Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](C3C=CC=CC=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:39])([CH3:38])[C:33]([O:35]CC)=[O:34].C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>CS(C)=O.CC(=O)CC>[C:1]1([N:8]2[C:9]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:39])[C:33]([OH:35])=[O:34])=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reactant: CCOC(=O)C(C)(C)CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCC(C)=O
Product: CC(C)(CCCCCCCc1c(-c2ccccc2)nc(-c2ccccc2)n1-c1ccccc1)C(=O)O

Procedure:
A mixture of 2,4,5-triphenylimidazole (4.13 g), ethyl 9-bromo-2,2-dimethylnonanoate (10.95 g), potassium carbonate (10 g) and 2-butanone was stirred at reflux for 48 hours. The mixture was filtered, solvent removed under reduced pressure and the residue was chromatographed on silica gel eluted with chloroform to give a clear oil which was dissolved in dimethyl sulphoxide (30 ml) and treated with potassium hydroxide (3 g). The mixture was stirred at 40° C. for 24 hours when the solvent was removed under reduced pressure. Water (50 ml) was added, the pH of the solution was adjusted to 4 and the aqueous was extracted with chloroform (3×50 ml). The chloroform extracts were dried over magnesium sulphate, filtered and the solvent removed to give a solid which was recrystallised from acetonitrile to give 9-(1,2,4-tri-phenylimidazolyl)-2,2-dimethylnonanoic acid as a white crystalline solid, m.p. 119°-120° C.; Found: C, 79.85; H, 7.64; N, 6.23% (C32H36N2O2); Requires: C, 79.96; H, 5.54; N, 5.82%
Reaction SMILES: [CH3:1][C:2]([CH3:18])([C:6](=[O:17])[NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:3]([OH:5])=[O:4].[F:19][C:20]([F:32])([F:31])C1C=CC(S(Cl)(=O)=O)=CC=1>>[CH3:1][C:2]([CH3:18])([C:6](=[O:17])[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:20]([F:32])([F:31])[F:19])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C(=O)O)C(=O)NS(=O)(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: CC(C)(C(=O)O)C(=O)NS(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
2,2-dimethyl-3-oxo-3-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)propanoic acid was prepared in the same manner as 2,2-dimethyl-3-oxo-3-[(phenylsulfonyl)amino]propanoic acid starting from 4-(trifluoromethyl)benzenesulfonyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36](Cl)=[CH:37][CH:38]=1)(=[O:33])=[O:32]>>[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:37][CH:38]=1)(=[O:33])=[O:32]
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Cl)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-chloro-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.39) (134 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (32 mg, 11%). MS (ISN) 586.1 [(M−H)−]; mp 178° C.
Reaction SMILES: [NH:1]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.C(O)(=O)C.[Br:17]Br>CCCCCC>[Br:17][C:10]1[CH:9]=[N:8][C:7]2[NH:1][CH2:2][C:3](=[O:12])[NH:4][CH2:5][C:6]=2[CH:11]=1
Reactant: BrBr
Reactant: O=C1CNc2ncccc2CN1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: O=C1CNc2ncc(Br)cc2CN1
Reaction time: 8 h

Procedure:
1,2,4,5-Tetrahydro-pyrido[2,3-e][1,4]diazepin-3-one (164 mg, 1.0 mmol) was dissolved into acetic acid (1 mL). Bromine (160 mg, 1.0 mmol) was added dropwise at room temperature and the solution was stirred overnight. Hexane (5 mL) was added and the orange precipitate was filtered and dried in vacuo. The title compound was isolated as an orange solid (190 mg, 78%). 1H NMR (300 MHz, DMSO-d6) δ 8.26 (t, J=5.7 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 7.81 (d, J=2.1 Hz, 1H), 4.35 (d, J=5.7 Hz, 2H), 4.08 (s, 2H).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>CN(C=O)C>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH2:22][CH3:23])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: CCI
Reactant: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of 7-allyl-1H-purine-2,6(3H,7H)-dione (15 g, 78.13 mmol) in DMF (200 mL) was added potassium carbonate (23.7 g, 171.74 mmol), followed by dropwise addition of iodoethane (3.6 mL, 44.54 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over sodium sulfate, and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum/ethyl acetate (6:1 to 3:1) to give 7-allyl-3-ethyl-1H-purine-2,6(3H,7H)-dione (7 g, 40.7% yield) as yellow solid. LCMS retention time 0.402 min; LCMS MH+ 221.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[OH:12])=[CH:7][CH:6]=1.Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)C>C1C=CC=CC=1>[N:27]1([CH2:26][CH2:25][O:12][CH:11]([C:8]2[CH:9]=[CH:10][C:5]([S:4][CH3:3])=[CH:6][CH:7]=2)[C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: ClCCN1CCCCC1
Reactant: CSc1ccc(C(O)c2cccc3ccccc23)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: CSc1ccc(C(OCCN2CCCCC2)c2cccc3ccccc23)cc1

