Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][C:16]#[N:17])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2.N.CO>CO.O1CCCC1.[Co]>[Cl:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH2:17])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: Cn1cc2c3c(c(Cl)cc2n1)CCC3=CC#N
Agent: [Co]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc2c3c(c(Cl)cc2n1)CCC3=CCN
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.6 %

Procedure:
(5-Chloro-2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)acetonitrile (116 mg, 2.87 mmol) was dissolved in a mixture of methanol (5 mL) and tetrahydrofuran (5 mL), Raney cobalt (1 g) and 8M ammonia/methanol solution (2 mL) were added to the solution, and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (118 mg, yield 100%).
Reaction SMILES: CCCCCCCCCCCCCCCCCC(OC[C@@H:22]([OH:30])[C@H:23]1[O:27][CH2:26][C@H:25](O)[C@H:24]1[OH:29])=O.[OH-].[C:32]([OH:36])(=O)[CH:33]=[CH2:34].C([O-])(=O)C=C.[Na+]>[OH-].[Na+].O.C1CCCCC1>[CH2:34]([O:30][CH2:22][CH2:23][O:27][CH2:26][CH:25]1[O:29][CH2:24]1)[CH:33]1[O:36][CH2:32]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O
Reactant: C=CC(=O)O
Agent: C=CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: O
Product: C(COCC1CO1)OCC1CO1
Reaction time: 2 h

Procedure:
Cyclohexane (850 ml), Tween 81® (3.30 g) and Span 60® 1.10 g) were placed in a 2L resin kettle equipped with a mechanical stirrer, Teflon® stir paddle, thermometer, condenser, and a nitrogen inlet. This surfactant system has an HLB of 8.7. In a 500 ml Erlenmeyer flask, sodium hydroxide (41.5 g) was dissolved in water (140 ml). The aqeous hydroxide solution was cooled to 5° C. and acrylic acid 95.0 ml) was added. The sodium acrylate solution was introduced into the resin kettle and the reaction vessel was purged with nitrogen. Potassium persulfate (145 mg) was added to initiate the polymerization. One hour after the polymerization was initiated, U.S. Silica F-75 (83.0 g) was introduced into the resin kettle through a powder funnel over a 5 minute period. The increased viscosity of the polymerization aided in the suspension of the silica. The silica was dispersed uniformly throughout the reaction mixture. After 2 hours, the polymerization formed discrete particles and ethylene glycol diglycidyl ether (335 mg) was added. The reaction was refluxed for 1 hour and the resultant product was dried in a rotary dryer for 1 hour at 100° C. Ninety percent of the product consisted of discrete particles ranging in size from 150-600 microns.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].Cl>>[F:13][C:10]1[C:4]2[C:5](=[O:7])[C:21]3[C:20](=[C:18]([OH:19])[CH:17]=[CH:16][C:14]=3[OH:15])[C:8](=[O:9])[C:3]=2[C:2]([F:1])=[CH:12][CH:11]=1
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1c2c(O)ccc(O)c2C(=O)c2c(F)ccc(F)c21
Temperature: 200 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
This compound was prepared by modifications to the literature method of Synth. Comm., 1990, 20, 2139. A mixture of the sublimed product (9) from the above reaction (100 g, 0.55 moles), hydroquinone (63.7 g, 0.58 moles), NaCl (127 g, 2.22 moles) and powdered anhydrous AlCl3 (833 g, 6.26 moles) was placed in a 5 L flask equipped with a condenser. The reactants were well-mixed by shaking, then heated over 1-2 hours to 200±5° C. (bath) under a nitrogen atmosphere (there was very large gas evolution during the heating process). After a further 2 hours at 200±5° C., the melt was poured onto ice and conc. HCl (1.6 L) was added. The mixture was stirred at room temperature overnight, and the reddish brown precipitate was collected, washed with H2O and dried to give crude 1,4-difluoro-5,8-dihydroxyanthracene-9,10-dione (4) (151 g, 98%), m.p. 301-304° C. (lit. m.p. 318-319° C.). This crude product was virtually insoluble in all solvents, and showed (by TLC in EtOAc/petroleum ether 1:3) only one minor impurity (probably 1-chloro-4-fluoro-5,8-dihydroxyanthracene-9,10-dione). 1H NMR agreed well with literature. This material was used for the next step without further purification.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13](Cl)=[O:14].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:13]([C:12]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:10]([Cl:9])[CH:11]=2)=[O:14])=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.081 g), commercially available 3,4-dichlorobenzoyl chloride (2.095 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. for 8 hours. The reaction mixture was partitioned between water and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to obtain 270 mg of the title compound (yield: 10%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:12]N1C(=O)CCC1=O>O1CCOCC1.COCCO>[CH2:1]([C:5]1[NH:6][C:7]([CH2:10][OH:11])=[C:8]([Cl:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCc1ncc(CO)[nH]1
Solvent: COCCO
Solvent: C1COCCO1
Product: CCCCc1nc(Cl)c(CO)[nH]1
Temperature: 40 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
In a mixture of 70 ml of dioxane and 60 ml of methyl cellosolve was dissolved 4 g of 2-butyl-5-hydroxymethylimidazole, and 3.9 g of N-chlorosuccinimide was added to the solution, followed by stirring at 40° C. for 1 hour. The reaction solution was evaporated to dryness under reduced pressure, and 100 ml each of water and ethyl acetate were added to the residue to shake for mixing. The ethyl acetate layer was evaporated to dryness under reduced pressure, and the residue was dissolved in 50 ml of ether. The solution was allowed to cool, thereby yielding 2.4 g of 2-butyl-4-chloro-5-hydroxymethylimidazole deposited as colorless prisms, m.p. 147°-148° C.
Reaction SMILES: O[C:2]1([C:24]2[C:33]([OH:34])=[CH:32][C:27]3[O:28][CH2:29][CH2:30][O:31][C:26]=3[CH:25]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[N:13]=[CH:12][S:11][C:9]3=2)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:3]1=[O:23].ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[OH:34][C:33]1[C:24]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]4[N:13]=[CH:12][S:11][C:9]4=3)[N:4]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:3]2=[O:23])=[CH:25][C:26]2[O:31][CH2:30][CH2:29][O:28][C:27]=2[CH:32]=1
Reactant: COc1ccc(CN2C(=O)C(O)(c3cc4c(cc3O)OCCO4)c3c2ccc2ncsc32)cc1
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: COc1ccc(CN2C(=O)C(c3cc4c(cc3O)OCCO4)c3c2ccc2ncsc32)cc1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 8-hydroxy-8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4-methoxybenzyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4-methoxybenzyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one was obtained (89%) as a colorless solid: MS (ES+) m/z 461.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>ClCCl.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1
Reactant: CC(=O)Nc1ncc(Br)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ncc(Br)cc1C#C[Si](C)(C)C
Temperature: 0 °C
Reaction time: 17 h
Yield: 81 %

