Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][Zn+])=[CH:18][N:17]=1.C1COCC1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:15][C:16]1[N:17]=[CH:18][C:19]([CH2:22][C:2]2[C:3]([CH3:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])=[CH:20][CH:21]=1
Reactant: Clc1ccc(C[Zn+])cn1
Reactant: COC(=O)c1cc(Br)c(C)cc1O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cc2ccc(Cl)nc2)c(C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-bromo-2-hydroxy-4-methylbenzoate (0.61 g) in THF (20.0 mL) were added 0.5M (2-chloro-5-pyridyl)methylzinc chloride/THF solution (12.5 mL) and bis(tri-tert-butylphosphine)palladium(0) (0.13 g), and the mixture was stirred overnight at room temperature under argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.52 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[SH:10].Br[CH2:12][C:13]1([CH3:39])[CH:17]([C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19])[N:16]2[C:26](=[O:38])[CH:27]([NH:28][C:29](=[O:37])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:15]2[S:14]1>P([O-])([O-])([O-])=O.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:12][C:13]1([CH3:39])[CH:17]([C:18]([O:20][CH2:21][C:22]([Cl:23])([Cl:24])[Cl:25])=[O:19])[N:16]2[C:26](=[O:38])[CH:27]([NH:28][C:29](=[O:37])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:15]2[S:14]1
Reactant: Sc1nc2ccccc2s1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC1(CSc2nc3ccccc3s2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 24 %

Procedure:
Benzothiazole-2-thiol (0.20 g) was dissolved in a mixture of pH 6.7 phosphate buffer (15 ml) and dioxane (15 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g) and the mixture was stirred for 7 hours at room temperature. After the reaction was completed, dioxane was distilled off and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with a 2% potassium carbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography on silica gel using chloroform as developing solvent to give oily 2,2,2-trichloroethyl 2-(benzothiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.15 g) from the second fraction of fractions each of which was separated into 30 ml.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]2[OH:27])=[CH:10][CH:9]=1)=[O:5])[CH3:2].Br[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1>>[CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]2[O:27][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:12][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: BrCc1ccc2ccccc2c1
Product: CCOC(=O)C=Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
Alkylation of tert-butyl (3 RS,4RS)-4-[4-(2-ethoxycarbonyl-vinyl)-phenyl]-3-hydroxy-piperidine-1-carboxylate with 2-bromomethyinaphthalene analogously to the procedure described in Example 22(i) gave tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-vinyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a light yellow resin; MS: 516 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7](C)[CH:8]=[O:9].[C:11]1([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH2:19][C:18]2=O)C=CC=CC=1.[OH-].[NH4+]>O.ClCCl.N1C=CC=CC=1>[CH3:11][N:17]([CH:18]=[C:19]1[C:20]2[C:6](=[N:22][CH:23]=[CH:24][CH:25]=2)[NH:7][C:8]1=[O:9])[CH3:21]
Reactant: CN(C)C=O
Reactant: O=C1Cc2cccnc2N1c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CN(C)C=C1C(=O)Nc2ncccc21
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
Phosphorous oxychloride (693 μL, 7.47 mmol) is added slowly to a stirred solution of dimethylformamide (714 μL) and dichloromethane (714 μL) cooled to 0-5° C. After 10 min, a solution of the above 1-phenyl-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (350 mg, 1.66 mmol), pyridine (357 μL) and dichloromethane (1.43 mL) is added and the reaction is stirred at room temperature for 24 hr. The reaction mixture is poured into water, the pH adjusted to 8 with ammonium hydroxide and extracted with dichloromethane (2×). The combined extract is dried, filtered and concentrated. The residue is purified by chromatography eluting with dichlormethane-2% methanol. Product containing fractions are combined and concentrated to afford 3-dimethylaminomethylene-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (211 mg, 47.9% yield).
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][OH:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:33][C:34]1([Br:50])[CH:36]([C:37]2[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=2)[CH:35]1[CH2:44][C:45]([O:47]CC)=[O:46].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(O)(C(F)(F)F)=O>C1COCC1>[Br:33][C:34]1([Br:50])[CH:36]([C:37]2[CH:42]=[CH:41][C:40]([O:13][CH2:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[CH2:6][CH2:7][CH2:8][NH:9][C:10]=4[N:1]=3)=[CH:39][CH:38]=2)[CH:35]1[CH2:44][C:45]([OH:47])=[O:46]
Reactant: CCOC(=O)CC1C(c2ccc(O)cc2)C1(Br)Br
Reactant: OCCc1ccc2c(n1)NCCC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1C(c2ccc(OCCc3ccc4c(n3)NCCC4)cc2)C1(Br)Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.3 %

