Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1I.[F:12][C:13]1[CH:14]=[C:15]([CH:37]=[CH:38][CH:39]=1)[CH2:16][C:17]1[CH:36]=[CH:35][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]#[C:27][Si:28]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:29][CH3:30])=[O:22])=[CH:19][CH:18]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[C:8]([C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:27]([Si:28]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:29][CH3:30])=[C:26]2[CH2:25][CH2:24][NH:23][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:15]2[CH:37]=[CH:38][CH:39]=[C:13]([F:12])[CH:14]=2)=[CH:36][CH:35]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)c(I)c1
Reactant: CC[Si](C#CCCNC(=O)c1ccc(Cc2cccc(F)c2)cc1)(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2ccc(C(C)=O)cc2c1CCNC(=O)c1ccc(Cc2cccc(F)c2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 21.3 %

Procedure:
1-(4-Amino-3-iodophenyl)ethanone (0.100 g; 0.383 mmol), 4-(3-fluorobenzyl)-N-(4-(triethylsilyl)but-3-ynyl)benzamide 0.151 g; 0.383 mmol), bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.016 g; 0.019 mmol), lithium chloride (0.016 mg; 0.383 mmol) and sodium carbonate (0.081 g; 0.766 mmol) were suspended in DMF (5 mL) and the mixture was stirred at 100° C. for 18 hours. The solution was concentrated under reduced pressure and diluted in ethyl acetate. The organic layer was successively washed with brine, sodium thiosulfate, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 60% ethyl acetate in heptane) to afford 0.043 g (21%) of the title compound as a yellow oil.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:19])[CH3:4].Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([CH3:31])=[CH2:30])[CH:22]=1>>[ClH:1].[CH3:4][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:8][C:7]1([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([CH3:31])=[CH2:30])[CH:22]=1)[OH:19])[CH3:2]
Reactant: C=C(C)COc1cccc(Br)c1
Reactant: CN(C)CC1CC(Oc2ccccc2)CCC1=O
Agent: Cl
Product: C=C(C)COc1cccc(C2(O)CCC(Oc3ccccc3)CC2CN(C)C)c1
Yield: 51 %

Procedure:
The base of compound (27) was reacted with 1-bromo-3-(2-methyl-allyloxy)-benzene corresponding to the conditions described in Example 1. The base obtained was purified with ether via a silica gel column and was taken up in 2-butanone. After adding trimethylchlorosilane/water, compound (31) was obtained in a yield of 51% theoretical. melting point: 193° C.-195° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[OH:26]OS([O-])=O.[K+]>C(Cl)(Cl)Cl>[O-:26][N+:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=2)=[O:13])[CH:1]=1
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2cnccc12
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c[n+]([O-])ccc12
Yield: 10.5 %

Procedure:
To a suspension of N-isoquinolin-5-yl-N′-[4-(trifluoromethyl)benzyl]urea (Example 14; 100 mg, 0.29 mmol) in chloroform (25 ml) was added Oxone (541 mg, 0.87 mmol), followed by wet alumina Grade III (1 g), and the resulting suspension heated at reflux for 60 minutes. Whilst the mixture was still hot it was filtered to remove alumina and Oxone, the solids were washed with more chloroform, then methanol, and the filtrate evaporated to dryness. The residue was purified by preparative TLC eluting with 10% MeOH in dichloromethane+0.5% NH4OH, and the product triturated with a mixture of dichloromethane/iso-hexanes, filtered and dried to give the title compound (11 mg, 10%) as a white solid. m/z (ES+) 362 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=[CH:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:63])[C:57]4[CH:58]=[N:59][NH:60][C:61]=4[CH:62]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C>[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:62]=[C:61]4[C:57]([CH:58]=[N:59][NH:60]4)=[C:56]([NH:63][C:9]([C:8]4[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=4)=[O:11])[CH:55]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: COc1ncccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 0.08 h
Yield: 5.2 %

