Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:8]([OH:24])([CH2:21][CH2:22]O)[C:9]([NH:11][C@H:12]([C:17](=[O:20])[NH:18][CH3:19])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:46])[NH:28][C@H:29]([C:34]([NH:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=1)=[O:35])[C:30]([CH3:33])([CH3:32])[CH3:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:25][O:26][C:27](=[O:46])[NH:28][CH:29]([C:34]([NH:36][N:37]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=1)[CH2:22][CH2:21][C:8]([C:9](=[O:10])[NH:11][CH:12]([C:17](=[O:20])[NH:18][CH3:19])[C:13]([CH3:16])([CH3:14])[CH3:15])([OH:24])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:35])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@](O)(CCO)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)NNCc1ccc(Br)cc1)C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNC(=O)C(NC(=O)C(O)(CCN(Cc1ccc(Br)cc1)NC(=O)C(NC(=O)OC)C(C)(C)C)Cc1ccccc1)C(C)(C)C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 27.7 %

Procedure:
A mixture of (2S)-2-Benzyl-N-((1S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-2,4-dihydroxy-butyramide (52S) (0.337 g, 1.00 mmol), IBX (0.560 g, 2.0 mmol) and 10 mL 1,2-dichloroethane in a reaction vial sealed with a screw cap was heated at 80° C. for 2 h. The resulting suspension was transferred to a 20 mL syringe and filtered through a syringe filter into a solution of hydrazide (9) (0.372 g, 1.00 mmol) in 15 mL DCE in a flame dried 50 mL round-bottom flask equipped with a septum. To this was added acetic acid (0.12 mL 2.0 mmol), mixture was stirred for 10 min and then sodium triacetoxyborohydride (0.636 g, 3.0 mmol) was added. The septum-sealed flask was flushed with nitrogen and the reaction was stirred at room temperature for 24 h. The reaction was quenched by addition of water and volatiles were evaporated. The residue was dissolved in 50% MeCN/water and purified by preparative RP-LC-MS (repeated 1 mL injections) to give 0.191 g of the title compound (28% yield).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([N:27]1[CH:31]=[C:30]([CH:32]=[CH:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[N:29]=[CH:28]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:27]1[CH:31]=[C:30]([CH:32]=[CH:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[N:29]=[CH:28]1
Reactant: O=C(O)CCCC=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCCC=Cc1c[nH]cn1
Yield: 60 %

Procedure:
2 ml of trifluoroacetic acid are added to 0.58 g (1.37 mmol) of 6-(1-trityl-1H-imidazol-4-yl)hex-5-enoic acid in suspension in 8 ml of dichloromethane. After the solvents have been evaporated off, the oil obtained is purified on a silica column (eluent 8/2 DCM/MeOH). 240 mg of 6-(1H-imidazol-4-yl)hex-5-enoic acid trifluoroacetate in the form of a yellow oil are isolated with a yield of 60%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH:16]3[CH2:18][CH:13]1[CH2:14][N:15]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:7][N:6]=[CH:5]2.[CH:26]1([NH:29][C:30](=[O:47])[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH:26]1([NH:29][C:30]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH:16]5[CH2:18][CH:13]3[CH2:14][N:15]5[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[N:7][N:6]=[CH:5]4)[CH:32]=2)=[O:47])[CH2:27][CH2:28]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2c1nncc2cc(Br)ccc12
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: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CC4CC3CN4C(=O)OC(C)(C)C)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A mixture of tert-butyl 5-(6-bromophthalazin-1-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate (0.18 g, 0.44 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.14g, 0.44 mmol), tetrakis(triphenylphosphine)palladium (25 mg, 0.022 mmol) and 2 M potassium carbonate (0.66 mL, 1.32 mmol) in 5 mL DME/EtOH (4:1) was stirred at 90° C. for 2 h. The mixture was transferred directly to a column and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2M ammonia in MeOH/DCM to give tert-butyl 5-(6-(5-(cyclopropylcarbamoyl)-2-methylphenyl) phthalazin-1-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate (0.20 g) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CC(N(C)C)=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:16]3[CH2:17][CH2:18][CH2:19][N:13]([CH3:12])[CH2:14][CH2:15]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: CN1CCCNCC1
Solvent: CC(=O)N(C)C
Product: CN1CCCN(c2nnc3ccc(F)cn23)CC1
Yield: 77 %

