Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:8][C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(N[C@H](C(O)=O)CC(C)C)(=O)=O)=CC=1.C(N[C@H](C(O)=O)CC(C)C)(=O)C>C1C=CC=CC=1.C(O)C>[CH2:12]([NH:19][C@H:9]([CH3:10])[CH2:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: NCc1ccccc1
Agent: CC(=O)N[C@@H](CC(C)C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)N[C@@H](CC(C)C)C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCO
Product: C[C@H](CCc1ccccc1)NCc1ccccc1
Temperature: 25 °C

Procedure:
In an apparatus fitted with a Dean Stark trap, reflux a solution of 1.0 kg (6.75 mol) of benzylacetone, 725 g (6.75 mol) of benzylamine and 5.0 g of p-toluenesulfonic acid hydrate in 7 liters of benzene for 14 hours. Remove the solvent in vacuo, and dissolve the residue in 6.5 liters of methanol. With cooling and stirring, carefully add 125 g of NaBH4 and stir the mixture for 16 hours at room temperature. Remove the methanol in vacuo, and add 2 liters water and 4 liters benzene, and extract the product into the benzene. After drying (MgSO4), filter and distill (b.p. 145°-150° C./0.5 mm). Dissolve 1,028 g (4.288 mol) of the distillate and 1.23 kg (4.328 mol) of N-p-toluenesulfonyl-(L)-leucine in 7.2 liters of boiling ethanol and allow to cool to room temperature without agitation. Wash the precipitate with a small amount of ice-cold ethanol, recrystallize from 4.8 liters of ethanol, wash with ice-cold ethanol and filter off the solid product that is highly enriched with the salt of the undesired S enantiomer. Combine the mother liquor from the original precipitation and that from the recrystallization, remove the solvent and recover the free base by basifying with 500 ml of 20% aqueous NaOH and extracting with benzene. After drying (MgSO4), filtering and removing the benzene, dissolve the residue [487 g (2.04 mol)] and 346 g (2.06 mol) of N-acetyl-(L)-leucine in 2.0 liters of boiling ethanol and allow the solution to cool to room temperature. Filter and recrystallize once from 1.8 liter of ethanol followed by recrystallization from 4.0 liters of acetonitrile to obtain the desired R salt, m.p. 151°-152° C. Basify with 400 ml of aqueous 2.5N NaOH, extract with ether, dry (MgSO4), filter and remove the solvent in vacuo to obtain the product (2), [α]26D =+4.5° (c=5.0, ethanol).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Cl:7].[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1>ClCCl>[Br:1][C:2]1[S:3][C:4]([C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([F:8])=[CH:10][CH:11]=2)=[CH:5][C:6]=1[Cl:7]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Clc1ccsc1Br
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1cc(Cl)c(Br)s1
Temperature: 18 °C
Reaction time: 0.83 h
Yield: 97.1 %