Procedure:
2-(Methyloxy)-3-pyridinecarboxylic acid (33 mg, 0.22 mmol) was treated with HATU (84 mg, 0.22 mmol) in DMF (0.25 ml) and DIPEA (0.069 ml, 0.40 mmol). The reaction mixture was shaken for 5 mins prior to treatment with 6-(1H-indol-4-yl)-1H-indazol-4-amine (25 mg, 0.1 mmol) in DMF (0.25 ml) and then left to stand at room temperature for 18 h. Solvent was removed in vacuo and the product re-dissolved in chloroform (0.3 ml) prior to application on to a pre-conditioned (methanol then chloroform) aminopropyl SPE cartridge (0.5 g). Product was eluted after 2 h with ethyl acetate/methanol (1:1, 3 ml), and concentrated under a stream of nitrogen using blow down apparatus. Purification by MDAP(Method D) afforded the title compound (2 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:16]#[N:17])=[N:5][N:6](COCC[Si](C)(C)C)[CH:7]=1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[C:4]([C:16]#[N:17])=[N:5][NH:6][CH:7]=1
Reactant: COc1cn(COCC[Si](C)(C)C)nc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1c[nH]nc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A mixture of 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile (compound 280.6, 500 mg, 1.97 mmol) and trifluoroacetic acid (10 mL) in TES (5 mL) was stirred for 2 h at room temperature, then concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) as the eluent to furnish 210 mg (86%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[C:8]1([C:14]2[C:18]([C:19](Cl)=[O:20])=[C:17]([CH3:22])[O:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>ClCCl>[CH3:22][C:17]1[O:16][N:15]=[C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:18]=1[C:19]([C:2]1[CH2:14][C:8]2[C:13]([C:1]=1[N:3]1[CH2:6][CH2:7][CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:20]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1C(=O)C1=C(N2CCCC2)c2ccccc2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The solid obtained from step a) was dissolved in dichloromethane (20 ml) and cooled to 0° C. Triethylamine (1 ml, 7.5 mmol) was added followed by 3-phenyl-5-methyl-4-isoxazolecarbonyl chloride (0.9 ml (1.8 mmol) of a 1.96M solution in dichloromethane. The reaction was warmed to 25° C. and stirred for 2 h. Water (10 ml) was added and the reaction mixture extracted into dichloromethane. The organic layer was dried (MgSO4) and evaporated to obtain the title compound as a brown oil m/z (ES+) 371(M+H)+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([S:26][C:23]3[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: Cc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2nc(-c3ccc(Cl)cc3)c(CCC(=O)O)o2)cc1
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 92.6 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), 4-methylthiophenol (0.68 g), potassium carbonate (2.07 g) and N,N-dimethylformamide (20 ml) was stirred under a nitrogen atmosphere at 100° C. for 40 minutes. Water was added to the reaction mixture, which was then acidified with 2 N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-(4-methylphenylthio)-5-oxazolepropionic acid (1.73 g, 93%). This was recrystallized from ethanol to give colorless needles. mp 160-161° C.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1.ClN1C(=O)CCC1=O.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([C:35]([F:38])([F:37])[F:36])=[CH2:34])[CH:30]=[C:29]([Cl:39])[CH:28]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]2([C:35]([F:38])([F:36])[F:37])[O:1][N:2]=[C:3]([C:4]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=3)[CH2:34]2)[CH:30]=[C:29]([Cl:39])[CH:28]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(C=NO)c2ccccc12
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
To a stirred solution of methyl 4-[(hydroxyimino)methyl]-1-naphthalenecarboxylate (i.e. the product from Step A) (1.0 g, 4.36 mmol) in N,N-dimethylformamide (5.0 mL) was added N-chlorosuccinimide (1.16 g, 8.72 mmol). This mixture was stirred for 1.5 h at room temperature, and then a solution of 1,3-dichloro-5-[1-(trifluoromethyl)ethenyl]benzene (i.e. the product from Step B) (3.20 g, 13.1 mmol) and triethylamine (6.1 mL, 43.6 mmol) in N,N-dimethylformamide (4.0 mL) was added. After stiffing for additional 2 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography using hexanes/ethyl acetate as eluent to afford the title compound as a pale yellow oil (700 mg, 34% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-:3])=[O:2].[OH-].[K+].[CH:19](I)([CH3:21])[CH3:20].O>CC(C)=O>[CH:19]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)([CH3:21])[CH3:20]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc2[nH]c3c(c2c1)CCCC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)n1c2c(c3cc([N+](=O)[O-])ccc31)CCCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 43.2 %

