Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:13].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[C:12]([C:14](=[C:9]([CH3:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:15]([O:17][CH3:18])=[O:16])#[N:13]
Reactant: COC(=O)CC#N
Reactant: CC(=O)CCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C(C#N)=C(C)CCc1ccccc1
Yield: 87.3 %

Procedure:
A mixture of 4-phenyl-2-butanone (1 g), methyl cyanoacetate (0.77 g), acetic acid (0.29 mL), ammonium acetate (0.11 g) and toluene (10 mL) was heated for reflux overnight removing the generated water. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give methyl 2-cyano-3-methyl-5-phenyl-2-pentenate (1.35 g). To this material were added methanol (10 mL) and N,N-dimethylformamide dimethyl acetal (0.95 mL), and the mixture was heated for reflux overnight. The reaction mixture was concentrated under reduced pressure. To the residue were added acetic acid (8 mL) and a solution of 30% hydrobromic acid in acetic acid (5.9 g), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into ice water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice, a saturated aqueous sodium hydrogen carbonate solution twice, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1) to give the title compound (1.7 g)
Reaction SMILES: [C:1]([CH:4]1[C:9](=O)[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:6][C:5]1=[O:19])(=O)[CH3:2].O.[NH2:21][NH2:22]>C(O)C>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:7]1[CH2:8][C:9]2[NH:22][N:21]=[C:1]([CH3:2])[C:4]=2[C:5](=[O:19])[CH2:6]1
Reactant: COc1ccccc1C1CC(=O)C(C(C)=O)C(=O)C1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccccc1C1CC(=O)c2c(C)n[nH]c2C1
Yield: 782 %

Procedure:
A solution of 2-acetyl-5-(2-methoxyphenyl)cyclohexane-1,3-dione (0.10 g) and hydrazine hydrate (0.21 g) in ethanol (20 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 6-(2-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.77 g).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[O:17][CH2:18][C:19]2[C:24](Cl)=[CH:23][CH:22]=[CH:21][C:20]=2[C:26]([O:28]C)=[O:27])=[C:8](/[CH:30]=[C:31](\[CH2:37][C:38]2[C:46]([O:47][CH3:48])=[CH:45][C:41]3[CH2:42][CH2:43][O:44][C:40]=3[CH:39]=2)/[C:32]([O:34]CC)=[O:33])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4].CCOC(C)=O.CCCCCC>CC(O)=O>[CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:26]([OH:28])=[O:27])=[C:8](/[CH:30]=[C:31](\[CH2:37][C:38]2[C:46]([O:47][CH3:48])=[CH:45][C:41]3[CH2:42][CH2:43][O:44][C:40]=3[CH:39]=2)/[C:32]([OH:34])=[O:33])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ncc(/C=C(\Cc2cc3c(cc2OC)CCO3)C(=O)OCC)c1-c1ccc(Cl)cc1OCc1c(Cl)cccc1C(=O)OC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCn1ncc(/C=C(\Cc2cc3c(cc2OC)CCO3)C(=O)O)c1-c1ccc(Cl)cc1OCc1ccccc1C(=O)O
Yield: 90 %