Procedure:
A solution of Intermediate 24b (451 mg, 2.50 mmol) and 1-methyl-[1,4]diazepane (1.14 g, 10.0 mmol) in DMA (10 mL) was heated in the microwave at 175° C. for 6 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20% (2M NH3 in MeOH) in DCM, to give the title compound as a brown oil (480 mg, 77%). LCMS (Method 3): Rt 0.44 min, m/z 250 [MH+].
Reaction SMILES: C(C1OC[C@@H](C(C)(C)C)N=1)(C1OC[C@@H](C(C)(C)C)N=1)(C)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[C:25]([F:31])[CH:24]=1.[N+](=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N-]>C(Cl)(Cl)Cl>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:30][CH:34]2[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:25]([F:31])[CH:24]=1
Reactant: C=Cc1ccc(Br)cc1F
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: CC(C)(C1=N[C@H](C(C)(C)C)CO1)C1=N[C@H](C(C)(C)C)CO1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CC1c1ccc(Br)cc1F
Reaction time: 1 h

Procedure:
To a suspension of copper(I) trifluoromethanesulfonate benzene complex (0.01 eq) in chloroform (100 mL) at rt, was added (R,R)-2,2′-isopropylidene-bis(4-tert-butyl-2-oxazoline) (0.01 eq). The mixture was stirred at for 1 h then cannulated through glass wool in a solution of styrene from step 5 (1.2 eq) in chloroform (0.1M) at 4° C. To this solution was added a solution of ethyl diazoacetate (0.8 eq) in of chloroform (1M) dropwise over 3 h. The final mixture was stirred overnight at 4° C. The mixture was concentrated. Flash chromatography (Hexane, EtOAc; 95:5) afforded the desired compound. (84:16, trans:cis isomers, methodology described in Evans et al. J. Am. Chem. Soc. 1991, 113, 726).
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]([C:19]#[CH:20])([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1C=CC=CC=1>[CH2:31]([O:30][C:28]([N:2]1[CH2:7][CH2:6][C:5]([C:19]#[CH:20])([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])[CH2:4][CH2:3]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C(=O)OCC)CC1
Yield: 83.9 %

Procedure:
A suspension of 223 g of N-methyl-4-ethynyl-4-(4-fluoro-2-nitrophenoxy)piperidine, 2 l of dry benzene, 165 g of anhydrous potassium carbonate and 130.3 g of ethyl chloroformate was stirred at reflux for 18 hr under nitrogen. The mixture was filtered and the solvent evaporated. The residue was dissolved in ether, washed with hydrochloric acid, saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The ether solution was dried over anhydrous sodium sulfate and filtered. Evaporation of solvent provided an oil, which was dried at 50°-55° (1 mm). The oil crystallized to provide 226 g (83.8%) of product, mp 56°-68°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.C(O)=O.[ClH:39]>C(O)C>[ClH:39].[ClH:39].[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][N:33]1[CH2:32][CH2:31][N:30]([CH:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)[CH2:35][CH2:34]1
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: Cl
Solvent: O=CO
Solvent: CCO
Product: COc1ccc(CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1OC
Temperature: 25 °C
Yield: 47.7 %

Procedure:
2,3,4-Trimethoxybenzaldehyde (42.1 g; 215 millimoles) and 61.9 g (215 millimoles) of bis(4-fluorophenyl)methylpiperazine were melted in an oil bath at 100° C., and 10 ml (265 millimoles) of formic acid was added dropwise. The mixture was stirred under heat for 30 minutes, and allowed to cool to room temperature. A mixture of 40 ml of conc. hydrochloric acid and 400 ml of ethanol was added, and the mixture was concentrated under reduced pressure. Ether was added, and the precipitated crystals were collected by filtration. Recrystallization of the crystals from ethanol-ether gave 55.5 g (yield 47.7%) of 1-(2,3,4-trimethoxybenzyl)-4-[bis(4-fluorophenyl)methyl]piperazine dihydrochloride as colorless crystals.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:6]=2/[CH:7]=[N:8]/[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:2]1.CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:1]1([S:4][C:5]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:6]=2[CH:7]2[CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:9][NH:8]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCC/N=C/c1cc([N+](=O)[O-])ccc1SC1CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCNC1c1cc([N+](=O)[O-])ccc1SC1CC1
Reaction time: 3 h
Yield: 36.2 %

