Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]([CH:19]2[O:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[O:21][CH2:20]2)=[O:18])[CH2:12][CH2:11]1)=[O:8].N1CCC(NC(NC2SC=CC=2)=O)CC1.BrCC(C1OC2C=CC=CC=2OC1)=O.[BH4-].[Na+]>CN(C=O)C.CCN(CC)CC.[OH-].[Na+]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH:17]([CH:19]2[O:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[O:21][CH2:20]2)[OH:18])[CH2:12][CH2:11]1)=[O:8]
Reactant: O=C(Nc1cccs1)NC1CCN(CC(=O)C2COc3ccccc3O2)CC1
Agent: O=C(CBr)C1COc2ccccc2O1
Agent: O=C(Nc1cccs1)NC1CCNCC1
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccs1)NC1CCN(CC(O)C2COc3ccccc3O2)CC1

Procedure:
1-[2-Thienyl]-3-[1-(2-[1,4-benzodioxan-2-yl]-2-oxoethyl)piperid-4-yl]urea, prepared by reacting 1-(piperid-4-yl)-3-(2-thienyl)urea with 2-bromoacetyl-1,4-benzodioxan in DMF/Et3N, may be reduced using sodium borohydride in 2 N sodium hydroxide to give the title compound.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:29][C:30](=[O:32])[CH3:31])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH3:19]>>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:12][CH2:13][N:14]([CH:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:29][C:30](=[O:32])[CH3:31])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[CH3:19])[CH2:15][CH2:16]1
Reactant: CC(=O)NC(C)(C)c1ccc(C(C)Cl)cc1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Product: CC(=O)NC(C)(C)c1ccc(C(C)N2CCN(c3ccc(F)cc3F)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2,4-difluorophenyl)piperazine dihydrochloride instead of phenylpiperazine and N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide obtained in Example 60(2) instead of N-(4-chloromethylphenylmethyl) acetamide, the title compound was obtained as a white amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](C3C=CN=C(C(OC)=O)C=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].BrC1C=CN=C(C(OC)=O)C=1.Br[C:47]1[CH:48]=[C:49]([CH2:53][C:54]#[N:55])[CH:50]=[CH:51][CH:52]=1>>[CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:47]3[CH:48]=[C:49]([CH2:53][C:54]#[N:55])[CH:50]=[CH:51][CH:52]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: N#CCc1cccc(Br)c1
Reactant: COC(=O)c1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)ccn1
Agent: COC(=O)c1cc(Br)ccn1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CC#N)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to methyl 4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)picolinate except that methyl 4-bromopicolinate was replace with 2-(3-bromophenyl)acetonitrile. LCMS, [M+H]+=439.3.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+].[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1.C(N(CC)CC)C>O1CCCC1>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C@H:7]([O:8][C:23]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:29])[O:9][C@@H:10]4[O:16]3)[CH2:4][CH2:3]1
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Reactant: O=C1CCC(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1[C@H](OC(=O)CCC(=O)O)O[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Artemisinin (500 mg) and cation exchange resin (1 g) are stirred in tetrahydrofuran (10 ml) at room temperature for 5 minutes. Sodium borohydride (250 mg) is added slowly for 10 minutes and the reaction mixture is stirred for about 30 minutes at room temperature (20-35 degree C.). After completion of the reaction succinic anhydride (250 mg) and triethylamine (0.7 ml) are added at room temperature and the reaction mixture is stirred further for 1 hours at room temperature. The resin is filtered. After usual workup and column chromatography of the crude product (710 mg), 480 mg of pure artesunic acid (yield=96% w/w) is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([OH:20])[C:6]2[C:7](=[O:19])[C:8]3[C:13]([C:14](=[O:17])[C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][C:9]=3[OH:18].[OH:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][OH:27]>CN(C)C=O>[OH:21][CH2:22][CH2:23][N:24]([CH2:2][C:3]1[CH:4]=[C:5]([OH:20])[C:6]2[C:7](=[O:19])[C:8]3[C:13]([C:14](=[O:17])[C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][C:9]=3[OH:18])[CH2:25][CH2:26][OH:27]
Reactant: OCCNCCO
Reactant: O=C1c2cccc(O)c2C(=O)c2c(O)cc(CBr)cc21
Solvent: CN(C)C=O
Product: O=C1c2cccc(O)c2C(=O)c2c(O)cc(CN(CCO)CCO)cc21
Reaction time: 2 h