Procedure:
Following the procedure of Example (1u) except substituting Ethyl (E)-3-[1-n-Butyl-5-[2-(2-methoxycarbonyl)phenylmethoxy-4-chlorophenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-2-propenoate for ethyl (E)-[1-n-butyl-5-[2-[2-(methoxycarbonyl)-6-chlorophenylmethoxy]-4-chlorophenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-2-propenoate, the title compound was prepared in 90% yield as a white solid: Rf 0.58 (1:1 EtOAc/hexane with 1% AcOH); 1H NMR (400 MHz CDCl3) d 8.19 (d, 1 H), 7.58 (s, 1 H), 7.53 (s, 1 H), 7.49 (t, 1 H), 7.30 (m, 2 H), 7.13 (m, 3 H), 6.77 (s, 1 H), 6.48 (s, 1 H), 5.52 (bs, 2 H), 4.45 (t, 2 H), 3.92 (m, 2 H), 3.82 (s, 3 H), 3.80 (bs, 2 H), 3.12 (t, 2 H), 1.65 (m, 2 H), 1.12 (m, 2 H), 0.76 (t, 3 H); MS(ESI) m/e 618 [M+H]+ ; mp: 116-118° C. Anal. (C34H33ClN2O7.0.5H2O) calcd: C, 65.22; H, 5.47; N, 4.47. found: C, 65.03; H, 5.33; N, 4.37.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:15][C:3]1[C:4]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cccc(Nc2ccccc2)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cccc(Nc2ccccc2)c1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
To a solution of 3-methyl-N1-phenylbenzene-1,2-diamine (381 mg, 1.92 mmol) in anhydrous DCM (10 mL) were added (S)-2-tertbutoxycarbonylaminopropionic acid (399 mg, 2.11 mmol), HOBt (285 mg, 2.11 mmol), 4-methylmorpholine (464 μL, 4.22 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (405 mg, 2.11 mmol). The mixture was stirred at RT for 2 h then additional amounts of (S)-2-tertbutoxycarbonylaminopropionic acid (145 mg, 0.77 mmol) and of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (148 mg, 0.77 mmol) were added. Stirring was continued for 18 h and then additional amounts of (S)-2-tertbutoxycarbonylaminopropionic acid (545 mg, 2.88 mmol), HOBt (285 mg, 2.11 mmol), 4-methylmorpholine (464 μL, 4.22 mmol) and of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (553 mg, 2.88 mmol) were added. Stirring was continued for 24 h and then the crude mixture was purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) affording [(S)-1-(2-methyl-6-phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester as an orange oil (395 mg, 56%). LCMS: RT 3.69 min [M+H]+ 370.2.
Reaction SMILES: CC(C)=O.[SH:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[Br:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](O)=[O:18].C(OC(=O)C)(=O)C>C(O)(=O)C>[Br-:15].[OH:18][C:17]1[N+:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[S:7][C:6]=2[S:5][C:16]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Sc1nc2ccccc2s1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: Oc1c(-c2ccccc2)sc2sc3ccccc3[n+]12
Product: [Br-]
Yield: 65 %

Procedure:
A 1 l. acetone solution of 33.4 g. (0.20 moles) 2-mercaptobenzothiazole and 43 g. (0.20 moles) α-bromophenylacetic acid containing 75 ml. glacial acetic acid and 50 ml. acetic anhydride is heated in an open flask to a volume of 400 ml. The precipitated yellow solid is collected and washed with acetone or ether and dried. The product, weighing 47.7 g. (65% yield) melts at 215° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](OCCOS(O)(=O)=O)=[C:5]([C@H:11]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[O:12]2)[CH:6]=[C:7]([I:10])[C:8]=1C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([SH:43])=[CH:39][CH:38]=1.C(N(CC)CC)C.[CH2:51]([OH:53])[CH3:52]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[O:12]2)[CH:6]=[C:7]([I:10])[C:8]=1[O:53][CH2:51][CH2:52][S:43][C:40]1[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=1
Reactant: CCO
Reactant: Sc1ccc(Cl)cc1
Reactant: COc1cc([C@H]2CC[C@H](c3cc(I)c(C)c(OC)c3OCCOS(=O)(=O)O)O2)cc(OC)c1OC
Solvent: CCN(CC)CC
Product: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(I)c1OCCSc1ccc(Cl)cc1