Procedure:
To a suspension of N-(5-bromo-3-iodo-pyridin-2-yl)-acetamide (6.42 g, 18.83 mmol) in dichloromethane (90 ml) was added triethyl amine (3.15 ml, 22.6 mmol), then the mixture was cooled to 0° C. and dichlorobis(triphenylphosphino)palladium (II) (66 mg, 0.094 mmol) and copper(I) iodide (36 mg, 0.188 mmol) were added sequentially. Finally trimethylsilylacetylene (2.93 ml, 20.71 mmol) was added dropwise, and the ice bath was removed. After stirring at room temperature for 17 hours, the crude mixture was directly adsorbed on silica gel. Purification by flash chromatography on silica gel with a gradient of ethyl acetate/hexane afforded the title compound as light yellow solid (4.75 g, 81% yield). 1H NMR (DMSO-d6): δ 9.99 (s, 1H), 8.31 (d, J=2.5 Hz, 1H), 7.95 (d, J=2.5 Hz, 1H), 1.82 (s, 3H), 0.00 (s, 9H); HPLC/MS m/z: 311, 313 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:32][C:31]=2[O:42][CH3:43])[C:26]([Cl:44])=[CH:25][N:24]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>>[Cl:44][C:26]1[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:32][C:31]=2[O:42][CH3:43])=[N:28][C:23]([NH:1][C:2]2[C:19]([O:20][CH3:21])=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:17])[C:13]([F:14])([F:15])[F:16])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:24][CH:25]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(C[C@H](O)C(F)(F)F)CC2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(C[C@H](O)C(F)(F)F)CC2
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
(S)-3-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol (88 mg, 0.29 mmol), (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (0.104 g, 0.292 mmol), and 10-Camphorsulfonic acid (0.10 g, 0.43 mmol) were heated in a microwave vial at 120° C. for a total of 5 h then for 1.5 h at 140° C. The dark brown solution was added to a stirred satd. sodium bicarbonate solution (15 mL), stirred for 5 min then the supernatant was removed and the solids were stirred with 10 mL water. These solids were purified by RP-HPLC (10-30% acetonitrile:water) followed by formation of the free base with Macroporous carbonate resin to afford (S)-3-{7-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-1,1,1-trifluoro-propan-2-ol as yellow solids (64 mg, 36%). m.p.=95-102° C.; LCMS (m/e) 624 (M+1); 1H-NMR (CD3OD, 400 MHz) δ 7.93 (m, 2H), 7.69 (d, 1H, J=8.7 Hz), 6.81 (s, 1H), 6.69 (s, 1H), 6.55 (m, 1H), 4.68 (m, 1H), 3.85 (m, 10H), 3.3-3.5 (m, 6H), 3.20 (m, 4H), 3.10 (m, 2H), 2.85 (m, 2H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]([N:15]=[C:16]=[S:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1.O>[C:18]1([N:24]2[C:25](=[S:26])[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([CH3:7])[NH:15][C:16]2=[S:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: S=C=Nc1ccccc1
Reactant: CC(N=C=S)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2ccccc2)NC(=S)N(c2ccccc2)C1=S
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
15.1 g (122 mmol) of potassium tert-butoxide are dissolved in 200 ml of tetrahydrofuran in a 500 ml, three-necked, round-bottomed flask under a dry argon atmosphere. The solution is cooled to -70° C. A solution containing 20 g (122 mmol) of alpha-methylbenzyl isothiocyanate, 16.55 g (122 mmol) of phenyl isothiocyanate and 50 ml of tetrahydrofuran is run in dropwise while keeping the temperature of the mixture below -60° C. On completion of addition, the mixture is held for 0.5 hour at -70° C. and then is left to return to more temperature. The mixture is poured into 500 ml of water. The mixture is acidified to pH=1 by addition of N hydrochloric acid. The product is extracted with ethyl acetate (2 extractions, each with 150 ml of solvent). The solution is dried over magnesium sulfate. The solution is concentrated under reduced pressure. The product is crystallized from 50 ml of ether. The precipitate is filtered. 21 g (yield: 58%) of 3,5-diphenyl-5-methyldithiohydantoin are thus obtained as a yellow powder melting at 157° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11](=[O:19])[CH:12]=[C:13]([CH2:17]Cl)[N:14]([CH3:16])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:20][C@H:21]([C:23]([NH:25][CH3:26])=[O:24])[CH3:22].Cl.C(N(C(C)C)CC)(C)C>CC#N>[CH2:2]([O:9][C:10]1[C:11](=[O:19])[CH:12]=[C:13]([CH2:17][NH:20][C@@H:21]([CH3:22])[C:23]([NH:25][CH3:26])=[O:24])[N:14]([CH3:16])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNC(=O)[C@H](C)N
Reactant: Cn1cc(OCc2ccccc2)c(=O)cc1CCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNC(=O)[C@H](C)NCc1cc(=O)c(OCc2ccccc2)cn1C
Temperature: 85 °C
Yield: 87.1 %