Procedure:
To 76B (ca 31 mmol) in CH2Cl2 (150 mL) at −15° C. was added Et3N (5.94 mL, 43 mmol) followed by TiCl4 (1.0 M in CH2Cl2, 37.2 mL, 37.2 mmol). The mixture was stirred from −15° C. to rt over 3.0 h before it was quenched with sat. K2CO3 (200 mL) at 0° C. and stirred at rt for 1.0 h. CH2Cl2 was removed under vacuo and EtOAc was added to the crude (for better filtration). The mixture was filtered through a pad of wet Celite®, extracted with EtOAc (3×100 mL). The organic layer was washed with water, dried over Na2SO4. The cude was purified by silica gel flash column chromatography using gradient CH2Cl2 in hexanes to give 76C (3.77 g, 56% yield) and retrieved 76A (2.8 g). LC-MS indicated a mixture of cis and trans isomer in ca. 1:1 ratio. LC-MS 337 (M+H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C:21](=[O:41])[C:22]([N:25]1[C:30](=[O:31])[C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:28]([CH2:38][S:39][CH3:40])[O:27][CH2:26]1)([CH3:24])[CH3:23]>ClCCl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C:21](=[O:41])[C:22]([N:25]1[C:30](=[O:31])[C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:28]([CH2:38][S:39]([CH3:40])=[O:6])[O:27][CH2:26]1)([CH3:24])[CH3:23]
Reactant: CSCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cc(F)ccc2F)CO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cc(F)ccc2F)CO1
Temperature: -20 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
m-Chloroperoxybenzoic acid (75% pure, 0.54 g) was added to a stirred solution of N-(2,5-difluorophenyl)-2-(2,3-dihydro-6-methylthiomethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 1, 100 g) in dichloromethane at -20° C. The mixture was stirred at -20° C. for 1 hour, diluted with dichloromethane, washed with 1M sodium carbonate, dried (magnesium sulphate) and solvent evaporated under reduced pressure. The residue was triturated with diethyl ether to give N-(2,5-difluorophenyl)-2-(2,3-dihydro-6-methylsulphinylmethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 5, 0.51 g) as a white solid, m.p. 124-128° C.
Reaction SMILES: [CH2:1]([N:5]1[C:11]([CH3:13])([CH3:12])[C:9](=[O:10])[NH:8][C:6]1=[O:7])[C:2](=[CH2:4])[CH3:3].[H-].[Na+].[CH2:16](Cl)[C:17](=[CH2:19])[CH3:18].O>CN(C=O)C>[CH2:1]([N:5]1[C:11]([CH3:13])([CH3:12])[C:9](=[O:10])[N:8]([CH2:18][C:17](=[CH2:16])[CH3:19])[C:6]1=[O:7])[C:2](=[CH2:3])[CH3:4]
Reactant: C=C(C)CN1C(=O)NC(=O)C1(C)C
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)CN1C(=O)N(CC(=C)C)C(C)(C)C1=O
Temperature: 15 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
In a 100 ml three necked flask is placed 10 g (0.055 mol) of N-methallyl-5,5-dimethylhydantoin in 100 ml DMF under nitrogen. The solution is cooled to 15° C. and 2.7 g of sodium hydride/mineral oil is added. The reaction is stirred for 2 hours at 15° C. and then warmed to 25°C. Methallyl chloride (5.1 g, 0.056 mol) is added dropwise over 10 minutes, keeping the temperature at 30° C. The reaction is stirred overnight, then poured into 200 ml water, extracted with 2 X 100 ml ether and dried over magnesium sulfate. After removing the ether in vacuo, the residue is distilled under vacuum (BP 100°-105°0 C. 0.3 mm Hg) to give 11.9 g N,N'-bismethallyl-5,5-dimethylhydantoin.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH3:10][O:11][P:12]([O:15]C)[O:13][CH3:14]>>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][P:12](=[O:15])([O:13][CH3:14])[O:11][CH3:10]
Reactant: Cc1ccccc1CBr
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccccc1C)OC

