Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:10]=[O:11])=[C:5](Cl)[C:6]=1[C:7]#[N:8].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[O-].[Na+]>CO>[NH2:1][C:2]1[S:3][C:4]([CH:10]=[O:11])=[C:5]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7]#[N:8]
Reactant: Sc1ccccc1
Reactant: N#Cc1c(N)sc(C=O)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(N)sc(C=O)c1Sc1ccccc1
Yield: 81 %

Procedure:
18.7 parts of 2-amino-4-chloro-3-cyano-5-formylthiophene are added to a solution of 11 parts of thiophenol, 5.4 parts of a 30% strength methanolic sodium methylate solution and 100 parts of methanol. The mixture is heated at the boil for 0.5 hour, after which it is allowed to cool and the precipitated product is filtered off under suction, washed with methanol, and then with water and dried. 21 parts (81% of theory) of 2-amino-3-cyano-5-formyl-4-phenylthiothiophene are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:21].O>CN(C=O)C>[Cl:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[N:9]([CH3:21])[C:4]=2[CH:3]=1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(Cl)cc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)Oc2cc([N+](=O)[O-])c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-2,2-dimethyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (2.29 g, 8.9 mmol) was stirred in DMF at 0° C. under an atmosphere of nitrogen then sodium hydride (60% dispersion in oil) (392 mg, 9.79 mmol) was added. The reaction was allowed to stir at room temperature for 30 min then iodomethane (1.89 g, 13.4 mmol) was added and the reaction was stirred at room temperature for 18 h. Analysis by LCMS indicated that the reaction was complete. Water (10 mL) was added carefully then the DMF was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The organic portions were combined then passed through a phase separation cartridge. The solvents were evaporated to afford an orange solid (2.4 g, quant.) which was taken through to the next step with no further purification.
Reaction SMILES: COC1C=CC(C[N:8]2[C@H:11]([S:12]([C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:14])=[O:13])[C@@H:10]([CH2:19][OH:20])[C:9]2=[O:21])=CC=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].P([O-])([O-])(O)=O.[K+].[K+]>C(#N)C.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[OH:20][CH2:19][C@@H:10]1[C@@H:11]([S:12]([C:15]([CH3:17])([CH3:16])[CH3:18])(=[O:14])=[O:13])[NH:8][C:9]1=[O:21]
Reactant: COc1ccc(CN2C(=O)[C@H](CO)[C@H]2S(=O)(=O)C(C)(C)C)cc1
Agent: [Cu+2]
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)S(=O)(=O)[C@H]1NC(=O)[C@@H]1CO
Reaction time: 2 h

Procedure:
A solution of 68.3 mg (0.2 mmol) of 1-p-methoxybenzyl-3-(S)-hydroxymethyl-4-(R)-tert.-butylsulphonyl-2-azetidinone in 4 ml of acetonitrile is added to a solution of 428 mg (1.8 mmol) of sodium peroxydisulphate, 174 mg (1 mmol) of dipotassium hydrogen phosphate, 1 mg of iron(II) sulphate heptahydrate and 2 mg of copper(II) acetate hydrate in 4 ml of water. The mixture is stirred for 2 hours under an argon atmosphere at a bath temperature of 65°. The resulting mixture is then concentrated to half its volume under reduced pressure and extracted with ethyl acetate. The extract is triturated with methylene chloride and ether and the pure title compound is obtained.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]([CH:13]1[CH2:15][CH2:14]1)=[O:12].[Cl-].[NH4+].C(OCC)C>C(O)C.C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[CH:11]([CH:13]1[CH2:15][CH2:14]1)[OH:12]
Reactant: Cc1ccc(C(=O)C2CC2)c(Cl)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(C(O)C2CC2)c(Cl)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 126.9 %