Procedure:
To a solution of 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1-ethanol (0.17 g, 0.96 mmol) and polymer bound PPh3 (0.32 g, 0.96 mmol) in dry THF (10 mL) was added ethyl [2,2-dibromo-3-(4-hydroxyphenyl)cyclopropyl]acetate (0.18 g, 0.6 mmol) followed by diisopropyl azodicarboxylate (0.2 mL, 1 mmol). The reaction mixture was stirred at room temperature. After 18 hours, polymer was filtered through Celite and washed with excess THF. Filtrate was concentrated. The concentrated residue in 50% acetonitrile in water (4 mL) was added LiOH (0.14 g). The reaction mixture was stirred 3 hours at room temperature. Reaction mixture was acidified by adding TFA and purified by reverse phase HPLC to afford 50 mg (12%) of desired product. 1H NMR (CD3OD) δ 7.59 (d, 1H, J=7.4 Hz), 7.21 (d, 2H, J=8.6 Hz), 6.88 (d, 2H, J=8.7 Hz), 6.73 (d, 1H, J=7.2 Hz), 4.27 (t, 2H, J=6.0 Hz), 3.49 (t, 2H, J=5.9 Hz), 3.14 (t, 2H, J=5.9 Hz), 2.82-2.78 (m, 3H), 2.71-2.59 (m, 2H), 2.25-2.19 (m, 1H), 1.97-1.90 (m, 2H). HRMS calcd for C21H22N2O3 (M+H): 421.1080. found 421.1069.
Reaction SMILES: [Na:1].[O:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)=[O:18])[C:11]=1[CH3:28].Cl[C:30]1C(C)=C[N+]([O-])=C(C)C=1C>>[Na:1].[O:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[CH2:8][O:9][C:10]1[C:15]([CH3:30])=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:19]2[NH:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)=[O:18])[C:11]=1[CH3:28]
Reactant: Cc1c[n+]([O-])c(C)c(C)c1Cl
Reactant: Cc1c(OCC2COCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: [Na]
Product: Cc1cnc(CS(=O)c2nc3ccccc3[nH]2)c(C)c1OCC1COCCO1
Yield: 18 %

Procedure:
The same procedure as in the steps (62a) to (62d) of Example 62 was repeated using 4-chloro-2,3,5-trimethylpyridine 1-oxide to obtain the title compound (355 mg, total yield: 18%) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].[F-].[K+]>O>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])([CH3:13])[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [F-]
Agent: [K+]
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1Nc1ccccc1[N+](=O)[O-]
Temperature: 180 °C
Yield: 47.9 %

Procedure:
2,6-diisopropylaniline (25 g, 141 mmol), 2-fluoronitrobenzene (10 g, 70 mmol), and potassium fluoride (6.2 g, 106 mmol) were mixed in a one-neck flask. The mixture was heated up to 180° C. under nitrogen for 48 hours. After cooled to room temperature, water (200 mL) was added. The mixture was then extracted with dichloromethane (200 mL) for three times. The solvent was evaporated and the residue was purified by column chromatography using 20% of dichloromethane in hexanes. 10 g of desired product was obtained.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[B:20]([OH:25])[OH:21])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O

