Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[C:18]([F:23])[CH:17]=1)(=[O:15])=[O:14])[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)(C)(C)C.C([Li])CCC.[O:30]1[CH:34]=[CH:33][C:32]([C:35]2[N:42]=[CH:41][CH:40]=[CH:39][C:36]=2[CH:37]=[O:38])=[CH:31]1.Cl>O1CCCC1.O.C(OCC)(=O)C>[F:23][C:18]1[CH:17]=[C:16]([S:13]([NH:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)(=[O:14])=[O:15])[CH:21]=[CH:20][C:19]=1[CH:37]([C:36]1[C:35]([C:32]2[CH:33]=[CH:34][O:30][CH:31]=2)=[N:42][CH:41]=[CH:40][CH:39]=1)[OH:38]
Reactant: O=Cc1cccnc1-c1ccoc1
Reactant: CC(C)(C)OC(=O)N(c1nccs1)S(=O)(=O)c1ccc(F)c(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccs1)c1ccc(C(O)c2cccnc2-c2ccoc2)c(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
100 mg (0.26 mmol) of tert-butyl((3,4-difluorophenyl)sulfonyl)(thiazol-2-yl)carbamate was dissolved in 5 mL of tetrahydrofuran under nitrogen gas, and cooled to −78° C. After adding 0.25 mL (0.39 mmol) of n-butyllithium (1.6M in tetrahydrofuran) slowly, the mixture was stirred for 30 minutes as maintaining −78° C. 23 mg (0.13 mmol) of 2-(furan-3-yl)nicotinaldehyde was dissolved in 0.5 mL of tetrahydrofuran, and added to the above reacting solution. As warming from −78° C. to room temperature, the reacting solution was stirred for 24 hours. Ethyl acetate and water/1 N-hydrochloride were added to the reacting solution, and it was stirred. After separating layers, the organic layer only was collected and concentrated under reduced pressure. The obtained residue was separated by column chromatography (developing solvent, hexane:ethyl acetate=1:1) to obtain 7 mg (6.1% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]2[C:28]3[C:27](=[O:29])[CH2:26][CH:25]([CH2:30][CH2:31][CH3:32])[CH2:24][C:23]=3[NH:22][C:21]([CH3:33])=[C:20]2[C:34]#[N:35])[CH:5]=[C:6]([OH:18])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.Br[CH2:37][CH2:38][OH:39].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]2[C:28]3[C:27](=[O:29])[CH2:26][CH:25]([CH2:30][CH2:31][CH3:32])[CH2:24][C:23]=3[NH:22][C:21]([CH3:33])=[C:20]2[C:34]#[N:35])[CH:5]=[C:6]([O:18][CH2:37][CH2:38][OH:39])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(O)c(OCc2cccc(OC)c2)c(Br)c1
Reactant: OCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(OC)c2)c(OCCO)c1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of 4-[3-bromo-5-hydroxy-4-(3-methoxy-benzyloxy)-phenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (100 mg), 2-bromoethanol (16 μl), tetrabutylammonium iodide (5 mg) and potassium carbonate (50 mg) in DMF (2 ml) was stirred at 70° C. for 17 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:14]2[NH:15]C(=O)[O:17][CH:13]2[CH2:12][CH:11]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:15][CH:14]1[CH:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:11]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:13]1[OH:17]
Reactant: O=C1NC2C(CC(COCc3ccccc3)C(OCc3ccccc3)C2OCc2ccccc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC1C(O)CC(COCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
To a mixture of rac-(3 aS,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-hexahydrobenzo[d]oxazol-2(3H)-one (280 mg, 0.592 mmol) in ethanol (2 mL) was added 2 N NaOH (10 mL). The mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was extracted with DCM (3×15 mL). The combined extracts were washed with brine and dried over Na2SO4. Solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 5% MeOH in DCM and 94:4:2 DCM-MeOH—NH4OH (28% aqueous) to give rac-(1R,2R,3S,4S,5S)-2-amino-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)cyclohexanol (Intermediate Example 2) (227 mg, 86%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.37-7.25 (m, 15H), 5.01 (d, J=11.5 Hz, 1H), 4.84 (d, J=10.9 Hz, 1H), 4.63 (d, J=11.5 Hz, 1H), 4.60 (d, J=10.9 Hz, 1H), 4.47 (s, 2H), 3.86 (q, J=2.8 Hz, 1H), 3.79 (dd, J=9.0, 4.2 Hz, 1H), 3.58-3.53 (m, 2H), 3.44 (dd, J=9.0, 2.5 Hz, 1H), 2.85 (d, J=6.7 Hz, 1H), 2.27-2.15 (m, 1H), 1.94 (dt, J=14.5, 3.5 Hz, 1H), 1.67 (ddd, J=14.8, 12.6 Hz, 2.4, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:8]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:21]3[CH2:26][C@H:25]([CH3:27])[CH2:24][C@H:23]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]3)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.[CH3:61][N:62]1[CH2:67][CH:66]=[C:65](B2OC(C)(C)C(C)(C)O2)[CH2:64][CH2:63]1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl.O>[C:32]([O:31][C:29]([NH:28][C@H:23]1[CH2:24][C@@H:25]([CH3:27])[CH2:26][N:21]([C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[NH:14][C:12]([C:8]2[C:7]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:6][C:5]3[C:10](=[CH:11][C:2]([C:65]4[CH2:66][CH2:67][N:62]([CH3:61])[CH2:63][CH:64]=4)=[CH:3][CH:4]=3)[N:9]=2)=[O:13])[CH2:22]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(C4=CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 90 °C
Yield: 29.7 %