Procedure:
51.3 mg (1.36 mmol) of sodium borohydride were added to 320 mg (1.23 mmol) of the compound from Example 125A in 5 ml of ethanol and 1 ml of ethyl acetate under argon, and the mixture was stirred at 40° C. for 2 h. Then a further 46.6 mg (1.23 mmol) of sodium borohydride were added, and the mixture was stirred at 40° C. overnight. The reaction mixture was added to saturated aqueous ammonium chloride solution and diethyl ether, the phases were separated, the aqueous phase was extracted twice with diethyl ether, and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 307 mg of the title compound were obtained and were reacted without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:16])([F:15])[F:14])=[C:8]([Cl:17])[N:7]=1)=[O:5])C.[OH-].[Na+].O.Cl>C(O)C>[NH2:12][C:11]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][C:8]([Cl:17])=[C:9]([C:13]([F:14])([F:16])[F:15])[N:10]=1
Reactant: CCOC(=O)c1nc(Cl)c(C(F)(F)F)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(C(F)(F)F)c(Cl)nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 3-amino-6-chloro-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Intermediate 7A) (165 mg, 0.612 mmol) in dry ethanol (10 ml), 2M NaOH (0.306 ml, 0.612 mmol) was added. After stirring at RT for 10 minutes, the reaction mixture was poured into water (30 ml) and the pH taken to 6 with the addition of 1M HCl. The product was extracted with EtOAc (2×30 ml). The organics were combined and washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo. The crude material was purified by preparative LC-MS using 0.1% TFA/MeCN/Water system to afford the title compound. MS m/z 244 [M+H]+
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][S:6][C:7]1[N:11]2[CH:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]2=[C:9]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:8]=1)C.Cl>>[NH2:16][C:15]1[C:10]2[N:11]([C:7]([S:6][CH2:5][C:4]([OH:26])=[O:3])=[N:8][C:9]=2[C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=[CH:13][N:14]=1
Reactant: CCOC(=O)CSc1nc(-c2cc3ccccc3[nH]2)c2c(N)nccn12
Agent: Cl
Product: Nc1nccn2c(SCC(=O)O)nc(-c3cc4ccccc4[nH]3)c12
Yield: 90 %

Procedure:
A solution of [8-amino-1-(1H-indol-2-yl)-imidazo[1,5-a]pyrazin-3-ylsulfanyl]-acetic acid ethyl ester (6.7 mg, 0.000018 mol) and conc. HCl (3.0 mL) was stirred at rt for 5 h. The conc. HCl was removed in vacuo to afford 6 mg, 90% yield, of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm =4.12 (s, 2H), 6.82 (s, 1H), 7.07 (t, J=7.83, 7.07 Hz, 11H), 7.14-7.22 (m, 2H), 7.48 (d, J=8.08 Hz, 11H), 7.63 (d, J=7.83 Hz, 11H), 7.71 (d, J=5.56 Hz, 1H) and 11.75 (s, 1H); MS (ES+): m/z 339.92 [M+]. HPLC: tR=1.94 min (OpenLynx: polar—5 min).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[CH2:16][CH2:17][N:18]([C:21](OC(C)(C)C)=O)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[N:9][CH:10]=1)=[O:4].[C:30]1(=O)[CH2:34]C[CH2:32][CH2:31]1>>[CH:21]1([N:18]2[CH2:17][CH2:16][C:15]3[CH:28]=[CH:29][C:12]([O:11][C:8]4[N:9]=[CH:10][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[N:6][CH:7]=4)=[CH:13][C:14]=3[CH2:20][CH2:19]2)[CH2:32][CH2:31][CH2:30][CH2:34]1
Reactant: CNC(=O)c1cnc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cn1
Reactant: O=C1CCCC1
Product: CNC(=O)c1cnc(Oc2ccc3c(c2)CCN(C2CCCC2)CC3)cn1

Procedure:
Example 254 (E254) was prepared from N-methyl-5-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-2-pyrazinecarboxamide (D49) and cyclopentanone using the method described for Example 223; MS (ES+) m/e 367 [M+H]+.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([O:7][C:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C1CCCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of cyclopentanecarboxylic acid (1.14 g, 10 mmol) in DMF (15 mL) is added K2CO3 (2.07 g, 15 mmol) and benzyl bromide (1.71 g, 10 mmol). The suspension is stirred at room temperature for 18 hours. The mixture is quenched with water and extracted with ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4 and filtered. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane:EtOAc, 10:1) to give cyclopentanecarboxylic acid benzyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=O)[CH3:10].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:10])[CH3:19]
Reactant: COc1ccccc1C(C)=O
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C(C)c1ccccc1OC
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2′-methoxyacetophenone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether.
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:29](Br)[CH:30]=[CH2:31]>>[CH2:29]([O:28][CH:16]1[CH:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:15][C:12]3[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=3)=[CH:10][CH:11]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17]1)[CH:30]=[CH2:31]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(O)C1
Reactant: C=CCBr
Product: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(Cc2ccccc2)cc1

