Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)O[O:31]1>CC(C)=O.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]2[CH:16]([CH2:17][CH2:18][CH2:19][CH3:20])[O:31]2)[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Reactant: CC1(C)OO1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCC1OC1c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-[2-benzyloxy-4-((E)-hex-1-enyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (10 mg, 0.275 mmol) in acetone (10 mL) is added a solution of DMDO (0.56 mM, 4.9 mL, 0.413 mmol) in acetone. This mixture is stirred at RT for 1 h, at which point LCMS of the reaction shows clean conversion to the desired epoxide. The reaction mixture is diluted with EtOAc and concentrated 3× to fully remove the volatile DMDO. The remaining EtOAc is removed under reduced pressure to afford the title compound which is used directly in the next step.
Reaction SMILES: [N:1]1[C:2]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=O)[CH:6]=1.[CH2:16]([SH:19])[CH2:17][SH:18].B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH2:16]1[S:19][C:5]2([NH:4][C:3]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14](=[O:15])[C:2]=3[N:1]=[CH:6]2)[S:18][CH2:17]1
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Reactant: SCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C1C2=C(NC3(C=N2)SCCS3)c2ccccc21
Temperature: 25 °C
Yield: 63.6 %

Procedure:
A suspension of 9H-indeno[1,2-b]pyrazine-3,9(4H)-dione (0.50 g, 2.52 mmol) in benzene (10 ml), 1,2-ethanedithiol (0.63 ml, 7.56 mmol) and boron trifluoride etherate (0.31 ml, 2.52 mmol) was refluxed for 23 hours. The reaction mixture was cooled to room temperature, and the precipitate was filtered off and washed with benzene and water and dried. The crude material (0.64 g) was recrystallized twice from ethanol to give 0.44 g (64%) of the title compound. M.p. 284°-290° C. 1 -NMR (DMSO-d6, δ): 3.75-3.94 (m, 4H), 7.46-7.57 (m, 2H), 7.8 (m, 2H), 7.95 (s, 1H), 12.6 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:38])[NH:23][CH2:24][CH2:25][CH2:26][C@H:27]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][NH2:29])([CH3:20])([CH3:19])[CH3:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][C:14]([NH:29][CH2:28][C@@H:27]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:25][CH2:24][NH:23][C:22]([O:21][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:38])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)CCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.10 g (0.45 mmol) of N-[(benzyloxy)carbonyl]beta-alanine and 0.185 g (0.58 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.112 g (0.58 mmol) of EDC and 0.018 g (0.134 mmol) of HOBt are added. The mixture is warmed slowly to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [C:1]([NH2:5])(=O)[CH:2]=[CH2:3].[CH3:6][C:7]([CH3:9])=[O:8].[CH3:10][C:11]([CH3:13])=[O:12].Cl.[NH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>O>[C:1](=[N:15][OH:16])([NH2:5])[CH:2]=[CH2:3].[CH3:6][C:7]([CH3:9])=[O:8].[CH3:10][C:11]([CH3:13])=[O:12]
Reactant: NO
Reactant: C=CC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CC(N)=NO
Yield: 82 %

Procedure:
To a solution of 408 g. (2.4 moles) of diacetone acrylamide ##STR12## and 200 g. (2.88 moles; 20% molar excess) of hydroxylamine hydrochloride in 1.5 l. of distilled water was added a solution of 200 g. (1.44 moles) of potassium carbonate in 250 ml. of water at room temperature of about 25° C. over a period of 15 min. A precipitate formed after about 15 minutes. Stirring was continued until a thick paste formed and the mixture was then allowed to stand for another hour. The solid product was isolated by filtration, washed with small portions of water (amounting to a total of 500 ml.) and dried at 40° C. in a vacuum oven. Yield of 365 g. of a white crystalline powder (82% yield), m.p. 103° C. The material was of sufficient purity to be directly employed in polymerization and was employed in the polymerization described in Example 2 hereinafter. If desired, further purification can be attained through recrystallization from benzene or toluene.