Procedure:
To a suspension of sodium hydride (0.09 g, 3.84 mmol) in dry benzene (15 ml), (4-methylthiophenyl)-naphth-1-yl-carbinol (0.3 g, 1.07 mmol) was added. The contents were refluxed for 10 minutes and then N-[2-chloroethyl]-piperidine hydrochloride (0.4 g, 2.17 mmol) was added. The reaction mixture was refluxed for 24 hours and neutralized by ethyl alcohol and concentrated. The concentrate was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous sodium sulfate and concentrated to give oil, which was purified by column chromatography on basic alumina by using benzene-hexane as eluent to yield the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][S:23][CH3:24])[CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18]CC)=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][S:23][CH3:24])[CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)CC1CCC(N(CCSC)C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CSCCN(C(=O)OC(C)(C)C)C1CCC(CC(=O)O)CC1
Reaction time: 3.75 h

Procedure:
To a solution of ethyl 2-[4-[tert-butoxycarbonyl(2-methylsulfanylethyl)amino]cyclohexyl]acetate (2.11 g, 5.89 mmol) in methanol (10 mL) and THF (10 mL) was added NaOH (10 mL, 1M aqueous). The resulting solution was stirred for 3.75 hours then acidified with HCl (2M, aqueous to pH 2). This mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by silica chromatography (25 g silica; eluted with 20-60% ethyl acetate in hexanes) to give the title compound as a 6.9:1 mixture of trans to cis isomers.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][NH:18][CH3:19])=[CH:15][CH:14]=1>ClCCl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][N:18]([CH3:19])[C:8](=[O:10])[CH3:9])=[CH:15][CH:14]=1
Reactant: CC(=O)Cl
Reactant: CNCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(C)Cc1ccc(Br)cc1
Reaction time: 0.17 h

Procedure:
A solution of triethylamine (0.22 ml, 1.6 mmol) in dichloromethane (10 ml) was treated with acetyl chloride (0.08 ml, 1.10 mmol), followed by 4-bromo-N-methylbenzylamine (210 mg, 1.05 mmol). This mixture was then stirred under an atmosphere of argon for 10 minutes. The reaction mixture was washed twice with water and the organic layer was separated and dried over sodium sulphate, and the solvent removed via rotary evaporation to give a yellow oil which was purified on a 5 g sep-pak column eluting from 0-100% ethyl acetate in petroleum ether to give the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15]Cl>>[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1O
Reactant: COCCOCCl
Product: COCCOCOc1ccccc1C=O
Yield: 71.6 %