Procedure:
A mixture of 3-bromomethyl-1,8-dihydroxy-9,10-anthraquinone (456 mg) and bis(2-hydroxyethyl)amine (600 mg) in N,N-dimethylformamide (20 mL) is stirred for 2 hours, and then partitioned between chloroform (100 mL) and water (100 mL). The organic layer is separated, washed with water (50 mL×3), dried over sodium sulfate, and then concentrated to dryness. The residue is chromatographed on a silica gel column using chloroform-methanol (15:1 v/v) as the eluent. Upon concentration of the major fraction, 3-[N,N-bis(2-hydroxyethyl)amino]methyl-1,8-dihydroxy-9,10-anthraquinone is obtained as a solid: 1H NMR (CDCl3) δ: 2.77 (4H, t, NCH2CH2O), 3.78 (4H, t, NCH2CH2O), 3.78 (2H, s, CH2N=), 7.21-7.79 (5H, m, aromatic H), 11.95 (1H, s, OH), 12.00 (1H, s, OH).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH3:22])[C:19]([NH2:21])=O)[C:11]3=[O:23])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH3:22])[C:19]([NH2:21])=[S:35])[C:11]3=[O:23])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@@H](C(N)=O)N1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Solvent: C1CCOC1
Product: C[C@@H](C(N)=S)N1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Reaction time: 72 h
Yield: 36.3 %

Procedure:
A mixture of (S)-2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-propionamide (171 mg, 0.5 mmol) and Lawesson's reagent (243 mg, 0.6 mmol) in tetrahydrofuran (20 mL) was stirrred at room temperature for 72 h. Then the mixture was evaporated and the residue was purified by chromatography (SiO2, CH2Cl2: 2N NH3/MeOH 99:1 to 19:1) to afford the title compound (65 mg, 36%) as an off-white solid after recrystallisation from MeOH. MS: m/e=359.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[SH:18]>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:9]
Reactant: Fc1ccc(S)c(Br)c1
Reactant: Fc1cc(Cl)ccc1I
Product: Fc1ccc(Sc2ccc(Cl)cc2F)c(Br)c1

Procedure:
Prepared from 4-chloro-2-fluoro-1-iodo-benzene and 2-bromo-4-fluoro-benzenethiol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].[Li]C(C)(C)C.[CH2:32]1[O:42][C:41]2[C:34](=[CH:35][C:36]([CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])=[C:37]([CH:40]=2)[CH:38]=[O:39])[O:33]1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:38]([OH:39])[C:37]1[CH:40]=[C:41]2[O:42][CH2:32][O:33][C:34]2=[CH:35][C:36]=1[CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:51])([CH3:50])[CH3:52])([CH3:47])[CH3:48])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc2c(cc1C=O)OCO2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2CCO[Si](C)(C)C(C)(C)C)OCO3)sc2ncccc12
Yield: 46.8 %

Procedure:
The title compound was prepared by the method of Example 4(B) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)thieno-[2,3-b]pyridine-3-sulfonamide (0.64 g, 1.5 mmoles) [Example 4(A)], THF (10 ml), t-BuLi (1.7 M, 1.2 ml, 2.0 mmoles), and 4,5-(methylenedioxy)-2-(2-{[(1,1-dimethylethyl)dimethylsilyl]oxy}ethyl)benzaldehyde (0.71 g, 2.3 mmoles; prepared according to Lin, et al. (1994) J. Am. Chem. Soc. 116:9791-9792). Flash chromatography (40% EtOAc/hexanes) provided 0.51 g (46%) of the title compound as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[O:15]=[S:16]1(=[O:33])[CH2:21][CH2:20][N:19]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[C:18]2=[N:17]1.[OH-].[Na+]>CS(C)=O>[O:12]1[CH2:13][CH2:14][CH:9]([CH2:8][O:32][C:29]2[CH:28]=[CH:27][C:26]([C:25]3[C:18]4=[N:17][S:16](=[O:33])(=[O:15])[CH2:21][CH2:20][N:19]4[CH:22]=[CH:23][CH:24]=3)=[CH:31][CH:30]=2)[CH2:10][CH2:11]1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OCC4CCOCC4)cc3)C2=N1
Temperature: 130 °C
Reaction time: 3 h
Yield: 43.8 %