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:33]=[CH:32][C:21]2[N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:23]=[N:24][C:20]=2[C:19]=1[CH3:34]>CN(C)C1C=CN=CC=1.C(Cl)Cl.ClCl>[C:28]([O:27][C:25]([N:22]1[C:21]2[CH:32]=[CH:33][C:18]([N:17]=[C:8]=[S:9])=[C:19]([CH3:34])[C:20]=2[N:24]=[CH:23]1)=[O:26])([CH3:29])([CH3:30])[CH3:31]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1c(N)ccc2c1ncn2C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: ClCl
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (DPT) (14.3 g) and 4-dimethylaminopyridine (0.1 g) in CH2Cl2 (500 mL) is added dropwise over 30 minutes a solution of 5-amino-1-tert-butoxycarbonyl-4-methylbenzimidazole (7.82 g) in CH2 Cl2 (250 mL). The mixture is stirred for 15 minutes at room temperature then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 10% ethyl acetate/hexane to afford 1-tert-butoxycarbonyl-4-methyl-5-benzimidazolylisothiocyanate as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:18][CH:17]([CH2:19][C:20](O)=[O:21])[CH2:16][C@@H:15]1[C@H:23]1[O:27][C:26]([CH3:29])([CH3:28])[N:25]([C:30](=[O:32])[CH3:31])[C@H:24]1[CH2:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[CH:35]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C>ClCCl>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH:17]([CH2:19][C:20](=[O:21])[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:16][C@@H:15]1[C@H:23]1[O:27][C:26]([CH3:29])([CH3:28])[N:25]([C:30](=[O:32])[CH3:31])[C@H:24]1[CH2:33][C:34]1[CH:35]=[C:36]([F:41])[CH:37]=[C:38]([F:40])[CH:39]=1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: C1CCNCC1
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC(CC(=O)O)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC(CC(=O)N3CCCCC3)CN2C(=O)OC(C)(C)C)OC1(C)C

Procedure:
Add piperidine (0.013 g, 0.151 mmol) to a solution of (R)-2-[(4S,5S)-3-Acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (mixture of isomers) (0.05 g, 0.101 mmol), bromo tris-pyrrolidinophosphonium hexafluorophosphate (0.094 g, 0.201 mmol), dimethylamino-pyridine (0.001 g, 0.01 mmol) and triethylamine (0.021 mL, 0.151 mmol) in 2.2 mL of dichloromethane. Stir the reaction overnight. Concentrate under reduced pressure and subject the residue to silica gel chromatography, eluting with hexane/ethyl acetate (70% gradient to 100%) to provide both isomers of the desired compound. The 4(R) isomer is the slower eluting (0.033 g, 60%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH2:21]([Zn]CC)[CH3:22]>C1COCC1.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>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH2:21][CH3:22])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC[Zn]CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 70 °C
Yield: 62.1 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.400 g, 1.125 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.130 g, 0.112 mmol) were combined in THF (7 mL) and treated with diethylzinc (1 M in heptane) (2.250 mL, 2.250 mmol) with stirring under an inert atmosphere. The reaction mixture was heated to 70° C. and stirred for 2 h. The reaction mixture was concentrated to dryness and partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted successively with EtOAc and 10% CH3OH/DCM to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethylbenzonitrile (0.213 g, 0.699 mmol, 62.1% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.44-7.54 (m, 3H), 7.12-7.20 (m, 2H), 3.76 (s, 2H), 2.64 (q, J=7.60 Hz, 2H), 1.90 (br. s., 2H), 1.15 (t, J=7.55 Hz, 3H). LC-MS (ES−) m/z 303.25, 305.16 [M−1]. LC-MS (ES+) m/z 305.01, 306.98 [M+H].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][CH2:23][CH2:24][CH2:25]I>CCCCCCC.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[N:10]([CH2:25][CH2:24][CH2:23][Cl:22])[C:9]=2[CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)NC(=O)CO2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)c1ccc2c(c1)N(CCCCl)C(=O)CO2