Procedure:
trans-2-(3-Methoxy-4-methylsulfoxyethoxy-5-iodophenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (2.5 g, 4.11 mmol) was dissolved in 50 mL ethanol. To this solution was added 4-chlorothiophenol (1.19 g, 8.22 mmol) and triethylamine (0.831 g, 8.22 mmol). The reaction mixture was refluxed for 16 hours and then the solvent was removed in vacuo. The residue was purified by column chromatography (silica, 3:1 hexane/ethyl acetate)(2.35 g, 87%). 1H NMR (CDCl3): 1.97 (m, 2H); 2.45 (m, 2H); 3.35 (t, 2H); 3.82 (s, 3H); 3.84 (s, 3H); 3.88 (s, 6H); 4.11 (t, 2H); 5.17 (m, 2H); 6.61 (s, 2H); 6.92 (s, 1H); 7.26 (d, 2H); 7.33 (d, 2H); 7.35 (s, 1H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26](O)=[O:27])[CH:22]=[CH:23][CH:24]=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(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[Br:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26]([NH:17]/[N:16]=[C:7]2\[NH:8][C:9](=[O:15])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:6]\2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCn1/c(=N/NC(=O)Cc2cccc(Br)c2)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
The mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (0.30 g, 1.3 mmol), (3-bromophenyl)acetic acid (0.30 g, 1.4 mol), benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (0.62 g, 1.4 mol) and triethylamine (0.53 mL, 3.8 mmol) in DMF (10 mL) were stirred at rt overnight. The reaction mixture was diluted with EtOAc. The solid was filtered, washed with EA and dried to yield the desired product (430 mg, 78.2%). LCMS calculated for C18H22BrN6O2 (M+H): 433.1. Found: 433.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:18][CH2:17]1)[CH:10]([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(OCC)(=O)C>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:17][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[CH:10]([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)C(F)C1(c2ccc(F)cc2F)CO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 21.4 %

Procedure:
A mixture of 2.4 g of ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2-fluorobutyrate (a mixture of diastereomers) and 6.4 g of 1,2,4-triazole was subjected to reaction at 90°-100° C. for 8 hours. To the reaction mixture were then added 10 ml of ethyl acetate and 5 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: chloroform/methanol=20/1) to obtain 650 mg of ethyl 3-(2,4-difluorophenyl)-2-fluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate (one of the diastereomers).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7](=[NH:9])[NH2:8])[CH3:3].C([O-])C.[Na+].[CH3:15][O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](=O)[CH2:22]Br)=[CH:19][CH:18]=1>C(O)C>[NH2:9][C:7]1[NH:8][C:21]([C:20]2[CH:25]=[CH:26][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:22][C:6]=1[C:5]([O:4][CH2:2][CH3:3])=[O:10]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCOC(=O)CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)[nH]c1N

Procedure:
Analogously to Step 8.1, 1.67 g (10 mmol) of 2-amidino-acetic acid ethyl ester hydro-chloride in 20 ml of abs. ethanol are reacted with 716 mg (10 mmol) of sodium ethanolate and 1.145 g (5.0 mmol) of 4-methoxy-phenacyl bromide (Fluka; Buchs/Switzerland) to form the title compound; m.p. 141-142° C.; TLC-Rf =0.4 (hexane/ethyl acetate [1:1]); FAB-MS: (M+H)+ =261.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:17](=[O:18])[N:16]([CH3:19])[CH:15]=[C:14]([C:20]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[N:40]=[CH:39][C:38]5[C:33](=[C:34]([F:45])[CH:35]=[C:36]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:37]=5)[C:32]4=[O:46])[C:21]=3[CH2:22][O:23]C(=O)C)[CH:13]=2)=[N:9][CH:10]=1)([CH3:4])[CH3:3].O.[OH-].[Li+].CO>O1CCOCC1>[NH2:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:17](=[O:18])[N:16]([CH3:19])[CH:15]=[C:14]([C:20]3[C:21]([CH2:22][OH:23])=[C:27]([N:31]4[N:40]=[CH:39][C:38]5[C:33](=[C:34]([F:45])[CH:35]=[C:36]([C:41]([CH3:42])([CH3:43])[CH3:44])[CH:37]=5)[C:32]4=[O:46])[CH:28]=[CH:29][CH:30]=3)[CH:13]=2)=[N:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(C)(C)N)cn3)c(=O)n(C)c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(C)(C)N)cn2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 679.8 %

Procedure:
Acetic acid 2-{5-[5-(1-amino-1-methyl-ethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzyl ester (159 mg, 0.0255 mmol) was dissolved in dioxane (3 ml). 2 M lithium hydroxide monohydrate solution (0.76 ml, 1.53 mmol) was added and stirred for 3hr at r.t. MeOH was added and the mixture purified purified by chromatography. Isolated product was dried under high vacuum at 50° C. to give 2-(3-{5-[5-(1-Amino-1-methyl-ethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-6-tert butyl-8-fluoro-2H-phthalazin-1-one (101 mg, 68%) as a off-white crystalline product. MS (H+)=583.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14](OC(=O)C1C=C(N2CCCCC2)C=CC=1N)C.S(Cl)(Cl)=O>CO>[CH3:14][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOC(=O)c1cc(N2CCCCC2)ccc1N
Reactant: Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 42 %