Procedure:
6-Nitro-1,2,3,4-tetrahydrocarbazole (5.04 g) prepared by the method described in Journal of Chemical Society, p.833 (1924) was dissolved in 50 mL of acetone, and the solution was added with 2.25 g of potassium hydroxide and 8.45 g of isopropyl iodide, warmed to 50° C. and stirred for 3 hours. The reaction mixture was added with water and the deposited precipitates were collected to obtain 2.60 g of N-isopropyl-6-nitro-1,2,3,4-tetrahydrocarbazole. The resulting N-isopropyl-6-nitro-1,2,3,4-tetrahydrocarbazole (2.60 g) was dissolved in 100 mL of acetic acid, and the solution was added with 2.75 g of iron powder, warmed to 50° C., and stirred for 3 hours. The reaction mixture was filtered and the filtrate was diluted by adding water. The reaction mixture was made basic with 1 N sodium hydroxide and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane/ethyl acetate=7/3) to obtain 1.35 g of N-isopropyl-6-amino-1,2,3,4-tetrahydrocarbazole.
Reaction SMILES: C1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]I)=[CH:4][C:3]=2[O:2]1.C1OC2C=CC(CCC=CCCI)=CC=2O1.[Li].[CH3:34][C:35](=[O:40])[CH2:36][C:37](=[O:39])[CH3:38].B(Br)(Br)Br>CCOCC>[OH:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:36]([C:35](=[O:40])[CH3:34])[C:37](=[O:39])[CH3:38])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: ICCCCCCc1ccc2c(c1)OCO2
Reactant: CC(=O)CC(C)=O
Agent: BrB(Br)Br
Agent: ICCC=CCCc1ccc2c(c1)OCO2
Agent: [Li]
Solvent: CCOCC
Product: CC(=O)C(CCCCCCc1ccc(O)c(O)c1)C(C)=O

Procedure:
[I; Ar is 3,4-(HO)2C6H3, R0 is H, R' and R" are CH3CO, Y is CH2CH2CH2CH2 ] was prepared from 6-(3,4-methylenedioxyphenyl)hexyl iodide (prepared by reduction of the compound of Preparation D2) and the lithium salt of 2,4-pentanedione, followed by ether cleavage with boron tribromide. The resulting product was obtained in the form of a light yellow viscous liquid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][CH:9]=1)(C)(C)C.Cl>O1CCOCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[S:12][C:8]([NH2:7])=[CH:9][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(-c2ccccn2)s1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cnc(-c2ccccn2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
A solution of (2-pyridin-2-yl-thiazol-5-yl)-carbamic acid tert-butyl ester (200 mg, 0.72 mmol) in dioxane (3 ml) was treated with 4M HCl in dioxane (3 ml) and the resulting suspension was stirred at ambient temperature overnight. The reaction mixture was filtrated and the precipitate was dissolved in sodium hydroxide (20 ml, 0.5M aqueous solution) and extracted with dichloromethane. The combined organic phases were dried and the solvent was evaporated to yield the product as orange solid (78 mg, 60%) which was used without any further purification. MS: M=178.1 (M+H)+
Reaction SMILES: Cl.Cl.[OH:3][CH2:4][C@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][C@@H:8]2[CH2:7][CH2:6]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[OH:3][CH2:4][C@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][N:12]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)[CH2:13][C@@H:8]2[CH2:7][CH2:6]1
Reactant: Clc1ccc(Cl)nc1
Reactant: OC[C@@H]1CC[C@H]2CNCCN2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: OC[C@@H]1CC[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Yield: 65.1 %