Procedure:
Ferric chloride (301.2 g) was added to a stirred solution of 2-bromo-3-chlorothiophene (148.5 g) and 4-fluorobenzoyl chloride (169.7 g) in dichloromethane (2230 ml), cooled to 18° C. in an icetwater bath. The temperature of the reaction mixture rose to 22° C. and was then cooled to 12° C. Cooling was removed and the reaction mixture was stirred for a further 50 min during which time the internal temperature rose to 16° C. The reaction mixture was re-cooled to 10° C., water (700 ml) was added carefully, keeping the internal temperature below 15° C., and the mixture was then stirred for 1 h. The dichloromethane layer was separated and the aq layer was washed with dichloromethane. The combined dichloromethane layer was washed with water and saturated sodium bicarbonate solution. The dichloromethane was separated and the aq. layer filtered through dicalite and extracted with dichloromethane. The extract was washed with water, dried (Na2SO4) and evaporated to dryness to give 2-bromo-3-chloro-5-(4-fluorobenzoyl)-thiophene as a solid (233.3 g).
Reaction SMILES: O.[OH:2][CH2:3][C:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12]O)[OH:11])O)O)=O.[ClH:14]>C1(C)C=CC=CC=1>[Cl:14][CH2:12][C:10]1[O:11][C:4]([CH:3]=[O:2])=[CH:6][CH:8]=1
Reactant: Cl
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CCl)o1
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
150 Ml of toluene was introduced to the same flask as used in Example 1, and while introducing a nitrogen gas with slow stirring of toluene, the temperature of the water bath was set at 75° C. Thereafter, a paste-like liquid prepared by well-mixing 18.0 g of crystalline fructose with 2.2 g of water, and then 20.4 g (one equivalent based on the fed fructose) of MgCl2.6H2O were successively added to the stirred toluene layer. After completion of the addition, stirring was carried out at 400 r.p.m. for about 30 minutes. Thereafter, 31.4 g of 35% hydrochloric acid was added dropwise in 5 minutes from the dropping funnel to the stirred solution. After completion of the dropwise addition, stirring was continued at 400 r.p.m. at 75° C. for 1 hour, at which point heating was stopped and the reaction system was immediately lowered to room temperature (about 25° C.). During that period, stirring was still continued. After standing at room temperature, the post treatment of the solution was carried out in the same manner as in Example 1 and was obtained 12.5 g (yield 86.6%) of 5-chloromethylfurfural as product.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:15]([F:18])([F:17])[F:16].[CH3:20][C:21]1([CH3:42])[O:25][CH:24]([C:26]2[CH:35]=[C:34]3[C:29]([C:30]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:31][CH2:32][O:33]3)=[CH:28][CH:27]=2)[CH2:23][O:22]1.C(N(CC)CC)C>ClCCl>[CH3:20][C:21]1([CH3:42])[O:25][CH:24]([C:26]2[CH:27]=[CH:28][C:29]3[C:30]4([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)[CH:31]([C:3]([C:4]5[O:8][N:7]=[C:6]([C:9]6[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=6)[C:5]=5[C:15]([F:18])([F:17])[F:16])=[N:2][O:1]4)[CH2:32][O:33][C:34]=3[CH:35]=2)[CH2:23][O:22]1
Reactant: ON=C(Cl)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: CC1(C)OCC(c2ccc3c(c2)OCC=C3N2CCOCC2)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OCC(c2ccc3c(c2)OCC2C(c4onc(-c5ccccc5)c4C(F)(F)F)=NOC32N2CCOCC2)O1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 12 %

Procedure:
To a solution of the N-hydroxy-3-phenyl-4-(trifluoromethyl)isoxazole-5-carbimidoyl chloride (Intermediate 1-12, 0.340 g, 1.170 mmol) in dichloromethane (3.5 mL) was added 4-(7-(2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromen-4-yl)morpholine (Preparation 60C, 0.473 M in dichloromethane) (2.47 mL, 1.17 mmol). The reaction mixture was cooled to 0° C., and triethylamine (0.324 mL, 2.34 mmol) was added dropwise over 10 min. The ice-bath was removed, and the resulting cloudy solution was stirred at room temperature for 1.5 h. The reaction mixture was diluted with dichloromethane (50 mL), washed with water (25 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the crude product as an orange oil. The compound was purified by flash silica gel chromatography using a mixture of ethyl acetate and hexane (5%-12%-20%) to give 7-(2,2-dimethyl-1,3-dioxolan-4-yl)-9b-morpholino-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,9b-dihydro-3aH-chromeno[3,4-d]isoxazole (0.080 g, 0.140 mmol, 12% yield) as a yellow solid. The product had an HPLC ret. time=3.25 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=572.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=[C:10]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][Br:24])=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=[C:10]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CBr
Yield: 100.9 %

Procedure:
N-(4-(4-fluorophenyl)-5-methyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (112.5 mg, 0.33 mmol, 1 equiv.) and N-bromosuccinimide (NBS) (126 mg, 0.72 mmol, 2.1 equiv.) were dissolved in 2 mL of acetonitrile. The mixture was irradiated with light of a wavelength A=310 nm for 4 hours at ambient temperature (about 20° C.). Then, water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×10 mL). The combined organic phases were washed with 10 mL of brine, and the obtained solution was dried with Na2SO4. Solvent was removed under the reduced pressure to give 138.6 mg of crude N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (II), which contained 93% of N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (II) as determined by 1H-NMR integral. This product can be further purified by crystallization from MTBE/hexane mixture to afford pure material.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:15][C:14]3[CH:16]=[C:17](OC)[CH:18]=[CH:19][C:13]=3[C:11](=O)[CH:10]2C2C=CC=CC=2)=[CH:5][CH:4]=1>[Pd].C(O)(=O)C>[CH:6]1([CH:9]2[CH2:10][CH2:11][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[O:15]2)[CH2:5][CH2:4][CH2:3][CH2:8][CH2:7]1
Reactant: COc1ccc(C2Oc3cc(OC)ccc3C(=O)C2c2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: c1ccc2c(c1)CCC(C1CCCCC1)O2
Temperature: 23 °C