Procedure:
5-Amino-2-nitro-benzoic acid (compound A′) (910 mg) was dissolved in methanol (50 ml). Thionyl chloride (0.74 ml) was added dropwise to the solution on an ice bath, and a reaction was allowed to proceed under reflux with heating for 12 hr. After the completion of the reaction, the reaction solution was allowed to stand for cooling to room temperature and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 5-amino-2-nitro-benzoic acid methyl ester (410 mg, yield 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[Br:25]Br>C(Cl)Cl>[Br:25][C:16]1[CH:15]=[C:14]2[C:5]([CH:6]3[CH:11]([CH:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C2Cc3ccc(OC)cc3C3CCCCC23)cc1
Reactant: BrBr
Solvent: ClCCl
Product: COc1ccc(C2Cc3cc(Br)c(OC)cc3C3CCCCC23)cc1
Reaction time: 1 h
Yield: 124.6 %

Procedure:
Combine 6-Methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene (chiral) (0.02 g, 0.32 mmol) and methylene chloride (10 ml) and add bromine (0.0162 ml, 0.32 mmol) at 0-5° C. over 15 minutes. Stir as such one hour. Remove volatiles in vacuo at 40° C. to yield the titled compound (0.16 g, 100%). 1H NMR (CDCl3): 7.38 (s, 1H), 7.25 (d, J=8.8 Hz, 2H), 6.9 (m, 3H), 3.93 (s, 3H), 3.85 (s, 3H), 3.2 (m, 3H), 2.85 (dd, J=4 and 11, 1H), 2.48 (d, J=14 Hz, 1H), 2.06 (m, 1H), 1.8-0.8 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@@H:10]([O:12]S(C)(=O)=O)[CH3:11].[N+:17]([C:20]1[N:25]=[CH:24][C:23]2[CH:26]=[CH:27][O:28][C:22]=2[C:21]=1O)([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:21]1[C:22]2[O:28][CH:27]=[CH:26][C:23]=2[CH:24]=[N:25][C:20]=1[N+:17]([O-:19])=[O:18])[CH3:11]
Reactant: C[C@H](OS(C)(=O)=O)c1c(Cl)ccc(F)c1Cl
Reactant: O=[N+]([O-])c1ncc2ccoc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](Oc1c([N+](=O)[O-])ncc2ccoc12)c1c(Cl)ccc(F)c1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Alternate synthesis: To a solution of Methanesulfonic acid (S)-1-(2,6-dichloro-3-fluorophenyl)-ethyl ester (109 mg, 0.380 mmol) and 6-nitrofuro[3,2-c]pyridin-7-ol (68.4 mg, 0.380 mmol) in DMF (1.0 mL) was added potassium carbonate (57.2 mg, 0.414 mmol), and the resulting suspension was stirred at ambient temperature for 1 h and at 60° C. overnight. Methanesulfonic acid (S)-1-(2,6-dichloro-3-fluorophenyl)ethyl ester (32.7 mg, 0.114 mmol) and potassium carbonate (16 mg, 0.12 mmol) were added to the reaction mixture, and the mixture was heated at 70° C. for 3 days. Water and EtOAc were added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with EtOAc (3×15 mL). The combined EtOAc extracts were washed with 1N NaOH (2×), water (2×), and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:40])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:25]=[C:24]3[C:19]([C:20]([OH:39])=[C:21]([C:28]([NH:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])=[O:29])[C:22](=[O:27])[N:23]3[CH3:26])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.O>ClCCl>[CH3:8][N:9]([CH3:40])[C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:25]=[C:24]3[C:19]([C:20]([OH:39])=[C:21]([C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[C:22](=[O:27])[N:23]3[CH3:26])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: CN(C)c1ccc(-c2ccc3c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n(C)c3c2)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(-c2ccc3c(O)c(C(=O)NCC(=O)O)c(=O)n(C)c3c2)cc1