Procedure:
A mixture of potassium carbonate (602 mg), 4-(bromomethyl)tetrahydro-2H-pyran (780 mg), 4-(bromomethyl)tetrahydro-2H-pyran (780 mg) and 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (602 mg) in DMSO (5 mL) was stirred at 130° C. for 3 hr. The mixture was poured into 1N NaOH aq. and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was passed through column chromatography (NH silica gel, eluted with MeOH) to give the title compound (357 mg) as a pale yellow solid.
Reaction SMILES: [O:1]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]2[C@H:20]3[C@H:30]([CH2:31][CH2:32][C@:15]12[CH3:16])[C@:28]1([CH3:29])[C:23](=[CH:24][C:25](=[O:33])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3>CS(C)=O>[OH:1][C@@H:21]1[CH2:22][C:23]2[C@:28]([CH3:29])([CH2:27][CH2:26][C:25](=[O:33])[CH:24]=2)[C@@H:30]2[C@@H:20]1[C@H:17]1[C@@:15]([CH2:32][CH2:31]2)([CH3:16])[C@@H:14]([OH:13])[CH2:19][CH2:18]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Solvent: CS(C)=O
Product: C[C@]12CC[C@H]3[C@@H]([C@H](O)CC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reaction time: 22 h

Procedure:
100 ml of a nutrient medium, containing 1% cornsteep liquor and 1% glucose, were adjusted to pH 6.5 and, after sterilization, inoculated with the mycelium of IFO 6469. After incubation at 26.5° on the rotary shaking machine during 22 hours, 100 mg of 17β-hydroxy-4-androsten-3-one in 1 ml of dimethyl sulphoxide were added and the incubation was continued at 26.5° for a further 8 days. Thereafter, the fermentation solution was filtered, the filtrate was extracted with ethyl acetate and concentrated to a small volume and under reduced pressure. The concentrate was chromatographed on silicic acid with chloroform-acetone. There were obtained 17.9 mg of 7α,17β-dihydroxy-4-androsten-3-one.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=2)O1.[OH-:23].[Na+].OO>C1COCC1>[CH3:19][Si:18]([CH3:21])([CH3:20])[CH2:17][CH2:16][O:15][CH2:14][N:12]1[CH:13]=[C:9]([OH:23])[CH:10]=[N:11]1
Reactant: [OH-]
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (compound 280.1, 9.7 g, 30.0 mmol) in THF (100 mL) was added 2M sodium hydroxide (aq.) (30 mL) dropwise. To this was added H2O2 (30%) (22.7 mL) dropwise at 0° C. The reaction mixture was stirred for 2 h at room temperature, then quenched with 50 mL of water. The aqueous phase was extracted with 2×150 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 4.3 g (67%) of the title compound as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].O[CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21]>S(=O)(=O)(O)O>[O:21]=[C:12]1[C:13]2[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:16])[N:11]1[CH2:10][C:5]1[O:1][C:2]([C:6]([OH:8])=[O:7])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccco1
Reactant: O=C1c2ccccc2C(=O)N1CO
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(CN2C(=O)c3ccccc3C2=O)o1
Reaction time: 18 h
Yield: 52.8 %