Procedure:
Following the procedure of Compound 11, 2-methylbenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Mg].C(Br)C.[Cl:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.[Cl-].[NH4+]>CCOCC>[Cl:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]([CH2:1][CH3:2])([OH:15])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1
Reactant: CC[Mg]Br
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCBr
Product: CCC(O)(c1ccc(O)cc1)c1ccc(Cl)cc1
Temperature: -10 °C

Procedure:
To a solution of ethyl magnesium bromide prepared from 3.9 g. of magnesium turnings and 17.4 g. of ethyl bromide in 50 ml. of dry ether a solution of 9.3 g. of 4-chloro-4'-hydroxy-benzophenone in 40 ml. of dry ether is added dropwise, with stirring at -10° C., in nitrogen atmosphere. The reaction mixture is allowed to warm up to room temperature, stirred at this temperature for an additional half an hour, and is then poured onto a solution of ammonium chloride in ice water under cooling. The aqueous phase is extracted with ether, the ethereal phases are combined, washed to neutral with water, and dried over anhydrous magnesium sulfate. After filtering the solvent is distilled off in vacuo, the residue is decolored with charcoal in methanol, the solution is filtered, and the solvent is evaporated under reduced pressure. The crude mixture is crystallized from a mixture of benzene and ethyl acetate to yield 5.5 g. of the named compound, melting at 148° to 149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:7](=[O:15])[CH2:6][CH2:5]2.[N-:16]=[N+]=[N-].[Na+]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:7](=[O:15])[NH:16][CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)c(C(F)(F)F)cc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2cc(Cl)c(C(F)(F)F)cc21
Yield: 54.8 %

Procedure:
5-Chloro-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (I-85d: 600 mg, 2.5575 mmol) in TFA (25 mL) was reacted with sodium azide (549 mg, 8.439 mmol) for 5 hours at 80° C. Purification by column chromatography on silica gel (1% methanol in CHCl3), afforded 350 mg of the product (54.8% yield).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5](C#N)[C:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([CH3:9])[CH:7]=[CH2:8])C.[OH-].[K+].Cl.O>C(O)CO>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:6]([CH3:9])([CH:7]=[CH2:8])[CH2:5][C:4]([OH:21])=[O:3])=[CH:12][CH:13]=1
Reactant: C=CC(C)(Cc1ccc(OC)cc1)C(C#N)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: C=CC(C)(CC(=O)O)Cc1ccc(OC)cc1
Temperature: 25 °C

Procedure:
A mixture of the product prepared in STEP 2 (5.8 g), ethylene glycol (15 mg) and KOH (5.6 g) was heated at 150 degrees for two days under nitrogen. The solution was cooled to room temperature and poured into 1% hydrochloric acid/water (200 ml). The aqueous portion was extracted well with ethyl acetate and the combined organic extract was washed with water, brine and dried over MgSO4. Solvent was removed to give the crude product that was used without further purification. The 1H NMR was consistent with the proposed structure.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([N:32]3[CH:36]=[N:35][C:34]([CH3:37])=[N:33]3)=[C:26]([F:38])[CH:25]=2)[N:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>CC(C)=O>[F:38][C:26]1[CH:25]=[C:24]([NH:23][C:20]2[N:19]=[C:18]3[CH:6]([C:7]4[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=4)[CH2:5][CH2:4][CH2:3][CH2:2][N:22]3[N:21]=2)[CH:29]=[C:28]([O:30][CH3:31])[C:27]=1[N:32]1[CH:36]=[N:35][C:34]([CH3:37])=[N:33]1
Reactant: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(OC(F)(F)F)cc3)n2)cc(F)c1-n1cnc(C)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2ccc(OC(F)(F)F)cc2)cc(F)c1-n1cnc(C)n1
Yield: 45.6 %