Procedure:
A mixture of 1.35 g (5.56 mmol) of (7R,9aS)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine dihyrochloride (Preparation 1), 4.11 g (27.8 mmol) of 2,5-dichloropyridine, 2.94 g (27.8 mmol) of sodium carbonate and 60 mL of isoamyl alcohol was heated at reflux for 48 h. The mixture was cooled and the solvent removed in vacuo. Purification by flash silica gel chromatography with 95:5 chloroform: methanol gave 1.02 g (65%) of the title compound. mp (base) 139.0–140.5° C. 13C NMR (CDCl3): δ 26.8, 29.1, 39.1, 45.3, 50.8, 54.6, 58.6, 60.6, 66.2, 107.7, 120.1, 137.1, 146.2, 157.6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](Cl)=[O:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.[CH3:34][NH:35][O:36][CH3:37].C(N(CC)CC)C>C(Cl)Cl>[CH3:37][O:36][N:35]([CH3:34])[C:24]([C:6]1[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)=[O:25]
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)Cl)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
To a solution of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride (200 mg) in methylene chloride (4 ml) were added N,O-dimethylhydroxylamin e hydrochloride (70 mg) and triethylamine (0.2 ml) and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and crystallized from diisopropyl ether to give the title compound (180 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:28]=1)[C:23](Cl)=[O:24]>>[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:28]=1)[C:23]([NH:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:12][C:13](=[O:15])[NH:14][C:7]=23)[CH:3]=1)=[O:24]
Reactant: O=C(Cl)c1cc(F)cc(N2CCOCC2)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cc(F)cc(N2CCOCC2)c1
Yield: 65 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-fluoro-5-morpholinobenzoyl chloride to afford the title compound as a light brown solid (38 mg, 65%). 1H-NMR (δ, ppm, DMSO-d6): 3.22 (m, 4H, CH2N), 3.74 (m, 4H, CH2O), 6.48 (d, 1H, HPy,5, J=6.0 Hz), 6.91 (d, 1H, Harom, J=8.0 Hz), 6.98 (d, 1H, Harom, J=10.5 Hz), 7.11 (d, 1H, Harom, J=9.0 Hz), 7.26 (s, 1H, Harom,Ph′), 7.42 (ps t, 1H, Harom, J=8.5 Hz), 7.61-7.64 (m, 2H, Harom), 7.81 (d, 2H, HPy,6, J=6.0 Hz), 10.28 (s, 1H, NHamide), 11.19 (s, 1H, NHPy3), 11.38 (s, 1H, NHPy2). 13C-NMR (δ, ppm, DMSO-d6): 47.76, 65.85, 104.17, 104.41, 106.58, 109.73, 110.86, 113.75, 114.57, 116.35, 130.16, 137.05, 140.61, 141.35, 144.60, 147.15, 152.65, 154.21, 154.73, 162.98, 164.81. HRMS (EI): m/z [M+H] calcd for C23H21FN5O4: 450.1578; found: 450.1571.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:10]2[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[I:15][C:12]1[CH:13]=[CH:14][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([NH:3][O:2][CH3:1])[C:10]=2[CH:11]=1
Reactant: CON=C1CCCCc2ccc(I)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CONC1CCCCc2ccc(I)cc21
Temperature: 23 °C
Reaction time: 9 h
Yield: 13 %