Procedure:
Analogously to Method D, 12 g of tert-butyl 4-(4-benzyloxyphenyl)-3-hydroxypiperidine-1-carboxylate and 5.4 ml of allyl bromide are reacted. The title compound is obtained as a yellowish oil. Rf=0.31 (1:3 EtOAc-heptane); Rt=5.80.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[CH:14]1([NH2:18])[CH2:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:14]1([NH:18][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[N:7][CH:6]=3)[N:1]=2)=[O:13])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: NC1CCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCC1)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1,6-naphthyridine-2-carboxylic acid (188 mg, 1.08 mmol), cyclobutylamine (114 mg, 1.6 mmol), BOP (708 mg, 1.6 mmol) and TEA (0.45 ml, 3.2 mmol) in DCM (15 ml) is stirred at rt overnight. The solvent is removed in vacuo and the residue is partitioned between water (20 mL) and EtOAc (20 mL). The layers are separated and the aqueous layer is extracted with EtOAc (10 ml). The combined extracts are washed with brine (10 mL), dried and evaporated. The residue is purified by PTLC to give the title compound as a light yellow oil; MS (M+1): 228.2.
Reaction SMILES: Cl.[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].[Cl:12][C:13]1[N:14]=[C:15]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:16]2[S:21][C:20]([CH:22]=O)=[CH:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:16]2[S:21][C:20]([CH2:22][N:9]3[CH2:10][CH2:11][CH:6]([S:3]([CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]3)=[CH:19][C:17]=2[N:18]=1
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl
Product: CS(=O)(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
4-Methanesulfonyl-piperidine hydrochloride salt was reacted with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 following General Procedure B-3. Purification on silica yielded 2-chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.[CH2:34]([OH:37])[C:35]#[CH:36]>>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:36]#[C:35][CH2:34][OH:37])[CH:3]=1
Reactant: C#CCO
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#CCO)c(OCc1ccccc1)c2=O
Yield: 84.4 %

Procedure:
Reaction of intermediate 174, N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.563 g, 1.00 mmol) with propargyl alcohol (0.18 ml, 3.2 mmol) using the conditions described for intermediate 178 gave 0.415 g (85% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.64 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2), 4.39 (2H, d, J=6.6 Hz, CH2), 4.68 (2H, d, J=6.0 Hz, CH2), 5.29 (2H, s, OCH2), 6.99 (1H, m, aromatic), 7.13 (1H,dd, J=2.5 Hz and J=9.1 Hz, aromatic), 7.22 (1H,dd, J=5.6 Hz and J=8.6 Hz, aromatic), 7.33-7.37 (3H, m, aromatics), 7.44-7.47 (2H, m, aromatics), 7.68 (1H, broad t, NH). HRMS (ESI+) calculated for C27H27FN3O5 [M+H+]: 492.1935; found: 492.1939.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[C:16]1([C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N+]=[N-])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C(OCC)(=O)C.O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:14]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCCCCCCCCCCO
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCCCCCCCCCCO)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
4.32 g of 12-hydroxydodecanoic acid were dissolved in 200 ml of ethyl acetate and 30 ml of water, and 5.5 g of diphenyldiazomethane were added to the resulting solution, which was then stirred at room temperature overnight. At the end of this time, about 10 ml of acetic acid was added to the resulting mixture to decompose the excess diphenyldiazomethane, after which the mixture was washed with 100 ml of water and the organic layer was separated. The organic layer was then washed twice, each time with 100 ml of a 5% w/v aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride. The washed organic layer was then dried over anhydrous magnesium sulfate and the solvent was removed by evaporation under reduced pressure, to afford 9.2 g of a thickly viscous yellow oily residue. This residue was purified by silica gel column chromatography using cyclohexane containing 10% by volume ethyl acetate was eluent, to afford 5.2 g of benzhydryl 12-hydroxydodecanoate as a thickly viscous pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([C:16]1([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH:28]=O)[CH2:19][CH2:18][CH2:17]1)=[O:15].N1CCCC1>CO>[CH3:12][O:13][C:14]([C:16]1([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2/[CH:28]=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH2:19][CH2:18][CH2:17]1)=[O:15]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2C=O)CCC1
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)C1(Oc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CCC1
Temperature: 80 °C
Yield: 23.9 %