Yield: 49.3 %

Procedure:
6-tert-Butyl-4H-benzo[1,4]oxazin-3-one (81MF2248a) (2.07 g, 10.0 mmol), Cs2CO3 (4.88 g, 15.0 mmol) and 3-chloro-1-iodopropane (2.25 g, 11.0 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) to give the title compound (81MF2248b) (1.39 g, 49%). 1H NMR (CDCl3) δ 7.12 (d, J=2.0 Hz, 1H), 7.03 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.54 (s, 2H), 4.14 (t, J=7.2 Hz, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.21-2.14 (m, 2H), 1.32 (s, 9H); 13C NMR (CDCl3) δ 164.8, 146.4, 143.1, 127.9, 120.9, 116.7, 112.2, 67.8, 42.6, 38.9, 34.8, 31.6, 30.2.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:30]=[C:29]([CH3:31])[C:28]([O:32]C(OC)=O)=[CH:27][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][N:8]=1.O.[ClH:38]>CO>[ClH:38].[F:3][C:4]1[CH:30]=[C:29]([CH3:31])[C:28]([OH:32])=[CH:27][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCCn4ccnc4)c(OC)cc23)c(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCCn1ccnc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
2M Aqueous sodium hydroxide (0.3 ml, 6 mmol) was added to a solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (257 mg, 5.5 mmol) in methanol (5 ml) and the mixture stirred for 1 hour at 40° C. Water and 1M hydrochloric acid (0.6 ml) were added and the mixture concentrated to half volume by evaporation. The resulting solid was collected by filtration, dissolved in methylene chloride/methanol and a solution of 7M hydrogen chloride in isopropanol (0.4 ml) was added. The volatiles were removed by evaporation, the solid residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline hydrochloride (160 mg, 60%).
Reaction SMILES: [CH3:1][C:2]([N:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:24])[CH:19]([NH2:23])[CH2:20][CH2:21][CH3:22])[N:14]=[CH:13]1)([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[F:25][C:26]1[CH:27]=[C:28]2[C:33](=[C:34]([F:36])[CH:35]=1)[CH2:32][C:31](=O)[CH2:30][CH2:29]2>>[CH3:1][C:2]([N:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:24])[CH:19]([NH:23][CH:31]2[CH2:30][CH2:29][C:28]3[C:33](=[C:34]([F:36])[CH:35]=[C:26]([F:25])[CH:27]=3)[CH2:32]2)[CH2:20][CH2:21][CH3:22])[N:14]=[CH:13]1)([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CCN2CCOCC2)cn1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CCN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-3-morpholin-4-yl-propyl)-1H-imidazol-4-yl]-amide was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: 13 C NMR 14.2, 19.5, 19.6, 28.2, 28.3, 28.5, 28.6, 28.6, 28.7, 28.8, 29.7, 29.8, 30.8, 36.5, 36.6, 39.8, 52.3, 52.7, 54.0, 57.2, 57.3, 60.3, 60.8, 67.1, 100.8, 101.1, 101.3, 104.6, 104.7, 110.5, 110.6, 110.8, 110.9, 130.5, 137.6, 137.7, 139.9, 159.7, 162.3, 172.3, 172.5; MS m/z 504.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.C(OC([NH:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)=O)(C)(C)C.C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:23][C:24]3[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=3)=[O:14])[CH:10]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: Cc1cc(N)c2cc(C(=O)O)ccc2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(N)c2cc(C(=O)Nc3ccc(N)cc3)ccc2n1