Procedure:
A mixture of 5-(benzyloxy)-2-(chloromethyl)-1-methylpyridin-4(1H)-one hydrochloride (7.55 g, 25.0 mmol), H-Ala-NHMe.HCl (5.14 g, 37.0 mmol) and diisopropylethylamine (12.5 mL, 72.0 mmol) in CH3CN (50 mL) was heated at 85° C. under a nitrogen atmosphere for overnight. Volatiles were removed in vacuo, and the residue was pre-purified by column chromatography on silica gel using a mixture of MeOH and ethyl acetate as eluant (solvent gradient of 10, 15 and 20% MeOH in ethyl acetate). The fractions rich in product were combined and evaporated to dryness. Further purification by column chromatography on silica gel using a mixture of H2O and CH3CN (1-5% H2O content) and then a 10% MeOH in dichloromethane solution afforded (S)-2-((5-(benzyloxy)-1-methyl-4-oxo-1,4-dihydropyridin-2-yl)methylamino)-N-methylpropanamide (7.17 g) in 87% yield. MS m/z 352 [M+Na]+, 330 (100%) [M+1]+, 228, 138, 91.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[C:10]1[CH:11]=[C:12]([C:13]([F:14])([F:15])[F:16])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH2:27][C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)=[CH:7][CH:6]=2)[N:9]=1
Reactant: O=Cc1ccncc1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: FC(F)(F)c1cc(C(F)(F)F)n(-c2ccc(NCc3ccncc3)cc2)n1
Reaction time: 8 h
Yield: 77.7 %