Procedure:
A suspension of the chromanone 2--2 (2.13 g, 9.25 mmol, 1 equiv) and 10% palladium on carbon (320 mg, 0.301 mmol, 0.0325 equiv) in acetic acid (20 mL) was heated at 70° C. under a hydrogen balloon for 16 h. After cooling to 23° C., the solids were removed by filtration through a pad of Celite® and were washed with ethyl acetate (100 mL). The filtrate was concentrated and the residue was purified by flash column chromatography (5% ethyl acetate in hexanes) to provide the benzopyran 2-3 as a colorless oil as well as recovered starting chromanone; 1H NMR (400 MHz, CDCl3), δ: 7.09 (m, 2H, ArH), 6.85 (m, 2H, ArH), 3.78 (m, 1H, OCH), 2.83 (m, 2H, ArCH2), 2.03 (m, 2H, ArCH2CH2 and CyH), 1.90-1.70 (m, 5H, ArCH2CH2 and CyH), 1.65 (m, 1H, CyH), 1.40-1.10 (m, 5H, CyH); TLC (5% ethyl acetate-hexanes), Rf =0.57 (UV).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].CCCCCC>CC(O)C>[C:5]1([C@H:3]([OH:4])[CH2:2][OH:1])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CO)c1ccccc1
Solvent: CC(C)O
Solvent: CCCCCC
Product: OC[C@@H](O)c1ccccc1

Procedure:
Regarding Example 31, except that the use amount of RuCl[(S)-xylbinap][(S)-daipen] was changed (3.0 mg, 0.0025 mol, 1/1,000 molar fold of 2-hydroxyacetophenone) and 2-propanol (2.5 mL) was used instead of methanol, the same procedure as Example 31 was carried out. As a result of analysis of the reaction solution by using gas chromatography (HP-1), the conversion rate was found to be 99% or more. The optical purity was measured by high performance liquid chromatography (CHIRALPAK AS-H, eluent; hexane:2-propanol=92:8), and it was found to be 90% ee.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36].NCC1C(NCC2C=CC3C(=CC=CC=3)C=2)=NC2N(C)C(=O)N(C)C(=O)C=2C=1C1C=C(F)C=CC=1OC>>[NH2:26][CH2:25][C:3]1[C:2]([NH:1][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:36])([F:37])[F:38])=[N:15][C:6]2[N:7]([CH3:14])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[C:4]=1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: COc1ccc(F)cc1-c1c(C#N)c(N)nc2c1c(=O)n(C)c(=O)n2C
Reactant: FC(F)(F)c1ccccc1CBr
Agent: COc1ccc(F)cc1-c1c(CN)c(NCc2ccc3ccccc3c2)nc2c1c(=O)n(C)c(=O)n2C
Product: COc1ccc(F)cc1-c1c(CN)c(NCc2ccccc2C(F)(F)F)nc2c1c(=O)n(C)c(=O)n2C

Procedure:
The synthesis of title compounds started from Compound 70a and 1-(bromomethyl)-2-(trifluoromethyl)benzene, according to procedures described in the synthesis of Compound 70. MS [m+H] calc'd C25H24FN5O3 518; found 518.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][C:11]([F:29])([F:28])[C:12]([F:27])([F:26])[C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C.CC#N>C(Cl)Cl.CO>[F:29][C:11]([F:28])([C:12]([F:26])([F:27])[C:13]([F:24])([F:25])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:18])([F:17])[F:19])[CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: O=P(O)(O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 6 h