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a solution of 270 mg (1.0 mmol) 4-amino-2-methyl-6-quinolincarboxylic acid, 220 mg (1.1 mmol) 4-t-butoxycarbonylaminoaniline, and 0.56 ml (4.0 mmol) triethylamine in 10 ml DMF was added 4.42 mg (1.0 mmol) BOP reagent. After 1 h stirring at room temparature the solution was evaporated. The residue was dissolved in 1M solution of NaOH and extracted with ethyl acetate and the organic layer was washed with water and brine, dried (MgSO4) and evaporated. The residue was treated with 4M HCl in dioxane at room temperature for 1 h. After evaporation the residue was purified by HPLC and lyophilized to give 86 mg (17%) of the title compound. MS 293.3 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)#[N:21].C(#N)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=1)#[N:21]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)NC1CCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCCc2ccc(OCc3cccc(C#N)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.9 %

Procedure:
tert-Butyl (7-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (0.026 g, 0.10 mmol) was combined with m-cyanobenzyl bromide (Aldrich, Cat. #145610) (0.029 g, 0.15 mmol), acetonitrile (2.0 mL) and cesium carbonate (0.065 g, 0.20 mmol) and allowed to stir at r.t. overnight. This was diluted with ethyl acetate, filtered to remove the solids and concentrated under reduced pressure to give crude tert-butyl 7-(3-cyanobenzyloxy)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (0.045 g) as a semisolid. Analytical LCMS (M+Na)+: m/z=401.0.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:17][CH2:16]1)=[O:14]>CN(C)C=O.C(OCC)(=O)C>[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH2:17][CH2:16]1)=[O:14]
Reactant: COC(=O)C1CCC(COS(=O)(=O)c2ccc(C)cc2)CC1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCC(Cn2ccc([N+](=O)[O-])n2)CC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 36.8 %

Procedure:
The 3-Nitro-1H-pyrazole (prepared in example 3, 130 mg, 1.16 mmol) was dissolved in N,N-dimethylformamide (4 mL) and a 60% suspension of sodium hydride in mineral oil (50 mg, 1.25 mmol) was added. After the effervescence ceased and the reaction stirred for an additional 10 min, the 4-(toluene-4-sulfonyloxymethyl)-cyclohexanecarboxylic acid methyl ester (380 mg, 1.16 mmol) was added and the reaction was heated to 80° C. while stirring for 4 h. The reaction continued to stir under nitrogen for 2 h. The solution was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (35 mL), 1.0 M aqueous hydrochloric acid solution (35 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 4-(3-nitro-pyrazol-1-ylmethyl)-cyclohexanecarboxylic acid methyl ester (114 mg, 37%) as a yellow oil: H1-NMR (400 MHz, CDCl3) δ 1.00-1.12 (2H, m), 1.36-1.50 (2H, m), 1.68-1.78 (2H, m), 1.90-2.08 (3H, m), 2.20-2.30 (1H, m), 3.66 (3H, s), 4.03 (2H, d, J=7.2 Hz), 6.88 (2H, d, J=2.4 Hz), 7.40 (2H, d, J=8.4 Hz).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:17])[CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.Cl>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:17])[CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(O)c2C(=O)c2cccc(O)c21
Agent: Cl
Solvent: CC(=O)O
Product: O=C1c2cccc(O)c2Cc2cccc(O)c21
Temperature: 5 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a suspension of 1,5-dihydroxyanthraquinone (10 g, 41.6 mmole) and stannous chloride (45 g, 237 mmole) in glacial acetic acid (150 ml), conc. hydrochloric acid (90 ml) was added at 16°-20° C. The mixture was stirred for 4 hours under reflux. After standing at room temperature overnight, the reaction mixture was cooled to 5° C. The precipitate was filtered, washed with H2O and dried to afford 8.0 g of 1,5-dihydroxyanthrone as dark brown needles having a m.p. of 231°-233° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]=[O:11])=[O:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[OH:11])=[O:9])=[CH:6][CH:7]=1