Procedure:
By the method described in Example 10, Step B, N-t-butylbenzenesulfonamide [G. Lombardino, J. Org. Chem., 36, 1843 (1971)] was deprotonated with n-butyllithium, and the resulting dianion was reacted with triisopropyl borate and worked up with acid to give the title compound, which was used directly in the next step without further purification.
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][N:16]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[C:17]1[N:18]=[N:19][N:20]([CH3:22])[N:21]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+]>C(O)C>[CH2:6]([N:7]([CH2:8][CH3:9])[C:4]([C:6]1[CH:14]([CH2:15][N:16]([CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:35])([F:37])[F:36])[CH:25]=2)[C:17]2[N:18]=[N:19][N:20]([CH3:22])[N:21]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:4]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)C(=O)C1=Nc2ccccc2C1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Yield: 95.1 %

Procedure:
To the solution of 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1H-indole-2-carboxylic acid ethyl ester (0.2 g, 0.38 mmol) in 5 mL ethanol, was added NaOH (0.076 g, 1.9 mmol). The reaction was refluxed under nitrogen atm for 1 h. The reaction mixture was acidified and the suspension was filtered to afford the title compound (0.1 g, 53%)
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C@@H:8]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH:9]([CH3:11])[CH3:10].[O:23]=[CH:24][C@@H:25]([C@H:27]([C@@H:29]([C@@H:31]([CH2:33]O)[OH:32])[OH:30])[OH:28])[OH:26]>[Au].CO>[CH2:33]([NH:7][C@@H:8]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH:9]([CH3:11])[CH3:10])[C:31]1([O:23][CH2:24][C@@H:25]([OH:26])[C@@H:27]([OH:28])[C@@H:29]1[OH:30])[OH:32]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)[C@@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: [Au]
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)[C@@H](NCC1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O)C(=O)N[C@@H](CC(=O)O)C(=O)O
Reaction time: 2.5 h

Procedure:
300 ml of pyridine and 3 l of methanol were added to 10 g of D-valyl-aspartic acid and 50 g of anhydrous D-glucose, and the stirred mixture was boiled for 2.5 hours. The reactants gradually dissolved during this time, and the reaction mixture assumed a yellow-gold color. After the reaction was complete, the mixture was concentrated in vacuo and further processed as described in Example 9. Freeze-drying resulted in 13.5 g of amorphous N-(1-deoxyfructopyranos-2-yl)-D-valyl-aspartic acid.
Reaction SMILES: C(OC(=O)N[C@H]1CC[C@@H](O)CC1)(C)(C)C.[Cl:16]C1C2C(=C(Cl)C(F)=CC=2)C=CN=1.Cl.Cl.[NH2:31][C@@H:32]1[CH2:37][CH2:36][C@H:35]([O:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][C:48]=2Cl)[C:45]([OH:50])=[N:44][CH:43]=[CH:42]3)[CH2:34][CH2:33]1>>[NH2:31][C@@H:32]1[CH2:37][CH2:36][C@H:35]([O:38][C:39]2[C:40]([Cl:16])=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45](=[O:50])[NH:44][CH:43]=[CH:42]3)[CH2:34][CH2:33]1
Reactant: Fc1ccc2c(Cl)nccc2c1Cl
Reactant: N[C@H]1CC[C@@H](Oc2cc3ccnc(O)c3cc2Cl)CC1
Agent: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Agent: Cl
Product: N[C@H]1CC[C@@H](Oc2ccc3c(=O)[nH]ccc3c2Cl)CC1

Procedure:
Starting from cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester and 1,5-dichloro-6-fluoro-isoquinoline (9), the title compound was prepared as hydrochloride following the route described for 6-(cis-4-amino-cyclohexyloxy)-7-chloro-isoquinolin-1-ol hydrochloride (10). Rt=1.04 min (Method B). Detected mass: 293.1/295.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]=[N:24][CH:23]=[CH:22]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH:25]1[C:26]2[C:21](=[CH:20][CH:19]=[CH:18][C:17]=2[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:22]=[CH:23][N:24]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Brc1cccc2ccncc12
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc3ccncc23)CCN(C)C1