Procedure:
2-Furoic acid (10.0 g) was dissolved in cold concentrated sulphuric acid (50 ml). The mixture was then added to N-hydroxy methylphthalimide (12.0 g) and the reaction mixture allowed to stand for 18 hrs at room temperature. The mixture was then poured into ice and the product extracted with dichloromethane, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was triturated with diethyl ether and recrystallised from methanol to afford 5-[(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl]-2-furoic acid (9.70 g) as a brown solid.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[C:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:22])([CH3:21])[CH:10]=1)#[N:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([N:8]1[CH2:7][CH2:6][N:5]([C:9]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:22])([CH3:21])[CH:10]=2)[C:4]1=[N:3][C:1]#[N:2])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)C=C(N2CCNC2=NC#N)c2cc(C#N)ccc2O1
Solvent: c1ccncc1
Product: CC(=O)N1CCN(C2=CC(C)(C)Oc3ccc(C#N)cc32)C1=NC#N
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(2-cyanoiminoimidazolidin-1-yl)-2,2 -dimethyl-2H-1-benzopyran-6-carbonitrile (0.59 g) and acetic anhydride (0.94 ml) in pyridine (5.9 ml) was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with 5% hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to give 4-(3-acetyl-2-cyanoiminoimidazolidin-1-yl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.41 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]1.[NH2:16][CH2:17][CH:18](O)[CH3:19]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10]2[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=2[C:12](=[O:14])[CH2:13]1
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Reactant: CC(O)CN
Solvent: C1CCOC1
Product: Cc1c[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 150 °C
Reaction time: 5 h
Yield: 55.7 %

Procedure:
A mixture of 5-(2-chlorophenyl)cyclohexane-1,3-dione (2.0 g), 3-aminopropan-2-ol (0.88 g), molecular sieves 4A (12 g) and tetrahydrofuran (30 ml) was refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (40 ml). To the solution were added 2-bromomesitylene(1.8 g), tetrakistriphenylphosphine palladium (0.26 g) and potassium carbonate (2.5 g), and the mixture was stirred at 150° C. for 5 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydroindol-4-one (1.3 g).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[C:11]([O:20][CH3:21])=[CH:10][C:4]=1[CH2:5][NH:6]C(=O)C>C(O)C>[ClH:1].[Br:2][C:3]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[C:11]([O:20][CH3:21])=[CH:10][C:4]=1[CH2:5][NH2:6]
Reactant: COc1cc(CNC(C)=O)c(Br)cc1OCC(O)CO
Agent: Cl
Solvent: CCO
Product: COc1cc(CN)c(Br)cc1OCC(O)CO

Procedure:
37% Hydrochloric acid (0.3 ml) was added to a solution of 2-bromo-4-(2,3-dihydroxypropoxy)-5-methoxy-N-acetyl benzylamine 4 (0.3 g, 0.86 mmol) in abs. ethanol (12 ml) and the mixture was refluxed for 12 hours. After cooling, the solvent was evaporated off under reduced pressure and the residue was recrystallized from a methanol/ethyl ether mixture to afford the title compound as pale orange solid in quantitative yield.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](Br)=[CH:21][CH:20]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C1(C)C=CC=CC=1>[Br:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([C:12]2[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:20]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: COCCOC
Product: Brc1cc(-c2cc3ccccc3c3ccccc23)cc2ccccc12
Temperature: 85 °C
Reaction time: 6 h
Yield: 47.8 %

Procedure:
In argon atmosphere, a mixture of 19.41 g (87.4 mmol) of 9-phenanthreneboronic acid, 25.00 g (87.4 mmol) of 1,4-dibromonaphthalene, 2.02 g (1.70 mmol) of tetrakis(triphenylphosphine)palladium (0), 50 ml of dimethoxyethane, 200 ml of toluene, and 132 g of a 2 M sodium carbonate aqueous solution was stirred at a bath temperature of 85° C. for 6 h. The reaction mixture was added with water and extracted with toluene. After washing with water, the organic phase was dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography to obtain 16.02 g (yield: 55.0%) of 4-bromo-2-(9-phenanthrenyl)naphthalene.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([F:16])[CH:15]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([F:16])[C:15]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Fc1cncc(Br)c1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(F)cncc1Br
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 68.1 %