Procedure:
(3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctyl)phosphonic acid diethyl ester (0.79 g, 1.6 mmol) was dissolved in CH2Cl2 (5 ml) under N2. Bromotrimethylsilane (0.8 ml, 6.1 mmol) was added via syringe and the mixture was stirred for 6 hours. Volatiles were removed in vacuo to give a thick orange oil; this was dissolved in MeOH (20 ml) with fuming to give a yellow solution. The mixture was stirred overnight and evaporated to dryness to give a pale yellow powder. Addition of MeCN caused separation of a white solid from the yellow solution. The solid was collected by filtration, affording the desired product as a white powder. Yield 0.56 g, 1.3 mmol, 82%. Analysis found (calculated) %: C, 22.35 (22.45); H, 1.25 (1.41). 1H NMR (d6-DMSO, 400 MHz, 298 K): δ 2.35 (m, 2H), 1.73 (m, 2H). 13C{1H} NMR (d6-DMSO, 100 MHz, 298 K): δ 121-105 (m, C-F coupling unresolved), 25.13 (t, JC-F=23 Hz), 17.10 (d, JC-P=138 Hz). 31P{1H} NMR (d6-DMSO, 162 MHz, 298 K): δ 22.87. MS (FAB, m/z): 429 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:6]([F:13])([F:12])[C:7]([F:11])([F:10])[CH2:8][CH3:9])=[CH:4][F:5].[FH:16]>>[F:1][C:2]([F:14])([F:15])[CH:3]([C:6]([F:12])([F:13])[C:7]([F:11])([F:10])[CH2:8][CH3:9])[CH:4]([F:16])[F:5]
Reactant: F
Reactant: CCC(F)(F)C(F)(F)C(=CF)C(F)(F)F
Product: CCC(F)(F)C(F)(F)C(C(F)F)C(F)(F)F

Procedure:
As another example, 2-difluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-hexanol may be prepared by fluorinating commercially available 3,4-hexanedione to form 3,3,4,4-tetrafluorohexane which may then be dehydrogenated to form 3,3,4,4-tetrafluoro-1-hexene. CF3 may then be added to the 3,3,4,4-tetrafluoro-1-hexene to form 2-trifluoromethyl-1,3,3,4,4-pentafluorohexane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-hexene. The 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-hexene may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,3,3,4,4-hexafluorohexane which may then be dehydrogenated to form 2-trifluoromethyl-1,1,3,3,4,4-hexafluoro-1-hexene which may then be reacted with sulfuric acid and then water to form 2-difluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-hexanol.
Reaction SMILES: N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[CH:38][C:39]([C:42]#[C:43][C:44]3[CH:45]=[CH:46][C:47]([CH2:50][CH2:51][CH2:52][OH:53])=[N:48][CH:49]=3)=[N:40][CH:41]=2)=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[CH:38][C:39]([C:42]#[C:43][C:44]3[CH:45]=[CH:46][C:47]([CH2:50][CH2:51][CH:52]=[O:53])=[N:48][CH:49]=3)=[N:40][CH:41]=2)=[CH:32][CH:31]=1
Reactant: OCCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=CCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.62 mL (20.07 mmol) of pyridine and 8.51 g (3.01 mmol) of Dess-Martin periodinane solution (15% in DCM) were added to a solution of 0.70 g (2.01 mmol) of 3-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]pyridin-2-yl}propan-1-ol in 50 mL of DCM and the mixture was stirred for 16 hours at RT. Semisaturated aqueous sodium bicarbonate solution was added and the aqueous phase was extracted with MTBE. The combined organic extracts were dried over magnesium sulfate and evaporated down in vacuo. The residue was purified by HPLC-MS (Zorbax Bonus C18 amide-phase 5 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). Yield: 115 mg (17% of theoretical); C21H15ClN2O (M=346.809); calc.: molpeak (M+H)+: 347/349 (Cl); found: molpeak (M+H)+: 347/349 (Cl); HPLC-MS: 6.70 minutes (method A).
Reaction SMILES: [N+](=[C:3]1[C:8](=[O:9])[CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5][C:4]1=[O:12])=[N-].ClC1C=CC=CC=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:34]([C:38]1[CH:39]=[C:40]([CH3:45])[CH:41]=[C:42]([CH3:44])[CH:43]=1)([CH3:37])([CH3:36])[CH3:35]>[Hg]>[CH3:45][C:40]1[CH:39]=[C:38]([C:34]([CH3:36])([CH3:35])[CH3:37])[CH:43]=[C:42]([CH3:44])[C:41]=1[CH:3]1[C:8](=[O:9])[CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5][C:4]1=[O:12]
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Reactant: CC1(C)CC(=O)C(=[N+]=[N-])C(=O)C1
Agent: O=C(c1ccccc1)c1ccccc1
Agent: [Hg]
Solvent: Clc1ccccc1
Product: Cc1cc(C(C)(C)C)cc(C)c1C1C(=O)CC(C)(C)CC1=O
Yield: 11 %