Procedure:
Trifluoroacetic acid (4.00 ml, 54 mmol) was added to a suspension of tert-butyl 2-(7-(4-(dimethylamino)phenyl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.057 g, 0.13 mmol) in dichloromethane (2.00 ml). After stirring at room temperature for 10 min water was added and the solution loaded in SCX MEGA BE column. The column was flushed with methanol extensible followed by 2M ammonia in methanol. The fractions obtained from the ammonia in methanol were collected and the solvent removed in vacuo. The residue was treated with 5N NaOH (2 ml) in THF (1 ml) and stirred at room temperature for 1 hour. The suspension was acidified with 5N HCl and the solids collected by filtration. The solids were washed with water, ether, dried in a vacuum oven at 50° C. to afford green solids (10 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]1[C:17]([CH3:18])=[C:16]([C:19](=O)[CH3:20])[CH:15]=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[ClH:22].NO.[OH-].[Na+].C[N:28]([CH3:31])C=O>>[CH2:6]([N:13]1[C:17]([CH3:18])=[C:16](/[C:19](/[Cl:22])=[CH:20]/[C:31]#[N:28])[CH:15]=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: CC(=O)c1cnn(Cc2ccccc2)c1C
Reactant: Cl
Agent: NO
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(/C(Cl)=C/C#N)cnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.4 %

Procedure:
To N,N-dimethylformamide (17.55 g) was added phosphorus oxychloride (36.8 g) by small portions under ice-cooling, the mixture was stirred at room temperature for 15 min. Thereto was added 1-(1-benzyl-5-methyl-1H-pyrazol-4-yl)ethanone (12.86 g) produced above by small portions under ice-cooling, and the reaction mixture was stirred at 50° C. for 30 min. Thereto was added a powder (33.40 g) of hydroxylamine hydrochloride at 50° C. by small portions, and the reaction mixture was stirred at 50° C. for 30 min. Ice water (200 mL) was added to the reaction mixture, and the mixture was neutralized with 1M aqueous sodium hydroxide solution, and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane), and crystallized from diethylether to give the title compound (6.71 g) as a pale-yellow powder.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
1-(2-Bromo-ethyl)-4-nitro-benzene (0.9 g, 3.9 mmol) was added to a mixture of 1-methyl-piperazine (520 μL, 4.7 mmol) and potassium carbonate (1 g, 4.7 mmol) in 5 mL of DMSO. The mixture was stirred at 100° C. for 2 hour. After cooling to room temperature, the mixture was extracted into ethyl acetate (EtOAc), washed with water, brine and then dried with sodium sulfate (Na2SO4). Removal of the solvent and chromatography on silica, eluting with EtOAc/CH3OH/NH4OH (10:1:0.1, v/v), gave 850 mg of 1-methyl-4-[2-(4-nitro-phenyl)-ethyl]-piperazine, which was converted to the title compound under normal hydrogenation conditions. The title compound was obtained as a yellow solid (780 mg, 91%). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.98 (d, J=8.3 Hz, 2H), 6.61 (d, J=8.3 Hz, 2H), 3.57 (br, 2H), 2.71 (br, 12H), 2.43 (br, 3H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=1.C(N(CC)CC)C>C(O)CCC>[Cl:14][C:15]1[N:16]=[N:17][C:18]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)nn2)CC1

Procedure:
A mixture of 13.52 g of tert-butyl 1-piperazinecarboxylate, 10.81 g of 3,6-dichloropyridazine and 20 ml of triethylamine in 100 ml of n-butanol is heated at reflux for 5 hours. It is concentrated under vacuum and the residue is chromatographed on silica gel, eluting with a DCM/AcOEt (90/10; v/v) mixture. This gives 14 g of the expected product, which is used as it is.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[CH:24](=[N:2][CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C(N)CC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(CC)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A solution of the product from step (a) (149.57 g), magnesium sulphate (74.32 g), and triethylamine (246 ml) in dichloromethane (1500 ml) was stirred at room temperature under nitrogen and benzaldehyde (94.91 g), Aldrich) was added dropwise. The mixture was stirred at room temperature for 3 hours then filtered. The filtrate was concentrated, triturated in diethyl ether, filtered and concentrated to yield the desired product as a yellow oil (174 g). 1H consistent with the proposed structure.