Procedure:
To the mixture of 6-chlorooxindole (10 g, 60 mmol) and 1-(4-chloro-2-formyl-phenoxy)-cyclobutanecarboxylic acid methyl ester (18 g, 67 mmol) in methanol (100 mL) was added pyrrolidine (4.5 mg, 63 mmol) dropwise. The mixture was then heated at 80° C. for 1 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give the title compound (6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[O:10][CH2:11][C@H:12]2[N:16]([C:17]([O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]=[N:32][C:33]4[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=4[Cl:42])=[CH:27][CH:26]=3)=[O:18])[CH2:15][C@H:14]([OH:43])[CH2:13]2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH:67]([N:70]([CH:78]([CH3:80])[CH3:79])[P:71](Cl)[O:72][CH2:73][CH2:74][C:75]#[N:76])([CH3:69])[CH3:68].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:50]2[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[O:10][CH2:11][C@@H:12]2[CH2:13][C@@H:14]([O:43][P:71]([N:70]([CH:78]([CH3:80])[CH3:79])[CH:67]([CH3:68])[CH3:69])[O:72][CH2:73][CH2:74][C:75]#[N:76])[CH2:15][N:16]2[C:17]([O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]=[N:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=3[Cl:42])=[CH:29][CH:30]=2)=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(OC[C@@H]2C[C@@H](O)CN2C(=O)OCCNCCc2ccc(N=Nc3ccc([N+](=O)[O-])cc3Cl)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(OC[C@@H]2C[C@@H](OP(OCCC#N)N(C(C)C)C(C)C)CN2C(=O)OCCNCCc2ccc(N=Nc3ccc([N+](=O)[O-])cc3Cl)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 4a (12.63 g, 15.91 mmol) dissolved in 440 ml of anhydrous methylene chloride, containing 8.0 ml of N,N-diisopropylethylamine, was added 5.94 ml of 2-cyanoethyl diisopropylchlorophosphoramidite. The solution was stirred 30 min under argon at room temperature. The reaction mixture was treated with 10 ml of methanol and poured into 400 ml of 5% sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting with a gradient of 40-20% hexane in ethyl acetate (2% triethylamine). The pure product fractions were evaporated affording an amorphous solid: 14.75 g (93% yield). 31P NMR (DMSO-d6) δ 146.93 (singlet). Anal. Calcd for C52H61ClN7O9+1.0H2O: C, 61.68; H, 6.27; N, 9.68. Found: C, 61.44; H, 6.47; N, 9.35.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:15]([CH3:17])[CH:12]([CH2:13][CH3:14])[CH:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][CH:29]=3)[S:3][C:4]=2[CH:10]=1)[N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(C(c1ccc2nc(-c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 80 °C

Procedure:
A mixture of 1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine (663 mg, 1.75 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (409 mg, 2.275 mmol), tetrakis(triphenylphosphine)palladium (505 mg, 0.437 mmol), potassium carbonate (725 mg, 5.25 mmol); DME (25 mL) and water (5 mL) was degassed, filled with N2, and heated to 80° C. for 3 h. The reaction mixture was evaporated, dissolved in 10% methanol in DCM, loaded onto a PTLC plate and eluted with 6% methanol in DCM to yield methyl 4-(6-(2-(dimethylamino)-1-(1H-imidazo 1-yl)butyl)benzo[d]thiazol-2-yl)benzoate. MS ESI: m/z 435.19 [M+1+].
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CCOC(=O)C1CCCNC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCOC(=O)C1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (400 mg, 0.98 mmol) was added to a solution of ethyl piperidine-3-carboxylate (771 mg, 4.90 mmol) and DMAP (600 mg, 4.90 mmol) in MeCN (50 mL). The reaction mixture was stirred overnight at ambient temperature and the solvent was concentrated. The product was purified by MPLC using 50-90% EtOAc/Heptane on silica gel to provide the title compound as colorless oil. Yield: 182 mg (38%); 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J=7.13 Hz, 3 H), 1.29-1.38 (m, 1 H), 1.49-1.57 (m, 4 H), 1.59 (s, 9 H), 1.63-1.83 (m, 2 H), 1.91-2.02 (m, 1 H), 2.30 (td, J=11.43, 2.93 Hz, 2 H), 2.44 (t, J=11.13 Hz, 1 H), 2.57-2.69 (m, 1 H), 3.28-3.40 (m, 2 H), 3.65-3.75 (m, 1 H), 3.91 (dd, J=11.82, 3.81 Hz, 1 H), 3.96-4.05 (m, 2 H), 4.13 (q, J=7.03 Hz, 2 H), 4.25 (d, J=7.23 Hz, 2 H), 7.43 (d, J=8.20 Hz, 1 H), 7.64 (dd, J=8.59, 1.76 Hz, 1 H), 8.19 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+ 491.9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=S)[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:37][OH:38].C([O-])(=O)C.[Na+]>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[N:37][OH:38])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=S)cc2)CCC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=NO)cc2)CCC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
A mixture of {1-[4-(2-phenyl-4-thioxo-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (33.4 mg, 0.069 mmol), hydroxylamine hydrochloride (14.4 mg, 0.207 mmol) and sodium acetate (17 mg, 0.207 mmol) in IMS (5 mL) was stirred at 80° C. for 16 hours. The cooled reaction mixture was partitioned between DCM and water. The aqueous phase was isolated and extracted with DCM. The combined organic extracts were evaporated to dryness. The resultant residue was subjected to flash chromatography (SiO2, 2% MeOH in DCM) to afford the title compound (27.2 mg, 82%) as a pale yellow solid. LCMS (Method A): RT=4.96 min, [M+H]+=483.