Procedure:
A solution of 7.00 g (0.042 mol) of 2-diazo-5,5-dimethylcyclohexane-1,3-dione in 300 ml of 5-t-butyl-m-xylene and 250 ml chlorobenzene containing 38.38 g (0.21 mol) of benzophenone was irradiated overnight with a 200 watt mercury arc lamp fitted with a borosilicate glass filter after degassing for 1 hour under nitrogen. The photolysis mixture was extracted with 0.25 N NaOH, washed with ether, acidified with 1 N HCl, and extracted with chloroform. The chloroform was dried over anhydrous MgSO4 and stripped to give a crude yellow solid. The photolysis was repeated and the combined crude product from these ractions was chromatographed through silica gel (0.063-0.2 mm) using benzene-ethyl acetate. The solid obtained from the chromatography was recrystallized from benzene to give 2.76 g (11%) of 2-(2',6'-dimethyl-4'-t-butylphenyl)-5,5-dimethyl-1,3-cyclohexanedione as white crystals, mp 224°-49° C.
Reaction SMILES: [NH2:1][C:2](=[O:22])[C:3]([CH3:21])([CH3:20])[C@H:4]([NH:6][C:7]1[C:8]2[N:9]([CH:16]=[C:17](Br)[CH:18]=2)[N:10]=[CH:11][C:12]=1[C:13]([NH2:15])=[O:14])[CH3:5].O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2](=[O:22])[C:3]([CH3:21])([CH3:20])[C@H:4]([NH:6][C:7]1[C:8]2[N:9]([CH:16]=[C:17]([C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[CH:18]=2)[N:10]=[CH:11][C:12]=1[C:13]([NH2:15])=[O:14])[CH3:5]
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C(C)(C)C(N)=O
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2cc3c(N[C@H](C)C(C)(C)C(N)=O)c(C(N)=O)cnn3c2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
(R)-4-((4-amino-3,3-dimethyl-4-oxobutane-2-yl)amino)-6-bromopyrrolo[1,2-b]pyridazine-3-carboxamide (50 mg, 0.136 mmol) was taken in a sealed tube contained in acetonitrile (8 mL) and water (0.8 ml) mixture was added 4-methoxyphenylboronic acid (37.1 mg, 0.204 mmol), sodium carbonate (43.2 mg, 0.407 mmol). The reaction was degassed for 10 min. Next, PdCl2(TPP)2 (14.90 mg, 0.020 mmol) was added and the reaction mixture was heated to 100° C. and stirred for 30 min. After completion of reaction, it was then quenched with water (30 ml) and extracted into EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and solvent was removed under vacuum. Crude product was purified by prep HPLC purification to get desired product as an off white solid (16 mg, 29.8% yield). 1HNMR (400 MHz, DMSO) δ ppm: 1.16-1.19 (d, J=12 Hz, 6H), 1.23-1.24 (d, J=4.0 Hz, 3H), 3.79 (s, 3H), 4.69-4.73 (t, J=16 Hz, 1H), 6.95-7.01 (m, 3H), 7.214-7.263 (d, J=19.6 Hz, 4H), 7.67-7.70 (d, J=12 Hz, 2H), 8.08 (s, 1H), 8.198 (s, 1H), 10.827-10.851 (d, J=9.6 Hz, 1H). column: Purospherstar RP-18 (4×55) mm, 3 μm. Buffer: 20 mM NH4OAc in Water, Mobile Phase: A-Buffer+ACN (90+10), B-Buffer+ACN (10+90); Flow: 2.5 mL/min, Retention Time: 1.520 min, Purity: 99.46%. HPLC: Column: SUNFIRE C18 (4.6×150) mm, 3.5 micron Buffer: 0.05% TFA in water pH 2.5 Mobile phase: A: Buffer:Acetonitrile (95:5) B: Acetonitrile:buffer (95:5) Flow: 1.0 mL/min Retention Time: 8.269 min Enantioselectivity: 98.66%.
Reaction SMILES: C([O-])([O-])=[O:2].[K+].[K+].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH2:17][C:18]#[N:19])=[CH:13][NH:14]2)=[CH:10][CH:9]=1.O.OO>CS(C)=O>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH2:17][C:18]([NH2:19])=[O:2])=[CH:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: N#CCc1c[nH]c2cc(Br)ccc12
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)Cc1c[nH]c2cc(Br)ccc12
Temperature: 25 °C
Yield: 58.3 %