Procedure:
To a stirred solution of crude 3-iodo-6,7,8,9-tetrahydrobenzocylohepten-5-one-O-methyl-oxime E/Z-mixture (793 mg; 5.95 mmol) prepared as described in example P3b in acetic acid (5 ml) was added portion wise sodium cyanoborohydride 95% (0.63 g; 10.1 mmol) at 15° C. The mixture was stirred for 9 hours at 23° C. Most of acetic acid was removed under reduced pressure. The residue was poured in 2N NaOH (50 ml) and was extracted with ethylacetate (3×30 ml). Combined organics were dried over sodium sulfate and solvent was removed in vacuo. The crude (840 mg) was subject to flash chromatography (eluant: c-hexane/ethyl acetate 100:0 to 10:90) to afford 88 mg (13% of theory) of N-(3-iodo-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-O-methyl-hydroxylamine in form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N:24]([CH2:45][C:46]#[CH:47])[CH2:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[CH:31][N:30](COC(=O)C(C)(C)C)[C:29]3=[O:44])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@H:7]([C:15]([O:17]CC)=[O:16])[CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[O:5].O=C1C2C(=CC=C(CN(CC#C)C3C=CC(C(N[C@H](C(OCC)=O)CCC(OCC)=O)=O)=CC=3)C=2)N=CN1COC(=O)C(C)(C)C>>[F:1][C:2]1[CH:23]=[C:22]([N:24]([CH2:45][C:46]#[CH:47])[CH2:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[CH:31][NH:30][C:29]3=[O:44])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5]
Reactant: C#CCN(Cc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)c(F)c1
Agent: C#CCN(Cc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1
Product: C#CCN(Cc1ccc2nc[nH]c(=O)c2c1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)c(F)c1

Procedure:
This compound was prepared from compound (10) in a similar manner to that for the preparation of CB 3804 from compound 5 in Example 1 using the reagent quantities and conditions set out in Table B.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: COc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)c1

Procedure:
From 3-methoxybenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+24.3° (c=0.79, CHCl3), ES-MS m/e (%): 401 (M+H+, 100).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]([OH:19])=O)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=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.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.O>[CH:21]1([CH2:20][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:11][CH:12]=2)[C:17](=[O:19])[NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(C(CC2CCCC2)C(=O)O)cc1)c1ccccc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A solution of 2-(4-benzoylamino-phenyl)-3-cyclopentyl-propionic acid (20.2 mg, 0.06 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (39.8 mg, 0.09 mmol), and 2-aminothiazole (9.0 mg, 0.09 mmol) in methylene chloride (2 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.25 mL, 0.18 mmol). The reaction mixture was stirred at 25° C. for 16 h. At this time, the mixture was poured into water (50 mL) and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with a 1N aqueous hydrochloric acid solution (1×25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded {N-{4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenyl}-benzamide (95%) as a white solid: mp 285-290° C.; EI-HRMS m/e calcd for C24H25N3O2S (M+) 419.1667, found 419.1667.
Reaction SMILES: [C:1]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[CH3:20][NH:21][CH3:22]>CO>[CH3:20][N:21]([CH3:22])[CH2:3][CH2:2][C:1]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)=[O:4]
Reactant: CNC
Reactant: C=CC(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc2C1
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)CCN(C)C)CC2
Temperature: 65 °C
Yield: 70.5 %

Procedure:
A solution of 2-acryloyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.8 g, 3 mmol) in methanol (10 mL) was treated with dimethyl amine (10 mL, 2 M in THF, 20 mmol, Aldrich) and heated at 65° C. in a sealed tube for 16 h. The mixture was cooled, concentrated, and partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was separated, dried over magnesium sulfate, filtered, and purified by chromatography on SiO2 (dichloromethane to 20% methanol/dichloromethane) to give N,N-dimethyl-3-[6-(methyloxy)-7-nitro-3,4-dihydro-2(1 H)-isoquinolinyl]-3-oxo-1-propanamine (0.65 g, 71%). ESIMS (M+H)+=308.