Procedure:
To a −78° C. solution of LDA (2 M solution in heptane/THF, 14.2 mL, 28.4 mmol) in anhydrous THF (45 mL) was added a solution of the 3-bromo-5-fluoropyridine (5.0 g, 28.4 mmol) in anhydrous THF (20 mL). The reaction mixture was stirred at −78° C. for 45 minutes. Then, a solution of ethyl chloroformate (24 mL, 284 mmol) was added slowly over 10 minutes. After stirring for 20 minutes, the reaction mixture was quenched with a saturated solution of NaHCO3. The mixture was extracted into ethyl acetate (3×100 mL). The combined organic extracts were extracted with water (2×200 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording ethyl 3-bromo-5-fluoropyridine-4-carboxylate (4.8 g, 69% yield). The product was used without further purification.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([C:6](=O)[CH2:7][C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.Cl.[CH:17]([NH:20][NH2:21])([CH3:19])[CH3:18]>CCO>[CH:17]([N:20]1[C:6]([CH:4]2[CH2:5][C:2](=[CH2:1])[CH2:3]2)=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)NN
Reactant: C=C1CC(C(=O)CC(=O)C(=O)OCC)C1
Agent: Cl
Solvent: CCO
Product: C=C1CC(c2cc(C(=O)OCC)nn2C(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 8b (6.29 g, 29.9 mmol) was dissolved in dry EtOH (65 mL, denaturated with 5% of MeOH) and isopropyl hydrazine hydrochloride (3.97 g, 35.9 mmol) was added. The reaction mixture was stirred for 3 h at rt. The solvent was removed and to the oily residue were added EA (100 mL), water (50 mL) and sat. NaHCO3 (50 mL) sequentially. The layers were separated and the aq. phase was re-extracted with EA (50 mL). The combined organic phases were washed with brine (70 mL) and dried over anh. Na2SO4. The solvent was removed under vacuum and the residue was dried under reduced pressure. Yield: 7.23 g (contains 3.4% of EtOAc by NMR, recalculated pure yield: 6.98 g, 94%). Crude product 8c is 98% pure by HPLC and NMR. 1H-NMR (CDCl3), δ (ppm): 6.62 (s, 1H), 4.88-4.82 (m, 2H), 4.42-4.32 (m, 3H), 3.56-3.45 (m, 1H), 3.17-3.07 (m, 2H), 2.88-2.79 (m, 2H), 1.49 (d, J=8.0 Hz, 6H), 1.37 (t, J=8.0 Hz, 3H).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:39][OH:40]>[Cl-].[Na+].O.CN(C=O)C>[CH:10]1[C:11]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:39][OH:40])=[O:25])=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: NO
Reactant: O=C(O)CCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(C=C1c2ccccc2-c2ccccc21)NCCCCCC(=O)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
6-(2-(9H-fluoren-9-ylidene)acetamido)hexanoic acid (335 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (147 mg, 42%) as a yellow solid. 1H NMR (DMSO-d6) δ1.19 (m, 2H, CH2), 1.30 (m, 2H, CH2), 1.48 (m, 2H, CH2), 1.92 (t, J=8.0 Hz, 2H, CH2CO), 3.24 (m, 2H, NCH2), 7.08 (s, 1H, ═CH—CO), 7.28 (m, 2H, Ar—H), 7.41 (m, 2H, Ar—H), 7.76 (m, 1H, Ar—H), 7.81 (m, 2H, Ar—H), 8.53 (t, J=4.0 Hz, 1H, CONH), 8.67 (d, J=8.0 Hz, 1H, Ar—H), 10.32 (s, 1H, NH—O). LC-MS (m/z) 351 (M+1).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]([NH:19][C@H:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH2:21][C:22]([O:24]CC)=[O:23])=[O:18])=[N:11]1>CC1CCCO1>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]([NH:19][C@H:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[N:11]1
Reactant: CCOC(=O)C[C@H](NC(=O)c1cc(OC)n(-c2ccccc2F)n1)c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Product: COc1cc(C(=O)N[C@@H](CC(=O)O)c2ccccc2C)nn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
82.8 ml of an aqueous 4 M solution of sodium hydroxide (331 mmol) were added to a solution of ethyl (S)-3-{[1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carbonyl]-amino}-3-(2-methyl-phenyl)-propionate (70.4 g, 165 mmol) in 2-methyltetrahydrofuran (500 ml) at room temperature. The mixture was stirred at room temperature for 2 h, then at 40° C. for 2 h and then at room temperature for 16 h. The phases were separated and the aqueous phase acidified to pH 3 with hydrochloric acid. The product partially precipitated upon acidification. The aqueous filtrate was extracted with EA. The extracts were evaporated and the residue was washed with isopropyl acetate. The two batches were combined to give 53.6 g (82%) of the title compound as a white crystalline powder.