Procedure:
A pressure vial was charged with benzyl (7-bromo-2-{[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}quinolin-3-yl)carbamate (0.029 g, 0.043 mmol), K3PO4 (0.0181 g, 0.0852 mmol), 1,4-dioxane (0.55 mL), water (0.092 mL) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.014 g, 0.063 mmol). The mixture was deoxygenated with nitrogen for 10 min. Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.0022 g, 0.0028 mmol) was added. The mixture was sealed with screw cap, then heated at 90° C. for 1.5 h. The mixture was quenched with water and extracted with EtOAc. The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by flash chromatography on 20 g silica gel, eluting with 0-30% MeOH in EtOAc, to yield the sub-title compound (0.009 g, 30%). LCMS calc. for C40H48N7O5 [M+H]+: m/z=706.4. found: 706.5.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[O:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1>>[CH:18]1([N:13]2[C:12]([C:33]3[CH:34]=[CH:35][O:31][CH:32]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: OB(O)c1ccoc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: c1cc(-c2c3c(nn2C2CCCC2)CCNCC3)co1
Yield: 83.6 %

Procedure:
The title compound (101 mg) was prepared according to Example 180 using 202 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 149 mg of 3-furanboronic acid. MS (ESI): exact mass calculated for C16H21N3O, 271.17; found, m/z 272.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.73-7.72 (m, 2H), 6.57-6.56 (m, 1H), 4.64 (m, 1H), 3.40-3.38 (m, 2H), 3.16-3.14 (m, 2H), 2.86-2.84 (m, 2H), 2.03-1.91 (m, 6H), 1.66-1.64 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9](OC[C@H]3CCCN3C(OC(C)(C)C)=O)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[O:29]1[CH2:34][CH2:33]OCC1>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:29][CH2:34][C@H:33]3[CH2:8][CH2:9][CH2:10][NH:11]3)=[N:11][C:12]=2[Cl:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(-c2ccccc2)c1
Reactant: C1COCCO1
Agent: Cl
Product: Clc1nc(OC[C@H]2CCCN2)ccc1-c1ccccc1
Reaction time: 40 h

Procedure:
To the 5-phenyl-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine compound from Example 69b (164 mg) was added HCl in dioxane (3 mL). The mixture was tirred at room temperature for 40 hours. The solvent was removed under vacuum at 50° C., and the residue was triturated with Et2O. The solid was dried under high vacuum to afford the title compound. mp 178-180° C. MS (CI/NH3) m/z 289 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 1.27-2.10 (m, 1H), 2.03-2.18 (m, 2H), 2.22-2.31 (m, 1H), 3.41 (t, J=7.5 Hz, 2H), 4.13 (m, 1H), 4.26 (m, 1H), 4.46 (dd, J=3.4, 10.8 Hz, 1H), 7.54 (m, 6H), 8.12 (d, J=3.0 Hz, 1H). Anal. Calcd for C16H17N2OCl.1.2 HCl: C, 57.79; H, 5.52; N, 8.42. Found: C, 57.73; H, 6.5.58; N, 8.27. [α]25D=−10.94° (c 0.64, MeOH).
Reaction SMILES: [O:1]1[C@H:3]([CH3:4])[CH2:2]1.[CH2:5]([Mg]Br)[CH2:6][CH2:7][CH:8]=[CH2:9]>>[CH3:4][C@@H:3]([OH:1])[CH2:2][CH2:9][CH2:8][CH2:7][CH:6]=[CH2:5]
Reactant: C[C@@H]1CO1
Reactant: C=CCCC[Mg]Br
Product: C=CCCCC[C@@H](C)O