Reactant: O=CC(=O)c1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(O)C(=O)c2ccc(Br)cc2)cc1
Reaction time: 5 h

Procedure:
A solution of 67 g. (0.314 mole) of p-bromophenyl-glyoxal in 300 ml. of dry toluene is added dropwise over 1 1/2 hours to a stirred suspension of 84 g. (0.6 mole) of anhydrous aluminum chloride in 1.25 l. of dry toluene cooled in an ice-bath. Stirring in the cold is continued for 5 hours and the mixture then is held at 5°-10°C. overnight. The mixture is poured into about 2 l. of ice and 6N hydrochloric acid. The aqueous phase is separated and re-extracted with three portions of benzene. The combined, washed and dried organic extracts are concentrated under reduced pressure to a volume of about 200 ml. Dilution with 150 ml. of petroleum ether precipitates the white crystalline product, m.p. 80°-82°C. Repeated recrystallization from 60% ethanol affords the analytical sample, m.p. 82°-83.5°C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]=[CH:27]5)=[O:22])[CH2:20][CH2:19]3)=[CH:17][C:12]=2[O:11][CH2:10]1.O>CN(C)C=O>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]=[C:27]5[Br:1])=[O:22])[CH2:20][CH2:19]3)=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(Nc1ccc2[nH]ccc2c1)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc2[nH]cc(Br)c2c1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
Freshly recrystallized N-bromosuccinimide (0.278 g, 1.56 mmol) was added portionwise to a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(1H-indol-5-yl)cyclopropanecarboxamide (0.500 g, 1.56 mmol) in N,N-dimethylformamide (2 mL) over 2 minutes. The reaction mixture was protected from light and was stirred bar for 5 minutes. The resulting green solution was poured into 40 mL of water. The grey precipitate which formed was filtered and washed with water to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-1H-indol-5-yl)cyclopropanecarboxamide (0.564 g, 91%). ESI-MS m/z calc. 398.0, found 399.3 (M+1)+. Retention time of 3.38 minutes. 1H NMR (400 MHz, DMSO-d6) 11.37 (s, 1H), 8.71 (s, 1H), 7.67 (d, J=1.8 Hz, 1H), 7.50 (d, J=2.6 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.22 (dd, J=2.0, 8.8 Hz, 1H), 7.02 (d, J=1.6 Hz, 1H), 6.96-6.88 (m, 2H), 6.03 (s, 2H), 1.43-1.40 (m, 2H), 1.09-1.04 (m, 2H).
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11](I)=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:3]12.N1CCCCC1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([C@:33]([OH:37])([C:35]#[CH:36])[CH3:34])[CH:29]=1>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.[Cu]I>[F:1][C:2]1([F:20])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([C:36]#[C:35][C@@:33]([OH:37])([C:30]3[CH:29]=[C:28]([CH3:27])[O:32][N:31]=3)[CH3:34])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:3]12
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-n2nc(C(N)=O)cc2C(F)(F)CO3)no1
Temperature: 60 °C
Yield: 48.3 %

Procedure:
To a pressure tube was added 4,4-difluoro-9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide (65 mg, 0.17 mmol) followed by piperidine (1.5 ml), tetrakis(triphenylphosphine)palladium (0) (19.2 mg, 0.02 mmol), copper(I) iodide (3.2 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (38 mg, 0.25 mmol). The reaction vessel was sealed and heated at 60° C. for 40 minutes. The reaction mixture was cooled and concentrated in vacuo. and then co-evaporated with dichloromethane (2×10 ml). The crude material was purified by FCC (silica, 1-8% methanol in dichloromethane) to provide 34 mg (49%) of the title compound as a pale brown solid. 1H-NMR (500 MHz, DMSO-d6): 1.81 (3H, s), 2.41 (3H, d, J=0.7 Hz), 4.85 (2H, t, J=11.7 Hz), 6.36 (1H, d, J=0.8 Hz), 6.56 (1H, s), 7.33 (1H, d, J=8.4 Hz), 7.35 (1H, s), 7.43 (1H, dd, J=8.4, 2.0 Hz), 7.60 (1H, s), 8.16 (1H, s), 8.37 (1H, d, J=2.0 Hz); M+23=437.