Procedure:
A solution of 5-(5-chloro-1-(4-(trifluoromethoxy)phenyl)pentyl)-N-(3-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (753 mg, 1.36 mmol), sodium iodide (1.02 g, 6.80 mmol), and diisopropylethylamine (1.19 mL, 6.80 mmol) in acetone (30 mL) was heated in a sealed vessel at 100° C. for 6 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (50% EtOAc/chloroform) to afford 321 mg (44% yield) of the titled compound as a white solid. LC-MS (M+H)+ 518.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.02 (s, 1 H), 7.20 (s, 4 H), 6.90-6.96 (m, 2 H), 6.73 (s, 1 H), 4.17-4.34 (m, 3 H), 3.72 (s, 3 H), 2.47 (s, 3 H), 2.13-2.26 (m, 1 H), 2.05-2.13 (m, 1 H), 1.92-2.04 (m, 2 H), 1.82-1.92 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][C:33](B(O)O)=[CH:34][CH:35]=2)[CH:30]=[N:29]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:33]5[CH:32]=[C:31]6[C:36](=[CH:35][CH:34]=5)[N:28]([CH3:27])[N:29]=[CH:30]6)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6c(cnn6C)c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 1-methyl-indazole-5-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.65 min; Mass spectrum (ESI+): m/z=489 [M+H]+.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]1([S:12](Cl)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[C:1]([NH:5][S:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.6 %

Procedure:
To a cooled (0° C.) solution of tert-butylamine (42.9 mL, 410.6 mmol) in THF (840 mL) was added dropwise benzenesulfonyl chloride (26.2 mL, 205 mmol) and the reaction mixture was stirred at room temperature under an argon atmosphere for 6 h. The mixture was then filtered and the collected solid washed with THF. The filtrate was concentrated, redissolved in CH2Cl2 and washed with 0.1N HCl and H2O. The organic solution was dried and concentrated to afford the desired product (41.8 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][C@H:20]([O:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[F:33])[C:19]3=[O:34])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:22][CH2:21][C@H:20]([O:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[O:29])=[CH:26][C:25]=4[F:33])[C:19]3=[O:34])[CH2:16][CH2:17]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(C(F)(F)F)cc4Cl)CC3)C2=O)c(F)c1
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(O[C@H]2CCN(C3CCN(c4ncc(C(F)(F)F)cc4Cl)CC3)C2=O)c(F)c1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.3 %

Procedure:
To a solution of (S)-4-(1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoic acid (0.040 g, 0.080 mmol) and pyrrolidine (0.028 g, 0.40 mmol) in DMF (1 mL) was added HTBU (0.060 g, 0.16 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc (20 mL) and washed with 1 N HCl (5 mL), 1 N NaOH (5 mL), and brine (5 mL), and the combined organic phases were dried over MgSO4, and concentrated under vacuum. The material was purified on silica, using EtOAc as eluent to yield (S)-1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(pyrrolidine-1-carbonyl)phenoxy)pyrrolidin-2-one (0.0026 g, 0.005 mmol, 6% yield). Mass spectrum (apci) m/z=555.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH3:24].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH3:24]
Reactant: CI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3c(Cl)cccc3Cl)c(=O)c12
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1c(Cl)cccc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 17.4 %

Procedure:
A mixture of (4S,7R)-2-(2,6-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 15; 1.2 g, 3.6 mmol) and iodomethane (0.45 mL, 8.0 mmol) in N,N-dimethylformamide (20 mL) was heated to 80° C. and stirred for 4.5 h. The reaction mixture was allowed to cool and water (200 mL) was added. A solid precipitated. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated sodium bicarbonate and brine, dried (sodium sulfate), filtered, concentrated and purified by chromatography, eluting with 5-80% ethyl acetate/dichloromethane. Fractions containing the product were combined, evaporated, and recrystallized from ethyl acetate/hexanes to give (4S,7R)-2-(2,6-dichloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (220 mg 18%) as a light tan solid. ES(+)-MS (M+H) 351