Procedure:
Powdered K2CO3 (408 mg, 2.95 mmol, 1.60 eq.) was heated to 50° C. in DMSO (3 mL) for 20 min, then cooled to rt. 6-Bromo-1H-indole-3-acetonitrile (434 mg, 1.85 mmol) was dissolved in DMSO (3 mL) and added to the reaction slurry. Water (0.2 mL) and aqueous 30% H2O2 (0.46 mL, 4.0 mmol, 2.2 eq.) were added, and the reaction mixture was stirred for 2–3 hours at rt. The reaction was quenched with 1N HCl and extracted with EtOAc. The organic layer was washed with 1.5 N sodium thiosulfate and dried (MgSO4). The solvent was removed in vacuo, and the residue crystallized from CH2Cl2 to give 273 mg (55%) of the title compound.
Reaction SMILES: [NH2:1][C@@:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:6][O:5][C@H:4]([CH3:7])[C@H:3]1[CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10].[C:21]([N:29]=[C:30]=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.CCOC(C)=O>[C:21]([NH:29][C:30]([NH:1][C@:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C@H:3]([CH:8]([OH:13])[C:9]([F:12])([F:10])[F:11])[C@@H:4]([CH3:7])[O:5][CH2:6]1)=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H]1OC[C@@](N)(c2ccccc2F)[C@@H]1C(O)C(F)(F)F
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H]1OC[C@@](NC(=S)NC(=O)c2ccccc2)(c2ccccc2F)[C@@H]1C(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
1-[(2R,3R,4S)-4-Amino-4-(2-fluoro-phenyl)-2-methyl-tetrahydro-furan-3-yl]-2,2,2-trifluoro-ethanol (Preparation Example 30-(4)) (550 mg, 1.87 mmol) was dissolved in DCM (15 mL) was transferred into the reaction vessel. Solution was cooled to 0° C. Benzoyl isothiocyanate (1.22 g, 7.50 mmol) was added drop-wise over 20 mins as a solution in DCM (100 mL). Reaction mixture was allowed to warm up to RT and stir overnight. TLC in neat EtOAc showed the weak SM spot was gone from Rf 0.10. Product was at Rf 0.40. (EtOAc:Hex 4:6), product was concentrated. Saturated aqueous sodium bicarbonate (30 ml) was added and then extracted with DCM (3×40 ml). The combined organic phases were combined and purified via flash chromatography (Hexane/EtoAc 0-50%). 0.75 g (87% yield) title compound (85%) and its epimer at the CF3 position (15%) were isolated as a brown solid. 1H NMR (400 MHz, CDCl3) ppm 1.36 (d, J=6.06 Hz, 3H) 2.66 (d, J=7.33 Hz, 1H) 4.53-4.59 (m, 1H) 4.59-4.69 (m, 2H) 4.89 (d, J=9.73 Hz, 1H) 7.05 (ddd, J=12.54, 8.18, 1.14 Hz, 1H) 7.12-7.17 (m, 1H) 7.28-7.32 (m, 1H) 7.43 (td, J=8.12, 1.58 Hz, 1H) 7.46-7.51 (m, 2H) 7.58-7.64 (m, 1H) 7.79-7.84 (m, 2H) 9.20 (s, 1H) 11.73 (s, 1H)