Procedure:
As shown in the reaction formula 2, the (R)-(+)-1,2-epoxypropane is added to separately synthesized 1M 4-pentenyl magnesium bromide, obtaining a (2R)-7-octen-2-ol (III).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]2=[O:19])[CH:7]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>C(OCC)(=O)C.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]3[C:9](=[O:19])[C:10]([CH3:18])([CH3:17])[O:11][C:12]([CH3:15])([CH3:16])[C:13]3=[O:14])[CH:7]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Cc1ccc(Cl)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(F)c(F)c2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 160 °C
Reaction time: 0.08 h
Yield: 75 %

Procedure:
To a microwave vial is added 4-(5-chloro-2-methylphenyl)-2,2,6,6-tetramethyl-pyran-3,5-dione (0.20 g, 0.68 mmol), 3,4-difluoro-phenylboronic acid (0.107 g, 0.68 mmol), potassium phosphate (0.722 g, 3.40 mmol), palladium(II) acetate (1.6 mg, 0.0068 mmol) and sodium S-phos-3′-sulphonate (7.0 mg, 0.0136 mmol). Distilled, degassed water (0.75 ml) is next added (washing-down any solids from the slides of the vial), followed by stirring for 5 minutes and flushing with argon. This mixture is then heated at 160° C. under microwave irradiation for 15 minutes, followed by the addition of extra 3,4-difluorophenylboronic acid (0.107 g, 0.68 mmol) and potassium phosphate (0.144 g, 0.68 mmol), then further heating at 160° C. under microwave irradiation for 15 minutes. After cooling to room temperature the reaction mixture is diluted with ethyl acetate (3 ml) and acidified to pH2 with dilute aqueous hydrochloric acid. The organic phase is separated and the aqueous phase is further extracted with ethyl acetate (3×3 ml). All organics are then combined, filtered through a silica plug and evaporated to give a crude product which is dissolved in N,N-dimethylformamide (2.5 ml) and purified by preparative reverse phase HPLC to afford 4-(3′,4′-difluoro-4-methylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.190 g) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]=[N+:22]=[N-:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:24]([O:28][CH3:29])(=[O:27])[C:25]#[CH:26]>>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]2[CH:26]=[C:25]([C:24]([O:28][CH3:29])=[O:27])[N:23]=[N:22]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN=[N+]=[N-])CC1
Reactant: C#CC(=O)OC
Product: COC(=O)c1cn(Cc2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)nn1
Temperature: 25 °C
Yield: 48.9 %

Procedure:
1-Boc-4-(2-Azidomethyl-phenyl)-piperazine (0.25 g, 0.79 mmol) was dissolved in deuterated chloroform (3 mL). Methyl propiolate (0.35 mL, 3.9 mmol) was added, and the mixture was heated to reflux for about 4 hours and then cooled to r.t. The mixture was concentrated under reduced pressure and purified using silica chromatography (50% ethyl acetate in hexanes) to give the title compound (0.155 g, 49%) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:23]([O:24]C)=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4.C[O-].[Na+].C(S)CCCCCCCCCCC.Cl>CN1C(=O)CCC1>[Br:1][C:2]1[C:23]([OH:24])=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4
Reactant: COc1cc2c(cc1Br)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Agent: CCCCCCCCCCCCS
Agent: C[O-]
Agent: Cl
Solvent: CN1CCCC1=O
Product: CC1(C)c2cc(O)c(Br)cc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 160 °C
Reaction time: 1 h
Yield: 194.9 %

Procedure:
9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E3-1-1, 1.0 g, 2.53 mmol) was dissolved in NMP (10 mL), added with NaOMe (683 mg, 5 eq.) and 1-dodecanethiol (3.0 mL, 5 eq.), and stirred at 160° C. for 1 hr. The reaction solution was added to 0.5 N aqueous solution of hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with MeOH, and the solid remaining after dissolution was filtered to obtain the title compound (yellow powder, 1.88 g, 65%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:17]=[C:16]([C:27](O)=[O:28])[C:15]=2[CH3:30])=[CH:10][CH:9]=1.C(N(CC)CC)C.[Cl-].[C:39]([C:42]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:47][CH2:46][NH2+:45][CH2:44][CH2:43]1)([OH:41])=[O:40]>ClCCl.CN(C)C=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:17]=[C:16]([C:27]([N:45]3[CH2:44][CH2:43][C:42]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:39]([OH:41])=[O:40])[CH2:47][CH2:46]3)=[O:28])[C:15]=2[CH3:30])=[CH:12][CH:13]=1
Reactant: O=C(O)C1(c2ccccc2)CC[NH2+]CC1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCC(C(=O)O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 67 %