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.499 mmol), 8-bromoisoquinoline (0.155 g, 0.748 mmol), potassium phosphate (0.317 g, 1.495 mmol), CuI (9 mg, 0.047 mmol) and L-Proline (11 mg, 0.095 mmol) in dry DMF (3 mL) was heated at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(isoquinolin-8-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) δ (ppm): 8.8 (d, 1H), 8.62 (d, 1H), 8.42 (bs, 1H), 8.4 (d, 1H), 8.3 (t, 1H), 8.0 (d, 1H), 7.42 (s, 1H), 7.0 (d, 1H), 6.87 (bs, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.16 (m, 4H), 2.8 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@@:8]([NH:18][S@@](C(C)(C)C)=O)([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][F:10])[CH:7]=1.CO.Cl>C(Cl)Cl>[NH2:18][C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:25])([CH2:9][F:10])[CH2:11][C@H:12]([OH:17])[C:13]([F:15])([F:16])[F:14]
Reactant: CC(C)(C)[S@@](=O)N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cc(Br)ccc1F
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cc(Br)ccc1F
Reaction time: 1 h

Procedure:
To a solution of (R)—N-((2S,4S)-2-(5-bromo-2-fluorophenyl)-1,5,5,5-tetrafluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (1.6 g, 3.54 mmol, step 6) in DCM (20 mL)/MeOH (10 mL) was added HCl (4.0M in dioxane; 1.075 ml, 35.4 mmol, Aldrich) at RT. The reaction was stirred for one hour. The reaction was concentrated under reduced pressure and the crude residue was taken up in EtOAc. The solution was washed sequentially with water, saturated aqueous sodium bicarbonate solution, and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound as yellow oil, used without further purification. MS m/z=347.9 M+. Calculated for C11H11BrF5NO: 348.11
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH3:27])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH3:27])[CH:21]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: Cc1cc(C(=O)CBr)ccc1Cl
Product: CCOC(=O)n1c(C(=O)c2ccc(Cl)c(C)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-4′-chloro-3′-methylacetophenone.
Reaction SMILES: N#N.[Mg].Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.II.[CH:22](N1CCCCC1)=[O:23]>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([CH:22]=[O:23])=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: O=CN1CCCCC1
Reactant: Clc1ccc(C#Cc2ccc(Br)cc2)cc1
Agent: II
Agent: N#N
Agent: [Mg]
Solvent: C1CCOC1
Product: O=Cc1ccc(C#Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 318.6 %

