced pressure to remove solvent. The residue is recrystallized from ethyl acetate. 2.78 g of 2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide are obtained. Yield: 82.2%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH2:12])=[CH:8][C:6]=2[N:7]=1.N1C(C)=CC=CC=1C.[CH:27]1([NH:30][C:31](=[O:34])[CH2:32]Cl)[CH2:29][CH2:28]1.CC1(C)C(C)(C)OB([C:43]2[CH:51]=[CH:50][CH:49]=[C:48]3[C:44]=2[CH:45]=[N:46][NH:47]3)O1>CN(C=O)C>[NH:47]1[C:48]2[C:44](=[C:43]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][CH2:32][C:31]([NH:30][CH:27]5[CH2:29][CH2:28]5)=[O:34])=[CH:8][C:6]=4[N:7]=3)[CH:51]=[CH:50][CH:49]=2)[CH:45]=[N:46]1
Reactant: O=C(CCl)NC1CC1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: NCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: O=C(CNCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)NC1CC1
Yield: 40 %

Procedure:
To (2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 from Example 11 (110 mg, 0.39 mM) in 5 mL DMF was added 48.2 uL (1.06 eq) 2,6-lutidine and N1-cyclopropyl-2-chloroacetamide (1.2 eq) followed by Suzuki coupling of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as per General Procedure K. Complete reaction was confirmed by LCMS and the reaction was concentrated in vacuo to give 6.5 mg of 382 after RP-HPLC purification (40% yield). MS (Q1) 464.3 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:17])[CH2:13][C:14]([OH:16])=O)[CH2:8][CH2:7]1)=[O:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:43]1([N:49]2[CH:53]=[C:52]([NH2:54])[CH:51]=[N:50]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:17])[CH2:13][C:14]([NH:54][C:52]2[CH:51]=[N:50][N:49]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:53]=2)=[O:16])[CH2:10][CH2:11]1)=[O:5]
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Reactant: Nc1cnn(-c2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1cnn(-c2ccccc2)c1
Reaction time: 0.03 h
Yield: 36 %

Procedure:
DMAP (68 mg, 0.56 mmol) was added to 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionic acid (100 mg, 0.28 mmol) in DMF (2 mL) followed by EDCI (64 mg, 0.33 mmol) and HOBT (45 mg, 0.33 mmol). After 2 minutes, 1-phenyl-1H-pyrazol-4-ylamine (54 mg, 0.33 mmol) was added and stirring was continued at room temperature overnight. Cold water was then added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford 50 mg (35.97% yield) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(1-phenyl-1H-pyrazol-4-yl)-propionamide. LC/MS [M+H]+: 596.09, 87.79%. 1H NMR (300 MHz, DMSO-d6): δ 10.4 (d, 1H), 8.5 (d, 1H), 7.84-7.64 (m, 4H), 7.54-7.2 (m, 5H), 4.0-3.8 (m, 7H), 3.2-3.1 (m, 2H).
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:18]1([C:24]23[CH2:31][CH2:30][C:27]([CH2:32][OH:33])([CH2:28][CH2:29]2)[CH2:26][CH2:25]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([O:33][CH2:32][C:27]23[CH2:26][CH2:25][C:24]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)([CH2:29][CH2:28]2)[CH2:31][CH2:30]3)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: OCC12CCC(c3ccccc3)(CC1)CC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC23CCC(c4ccccc4)(CC2)CC3)cc1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
Pyridine (4 mL), then a solution of toluene-4-sulfonyl chloride (7.4 g, 38.81 mmol) in dry DCM (30 mL), were added to a stirred solution of (4-phenylbicyclo[2.2.2]oct-1-yl)methanol (7.0 g, 32.36 mmol) in DCM (70 mL), maintaining 0-5° C. throughout. The reaction mixture was stirred at 0° C. overnight, refluxed for 2 h then cooled to 35° C. Further pyridine (2 mL) and a solution of toluene-4-sulfonyl chloride (3.9 g) in DCM (10 mL) were added and the mixture stirred at reflux for 2 h. As some starting material remained, a catalytic amount of 4-dimethylaminopyridine was added and the mixture stirred under reflux overnight. The mixture was cooled, diluted with DCM (200 mL) then washed with water (100 mL), hydrochloric acid (2M; 150 mL), water (50 mL), sat. aq. NaHCO3 (100 mL), water (50 mL) and brine (50 mL). After drying (MgSO4) the solution was concentrated to give crude product which was purified by silica column chromatography (silica 40-63 micron) eluting with hexane:ethyl acetate (19:1 to 4:1) to afford the title compound as a pale yellow solid (10.7 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[O:17][CH3:18].[OH-].[K+].O>CS(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[O:17][CH3:18])[CH:6]=1
Reactant: Clc1c[nH]cn1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A mixture of 4-chloro-1H-imidazole (5.0 g, 48.8 mmol), 1-chloro-2-methoxy-4-nitrobenzene (9.15 g, 48.8 mmol), and potassium hydroxide flakes (2.74 g, 48.8 mmol) in anhydrous DMSO (50 mL) was heated at 80° C. for 20 h. The reaction mixture was allowed to cool to rt and was poured into 800 mL of water with vigorous stirring. The resulting yellow-orange precipitate was collected by vacuum filtration using a coarse sintered glass funnel. The crude wet solid was transferred to a 1 L Erlenmeyer flask. Absolute ethanol (250 mL) was added to the flask and the resulting suspension was heated until all of the solids dissolved. The clear solution was cooled to rt and the desired product slowly crystallized. After 2 h, the crystalline solid was collected by vacuum filtration and rinsed with 100 mL of fresh ethanol. The solid was dried under high vacuum to afford 4-chloro-1-(2-methoxy-4-nitrophenyl)-1H-imidazole (5.2 g, 42% yield) as an off-white crystalline solid. LC-MS (M+H)+=254.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.94-8.01 (m, 2H) 7.76 (d, J=1.53 Hz, 1H) 7.45 (d, J=8.55 Hz, 1H) 7.21 (d, J=1.53 Hz, 1H) 4.02 (s, 3H).