Procedure:
A 2 M solution of oxalyl chloride in dichloromethane (3 eq., 0.19 mL, 0.377 mmol) was added to 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1 eq., 48 mg, 0.126 mmol) in dichloromethane (5 mL). Next, 2 drops of anhydrous N,N-dimethylformamide was added the reaction was stirred for 2 h. The reaction was concentrated in vacuo. The reaction mixture was dissolved in dichloromethane (5 mL). Triethylamine (3 eq., 0.05 mL, 0.377 mmol) and 4-carboxy-4-phenylpiperidin-1-ium chloride (1.5 eq., 45.7 mg, 0.189 mmol) was added and the reaction was stirred for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-10% methanol/dichloromethane with 1% acetic acid to yield pure 1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxylic acid (48 mg, 67%). (77) 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.87-2.09 (m, 2H) 2.15 (s, 3H) 2.61 (t, J=16.18 Hz, 2H) 3.21 (t, J=12.03 Hz, 1H) 3.47 (t, J=11.94 Hz, 1H) 4.26 (d, J=13.61 Hz, 1H) 4.57 (d, J=13.56 Hz, 1H) 7.05 (d, J=8.34 Hz, 2H) 7.12-7.45 (m, 10H).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([N:17]([CH2:29][CH2:30][C:31]([OH:33])=O)[C:18]([NH:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])=[S:19])[CH:15]=[CH2:16].C([O-])(O)=O.[Na+]>>[CH2:14]([N:17]1[CH2:29][CH2:30][C:31](=[O:33])[N:20]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[C:18]1=[S:19])[CH:15]=[CH2:16]
Reactant: C=CCN(CCC(=O)O)C(=S)Nc1c(C)cccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=CCN1CCC(=O)N(c2c(C)cccc2C)C1=S
Reaction time: 4 h
Yield: 49.7 %

Procedure:
To a cooled solution of trifluoroacetic anhydride (19.5 g), was added 9 g of 3-[1-allyl-3-(2,6-dimethylphenyl)-thioureido]propionic acid. The reaction mixture was stirred at 0°-5° C. for 4 hours, then stirred at ambient temperature for 72 hours. The reaction mixture was poured into ice-H2O, basified with saturated NaHCO3 solution, and extracted with methylene chloride (100 mL). The organic phase was dried over anhydrous magnesium sulfate, then evaporated to a gum. Purification was achieved by flash chromatography on silica gel (9:1=CH2Cl2 :MeOH). Crystallization from hexane afforded the title compound (4.2 g) as a white solid, m.p. 88°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:31][O:32][C:33]([C:35]1([O:38][C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[C:41]([F:46])[CH:40]=2)[CH2:37][CH2:36]1)=[O:34]>CN(C1C=CN=CC=1)C>[CH3:31][O:32][C:33]([C:35]1([O:38][C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:18](=[O:19])[CH:17]([C:16]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:9]=[C:10]4[C:15]=3[CH2:14][CH2:13][CH2:12][CH2:11]4)[CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:41]([F:46])[CH:40]=2)[CH2:37][CH2:36]1)=[O:34]
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: COC(=O)C1(Oc2ccc(N)c(F)c2)CC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(Oc2ccc(NC(=O)C(c3c4c(nn3-c3ccc(Cl)cc3)CCCC4)C3CCCCC3)c(F)c2)CC1

Procedure:
In analogy to the procedure described in example 6, [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 5.1) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 1-(4-amino-3-fluoro-phenoxy)-cyclopropanecarboxylic acid methyl ester in the presence of DMAP to give the title compound as yellow oil. MS: m/e=580.4 [M+H+].
Reaction SMILES: CC1(C)[N:6]2[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH2:9][CH:5]2[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:3][CH2:4][C@H:5]1[NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH2:9]1
Reactant: CC1(C)CC2COC(C)(C)N2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC1(C)C[C@@H](CO)NC1=O