Procedure:
To a dry 100 mL three-necked flask under a flow of N2 containing magnesium turnings (0.595 g; 24.50 mmol) in dry THF (10 mL) at reflux, an activating, small amount of 1-bromo-4-[(4-chlorophenyl) ethynyl] benzene (VIId) (0.39 g; 1.33 mmol) was added in one portion. N2 flow and stirring were stopped. Reaction mixture was heated at reflux for 5 minutes then iodine crystal was added keeping vigorous reflux to start the reaction. The reaction mixture went colourless after 5minutes and reaction mixture turned black-blue after an additional minute. A solution of the remaining amount of 1-bromo-4-[(4-chlorophenyl) ethynyl] benzene (VIId) (6.104 g; 20.93 mmol) in dry THF (35 mL) at 55° C. was added drop wise into the reaction mixture while keeping gentle reflux. Reflux was maintained for 15minutes then temperature was allowed to cool to RT under stirring for 1 h. The reaction mixture was cooled to 3° C. and a solution of dry 1-formyl-piperidine (3.71 mL; 33.40 mmol) in dry THF (10 mL) was added drop wise maintaining temperature at 5° C. The reaction mixture was then allowed to warm to RT and it was stirred overnight. Protocol and work-up was then similar with those described above. Purification was performed by flash chromatography (SiO2) using (cyclohexane 9-ethyl acetate 1). The title compound (m=1.02 g) was obtained as a white solid in a19% yield. Melting point: 164° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(C)=[O:21].ClC1C=CC=C(C(OO)=O)C=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N+:15]([O-:21])=[CH:14][CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc2ncccc2c1
Reactant: CC(C)=O
Agent: O=C(OO)c1cccc(Cl)c1
Product: CCCCCCCOc1ccc2c(ccc[n+]2[O-])c1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
6-Heptyloxyquinoline (1000.0 mg, 0.0041094 mol) was dissolved in acetone (20 mL, 0.3 mol), followed by m-chloroperbenzoic acid (1060 mg, 0.00493 mol) in small portions at 23° C. The reaction mixture was then stirred at 23° C. for 3 hours, and LC/MS indicated all the SM was converted to the desired product. A solution of sodium thiosulfate (1950 mg, 0.0123 mol) was added. The reaction mixture was then allowed to stir for 1 hour. Excess of solvents were removed under vacuum, and the residue was treated with DCM (100×3 mL). Combined organic layers were treated with sodium sulfate and filtrated. The crude mixture was then purified via chromatography (SiO2, 120g, 0-8% MeOH/DCM) to give 653 mg (53%) pure product. 1H NMR (CHLOROFORM-d) δ: 8.65 (d, J=9.5 Hz, 1H), 8.38 (d, J=5.8 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.38 (dd, J=9.5, 2.5 Hz, 1H), 7.23 (dd, J=8.3, 6.0 Hz, 1H), 7.09 (d, J=2.5 Hz, 1H), 4.08 (t, J=6.5 Hz, 2H), 1.80-1.92 (m, 2H), 1.44-1.57 (m, 2H), 1.28-1.44 (m, 6H), 0.90 (t, J=6.8 Hz, 3H). MS (M+1): 260.20.
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:29]2[C:34](=O)[CH2:33][CH2:32][CH2:31][C:30]=2[O:36]CC)[NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[O:17])=[C:10]([O:39][CH3:40])[CH:9]=1.O>C(#N)C>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:29]3[C:30](=[O:36])[CH2:31][CH2:32][CH2:33][C:34]=3[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=3)[C:16](=[O:17])[NH:15]2)=[C:10]([O:39][CH3:40])[CH:9]=1
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(Br)cc2OC)C(=O)CCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reaction time: 0.33 h

Procedure:
Sodium tert-butoxide (175 mg, 1.82 mmol) is added to a solution of 1-((4-bromo-2-methoxyphenyl)(2-ethoxy-6-oxocyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)-urea (intermediate 49, 760 mg, 1.40 mmol) in acetonitrile (4 mL), and the mixture is shaked in an ultrasound bath for 20 min Water is added, and the mixture is extracted with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 41 mg; ESI mass spectrum [(79Br)-M+H]+=495, [(81Br)-M+H]+=497; Retention time HPLC: 0.96 min (Z011_S03).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8](/[CH:12]=[CH:13]/[CH2:14][OH:15])[CH:7]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:15][CH2:14]/[CH:13]=[CH:12]/[C:8]1[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: OC/C=C/c1cccnc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC/C=C/c1cccnc1
Reaction time: 0.5 h

Procedure:
Methane sulfonyl chloride (0.22 ml) was added to a mixture of (E)-3-(3-pyridyl)-2-propen-1-ol (0.36 g) and triethylamine (0.74 ml) in dichloromethane (5 ml) under −10° C. After being stirred at the same temperature for 0.5 hour, the reaction mixture was washed with saturated sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure to give (E)-3-(3-pyridyl)-2-propen-1-yl methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])=O)=[CH:4][CH:3]=1.[CH2:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:27]([NH2:29])=[O:28])[CH3:23].BrC1C=CC(CBr)=CC=1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])=[CH:4][CH:3]=1.[CH2:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:27]([NH2:29])=[O:28])[CH3:23]
Reactant: COc1ccc2c(c1)cc(C)n2C(=O)c1ccc(Cl)cc1
Agent: BrCc1ccc(Br)cc1
Agent: CCc1cc(C(N)=O)ccc1Cl
Product: COc1ccc2c(c1)cc(C)n2Cc1ccc(Cl)cc1

Procedure:
The procedure employed for preparation of Compound 9e was repeated except as follows. In the treatment of Compound 8e, 4-bromobenzyl bromide for N-alkylation was used instead of 4-CBC for N-acylation, so the resultant was 9h instead of 9e.