Procedure:
The hydroxyl group of 2-hydroxybenzaldehyde (3.0 g) was protected by use of 2-methoxyethoxymethyl chloride (3.1 g) in accordance with (production process 1), to thereby produce 2-methoxyethoxymethoxybenzaldehyde (3.7 g, yield: 70%). The thus-produced 2-methoxyethoxymethoxybenzaldehyde (2.0 g) and 3,4-dimethoxybenzyl cyanide (1.7 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.4 g, yield: 52%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[C:19]([NH2:23])=[N:20][CH:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:31])C(=O)C1.O>CN(C=O)C>[I:31][C:22]1[C:17]2[S:16][CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][CH:12]=3)[C:18]=2[C:19]([NH2:23])=[N:20][CH:21]=1
Reactant: Nc1nccc2scc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(I)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
A solution of Example 10A (1.69 g, 5.3 mmol) in DMF (20 mL) was treated with NIS (1.26 g, 5.6 mmol), stirred at room temperature for 3 hours, poured into water, and filtered. The filter cake was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide 1.64 g (70% yield) of the desired product. MS (ESI(+)) m/e 444.8 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[CH3:21][O:22][C:23]([C:25]1[C:30]([Cl:31])=[N:29][C:28](Cl)=[C:27]([Cl:33])[N:26]=1)=[O:24].C(N(C(C)C)CC)(C)C>CS(C)=O.C([O-])(O)=O.[Na+]>[CH3:21][O:22][C:23]([C:25]1[C:30]([Cl:31])=[N:29][C:28]([N:1]2[CH2:2][CH2:3][C:4](=[N:7][O:8][CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[CH2:5][CH2:6]2)=[C:27]([Cl:33])[N:26]=1)=[O:24]
Reactant: COC(=O)c1nc(Cl)c(Cl)nc1Cl
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1nc(Cl)c(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2d (99 mg, 0.35 mmol), 56a (92 mg, 0.35 mmol) and diisopropylethylamine (0.1 mL, 0.6 mmol) were combined in 0.5 mL of DMSO and stirred at room temperature for 18 h. The mixture was diluted with aqueous NaHCO3 (5 mL) and extracted with EtOAc (5 mL). The organic layer was concentrated under vacuum to afford the crude 56b. 20 mg of this crude material was purified by preparative HPLC to afford 56b: LC-MS 488.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Cl[C:14]1[CH:15]=[C:16]2[N:23](C(OC(C)(C)C)=O)[C@@H:22]([CH3:31])[CH2:21][N:17]2[C:18](=[O:20])[N:19]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][O:10][C:14]1[CH:15]=[C:16]2[NH:23][C@@H:22]([CH3:31])[CH2:21][N:17]2[C:18](=[O:20])[N:19]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Reactant: OCc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1Cn2c(cc(OCc3ccc(F)c(F)c3)nc2=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3,4-difluorophenyl)methanol (45.4 mg, 0.315 mmol) in tetrahydrofuran (THF) (3 mL) was added dropwise sodium hydride (37.8 mg, 0.945 mmol) at 0° C. After 30 min, (S)-tert-butyl 7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (90 mg, 0.32 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, then concentrated. Purification via pre-TLC (ethyl acetate) afforded the title product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][O:22][CH2:23][CH3:24])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[ClH:25].[CH2:26]([O:33][NH2:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[ClH:25].[CH2:26]([O:33][N:34]=[C:18]([CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:21][O:22][CH2:23][CH3:24])[CH3:19])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NOCc1ccccc1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=O
Agent: Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=NOCc1ccccc1

Procedure:
By the general methods described in Example 35, 5-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one was reacted with O-benzylhydroxylamine hydrochloride to provide 5-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one O-benzyloxime hydrochloride in about a 16 to 1 mixture of E and Z isomers as a white solid after recrystallization of the hydrochloride salt from a mixture of toluene and methanol, mp 184-186° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([OH:18])[C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=C(OC)N=1.[CH3:21][O:22][C:23]1C(OC)=C(C=O)C=C[N:24]=1>>[CH3:21][O:22][C:23]1[C:3]([O:2][CH3:1])=[C:8]([CH:9]([OH:18])[C:10]#[C:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:24]=1
Reactant: COc1nccc(C=O)c1OC
Reactant: COc1ccc(C(O)C#Cc2ccccc2)c(OC)n1
Product: COc1nccc(C(O)C#Cc2ccccc2)c1OC
Yield: 86 %