Procedure:
A mixture of 27.15 g I.46 (3,3,6,6-tetramethyl-tetrahydro-pyrrolo[1,2-c]oxazol-5-one) and 0.282 g p-toluenesulfonic acid in 500 ml methanol was stirred at reflux overnight. The mixture was concentrated. Additional 500 ml methanol and 2.8 g p-toluenesulfonic acid were added and the mixture was stirred 4 h at reflux. The mixture was diluted with water and treated with sodium carbonate to obtain a basic pH. The organic layer was separated, dried with magnesium sulfate and concentrated to give 1 g (60% content; 3% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.CS(C)=O.[OH-].[Na+].[CH2:22]([CH:24]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:25]Br)[CH3:23]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)C.O>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[C:5]([CH2:5][CH:4]([CH2:12][CH3:11])[CH2:3][CH2:2][CH2:14][CH3:13])([CH2:25][CH:24]([CH2:22][CH3:23])[CH2:27][CH2:28][CH2:29][CH3:30])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Cc1cc(Cl)ccc1-2
Reactant: CCCCC(CC)CBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(CC)CC1(CC(CC)CCCC)c2cc(Cl)ccc2-c2ccc(Cl)cc21
Reaction time: 2 h
Yield: 94 %

Procedure:
To a stirred mixture of 2,7-dichlorofluorene (43 g, 0.183 mole) and 120 mL of dimethylsulfoxide (DMSO) under nitrogen was added benzyltriethylammonium chloride (2.3 g, 0.01 mole) and 60 mL of a 50 weight percent aqueous solution of sodium hydroxide. 2-Ethylhexyl bromide (85 g, 0.44 mole) was added and the mixture was agitated well for 2 hours. The reaction was exothermic, the temperature reaching 80° C. within 5 minutes after the addition of 2-ethylhexyl bromide and then falling off to 30° C. over the 2-hour reaction time. Analysis of an aliquot by high pressure liquid chromatography (HPLC) showed the complete disappearance of 2,7-dichlorofluorene and the formation of new product. Water (200 mL), and diethyl ether (250 mL) were added to the reaction mixture, stirred for 15 minutes and the layers were separated. The organic layer was washed with a saturated aqueous NaCl solution, water, dried (MgSO4) and evaporated to remove ether. Fractional vacuum distillation of the residue provided 2,7-dichloro-9,9-di(2-ethylhexyl)fluorene as clear liquid, boiling point 200° C./1 mm Hg, (79 g, 94 percent yield); HPLC analysis showed that the product was 99 percent pure; Proton Magnetic Spectrum (PMR) analysis was consistent with the title structure.
Reaction SMILES: [CH2:1]([C@@:3]12[CH2:27][CH2:26][C@@:25]([C:29]#[CH:30])([OH:28])[CH2:24][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2]>[Pd].C1COCC1>[CH2:29]([C@:25]1([OH:28])[CH2:24][C@H:4]2[CH2:5][CH2:6][CH2:7][C:8]3[C:9](=[CH:10][C:11]4[CH:12]=[N:13][N:14]([C:17]5[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=5)[C:15]=4[CH:16]=3)[C@:3]2([CH2:1][CH3:2])[CH2:27][CH2:26]1)[CH3:30]
Reactant: C#C[C@@]1(O)CC[C@@]2(CC)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@@H]2C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC[C@@]1(O)CC[C@@]2(CC)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@@H]2C1
Reaction time: 2 h

Procedure:
A solution of (3R,4aR,12bR)-12b-ethyl-3-ethynyl-9-(4-fluorophenyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-Fluorophenyl, R2=Ethyl, R3=Ethynyl) (0.0331 g, 0.082 mmol) and THF (1.00 mL) was added to 10 wt % Pd/C (wet) (0.006 g). The mixture was placed under a hydrogen atmosphere using a balloon. After about 2 h, the hydrogen was evacuated. The mixture was filtered through Celite® rinsing with DCM (20 mL). The organic volatiles were removed under reduced pressure. The residue was purified on silica gel (4 g) using a gradient of 0-4% EtOAc in DCM. The fractions containing product were combined and concentrated under reduced pressure. The residue was dissolved in MeCN and MeOH, treated with water, and concentrated under reduced pressure to remove the organic volatiles. The mixture was frozen then lyophilized to afford (3R,4aR,12bR)-3,12b-diethyl-9-(4-fluorophenyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-Fluorophenyl, R2=Ethyl, R3=Ethyl) (0.031 g, 91%) as an ivory solid. LC/MS, method 2, Rt=3.07 min, MS m/z 407 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 7.87 (s, 1H), 7.84-7.74 (m, 2H), 7.54 (s, 1H), 7.45-7.35 (m, 2H), 4.03 (s, 1H), 3.24-3.12 (m, 1H), 2.98-2.86 (m, 1H), 2.20-2.03 (m, 2H), 2.03-1.92 (m, 1H), 1.91-1.62 (m, 4H), 1.61-1.20 (m, 8H), 0.83 (t, J=7.3 Hz, 3H), 0.37 (t, J=7.1 Hz, 3H). Sign of rotation is positive.