Procedure:
Following the procedure used to prepare 1-(2,6-dimethoxy-pyridin-3-yl)-3-phenyl-prop-2-yn-1-ol, 2,3-dimethoxy-pyridine-4-carbaldehyde was reacted to give the title compound (1.08 g, 86%) as a white solid. LCMS (Method A): RT=4.11 min, [M+H]+=270.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1.[NH2:20][C:21]1[N:26]=[CH:25][C:24]2[CH2:27][C:28]3([CH2:38][C:23]=2[CH:22]=1)[C:36]1[C:31](=[N:32][CH:33]=[CH:34][CH:35]=1)[NH:30][C:29]3=[O:37].C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([NH:20][C:21]2[N:26]=[CH:25][C:24]3[CH2:27][C:28]4([CH2:38][C:23]=3[CH:22]=2)[C:36]2[C:31](=[N:32][CH:33]=[CH:34][CH:35]=2)[NH:30][C:29]4=[O:37])=[O:10])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1
Reactant: O=C(O)Cn1c(=O)n(C2CCOC2)c2ccccc21
Reactant: Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1c(=O)n(C2CCOC2)c2ccccc21)Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (±)-(2-oxo-3-tetrahydrofuran-3-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (60 mg, 0.23 mmol, described in Intermediate 16), (±)-3-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 3), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH2:10][Br:22])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc(C)ccc1NC(=O)c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(CBr)ccc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of compound 11.1 (1.0 mmol) in benzene (2.0 mL) is added N-bromosuccinimide (1 equivalent) and benzoyl peroxide (0.33 equivalent). The reaction mixture is refluxed overnight under N2. After cooling to room temperature, the solution is diluted with EtOAc, washed with H2O, brine, dried, filtered and concentrated under reduced pressure. The crude product is purified by flash column chromatography on silica gel to provide 5-bromomethyl-2-(4-chloro-benzoylamino)-benzoic acid methyl ester (compound 11.2).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:35][CH2:36][CH2:37][OH:38])=[C:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:66][C:67]1[CH:72]=[CH:71][C:70](O)=[CH:69][CH:68]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:45])[CH3:46])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:35][CH2:36][CH2:37][O:38][C:70]3[CH:71]=[CH:72][C:67]([I:66])=[CH:68][CH:69]=3)=[C:26]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCO
Reactant: Oc1ccc(I)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 2-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-hydroxypropyl)thiazole-4-carboxylate (92 mg, 0.135 mmol), triphenylphosphine (35.4 mg, 0.135 mmol) and 4-iodophenol (29.7 mg, 0.135 mmol) in THF (2 mL) was added DBAD (32 mg, 0.135 mmol). The mixture was stirred at rt for 4 hours. LC/MS showed the expected product as a single peak. The mixture was diluted with EtOAc and washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 3% EtOAc in hexanes to provide 110 mg (92%) of the desired product: 1H NMR (300 MHz, CDCl3) δ ppm 8.30 (1H, m), 7.72 (1H, d), 7.54 (4H, m), 7.34 (3H, m), 6.67 (2H, d), 6.00 (2H, s), 5.14 (2H, s), 3.96 (4H, m), 3.75 (2H, t), 3.22 (2H, t), 3.06 (2H, t), 2.13 (2H, m), 1.59 (9H, s), 0.97 (2H, t), 0.01 (9H, m). MS (ESI(+)): m/z 833 (M+H).
Reaction SMILES: [ClH:1].[O:2](CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:3]1C=CC=C[CH:4]=1.Cl.[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47](C(C)(C)C)=[CH:46][CH:45]=1)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1.Cl.O[C@H](COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([O:2][CH2:3][CH3:4])=[CH:46][CH:45]=1)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: CCOc1ccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 358 (M−15, 0.1), 253 (17), 252 (100), 163 (6), 121 (21), 114 (8), 108 (8).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH3:17])=[CH:12]2)=[O:5].[Br:23]N1C(=O)CCC1=O.N(C(C)(CC(C)(OC)C)C#N)=NC(C)(CC(OC)(C)C)C#N>ClCCl.C(OCC)(=O)C>[Br:23][C:10]1[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:2]=2[Cl:1])=[C:16]2[C:11]=1[CH:12]=[C:13]([CH3:17])[CH:14]=[N:15]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)ccc(Br)c2c1
Yield: 17.5 %

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-3-methylquinoline (250 mg), N-bromosuccinimide (175 mg) and 2,2'-azobis(2,4-dimethyl-4-methoxyvaleronitrile) (23.3 mg) in dichloromethane was refluxed for 2 hours. After cooling, the mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane) to give 5-bromo-8-(2,6-dichlorobenzoylamino)-3-methylquinoline (54.2 mg).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[CH2:4][C:5]([Cl:20])=[C:6]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].N1C=CC=CC=1.[N:27]([CH:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:31](Cl)=[O:32])=[N+:28]=[N-:29]>C(Cl)Cl>[N:27]([CH:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:31]([NH:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[CH2:4][C:5]([Cl:20])=[C:6]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:32])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=NC(C(=O)Cl)c1ccccc1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Solvent: c1ccncc1
Solvent: ClCCl
Product: [N-]=[N+]=NC(C(=O)NC1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of benzyl 6-amino-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (0.2 mmol) in methylene chloride (2 ml) containing anhydrous pyridine (0.1 ml) is added α-azidophenylacetyl chloride (0.2 mmol). After stirring in the cold for 60 mins, the solution is washed with water, pH 3 phosphate buffer, 5% sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to give benzyl 6-(α-azido-phenylacetamido)-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.