Procedure:
A mixture of 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.059 g, 0.2 mmol) and pyridine-4-carboxaldehyde (20 μL, 0.2 mmol) in methanol (0.8 mL) and acetic acid (0.2 mL) was stirred at room temperature for 15 minutes Sodium cyanoborohydride (0.032 g, 0.5 mmol) was added, and the reaction mixture stirred overnight. The reaction mixture was diluted with CH2Cl2 (50 mL), washed with brine (2×20 mL), dried over anhydrous Na2SO4 and evaporated. The residue was purified by flash column chromatography over silica gel (2% acetone in CH2Cl2) to give the above-named compound (0.060 g, 78%): mp 92-94° C. NMR (DMSO-d6) δ 4.40 (2H, d), 6.65 (2H, d), 6.97 (1H, t), 7.23 (2H, d), 7.35 (2H, d), 6.65 (2H, d), 7.7 (1H, s), 8.51 (2H, d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:12]([NH:34][S@@](C(C)(C)C)=O)([C:20]2[CH:25]=[C:24]([O:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])[CH:23]=[C:22]([F:33])[CH:21]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>CO.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C@:12]([C:20]2[CH:25]=[C:24]([O:26][C:27]([F:31])([F:32])[CH:28]([F:29])[F:30])[CH:23]=[C:22]([F:33])[CH:21]=2)([NH2:34])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc([C@@](Cc2ccccc2)(N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1F
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)Oc1ccc([C@](N)(Cc2ccccc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1F
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a solution of (R)—N—((R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (398 mg, 0.678 mmol) in MeOH (1.5 mL) was added HCl (1.5 mL, 4 M solution in dioxane) and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with ether (50 mL) and the organic layer was washed with sat. NaHCO3 (20 mL), dried over Na2SO4, filtered and concentrated to give (R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine as a colorless oil (334 mg, 100% yield). LCMS: RT=1.76 min [M−NH2] 467.24 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.04 min, Purity 95% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm) NMR: 400 MHz 1H (CDCl3) 7.15 ppm, 3H, m; 6.99 ppm, 4H, m; 6.89 ppm, 1H, m; 6.84 ppm, 1H, d, J=8.79 Hz; 6.74 ppm, 2H, d, J=6.15 Hz; 5.87 ppm, 1H, m; 4.42 ppm, 1H, m; 3.47 ppm, 2H, s; 1.27 ppm, 6H, dd, J=7.91, 6.15 Hz.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:13]3[O:14][C:15]4[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:32][C:33]1(C)[C:37](C)(C)OB(C(C)=C)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:21]([C:20]1[C:15]2[O:14][C:13]3[C:8]([C:4]4[CH:3]=[C:2]([C:33]([CH3:37])=[CH2:32])[CH:7]=[CH:6][N:5]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1)([CH3:23])[CH3:22]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)c1cccc2c1oc1c(-c3cc(Cl)ccn3)cccc12
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)c1ccnc(-c2cccc3c2oc2c(C(C)C)cccc23)c1
Yield: 59 %

Procedure:
4-chloro-2-(6-isopropyldibenzo[b,d]furan-4-yl)pyridine (10.5 g, 32.6 mmol) and potassium phosphate (22.54 g, 98 mmol) were dissolved in 500 mL of toluene and 50 mL of water. The reaction was purged with nitrogen for 20 minutes and then 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (6.13 mL, 32.6 mmol), Pd2(dba)3 (0.598 g, 0.653 mmol) and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.072 g, 2.61 mmol) were added. The reaction was refluxed for 18 hours. After cooling the reaction to room temperature, 100 mL of water was added to the reaction mixture. The aqueous layer was extracted twice with 100 mL of ethyl acetate. The organic layer was passed through a plug of silica gel, eluting with DCM. After evaporation of the solvent, the crude product was subjected to column chromatography (SiO2, 3% ethyl acetate in hexane to 5% ethyl acetate in hexane, v/v) to yield 6.3 g (60.1%) of pure product.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=1[C:25]([F:28])([F:27])[F:26].CI.Cl>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:1])[C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=1[C:25]([F:26])([F:27])[F:28]
Reactant: COC(=O)Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: -75 °C
Reaction time: 0.08 h
Yield: 74.3 %

Procedure:
A solution of diisopropylamine (2.97 mL, 20.85 mmol) in THF (22 mL) was stirred at 0° C. and treated dropwise with n-butyllithium (1.6 M in hexane, 13.03 mL, 20.85 mmol). The resulting solution was stirred for 5 min, and then was cooled to about −75° C. Once at the prescribed temperature, a solution of methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)acetate (4.39 g, 17.38 mmol) in THF (44 mL) was added dropwise over a 15 min period. The resulting solution was stirred at about −75° C. for 30 min, and then warmed to 0° C. Once at the prescribed temperature, the solution was rapidly treated with methyl iodide (1.630 mL, 26.1 mmol). The resulting solution was stirred for 30 min, treated with 1.0 M aqueous HCl and then extracted three times with ethyl acetate. The combined organic phases were washed with 5% aqueous sodium bisulfite (2×25 mL) followed by saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel, eluting with 5-15% ethyl acetate-hexane, to provide racemic methyl 2-(4-chloro-3-(trifluoromethyl)-phenyl)propanoate as a colorless oil (3.444 g, 72%). 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=2.0 Hz, 1 H), 7.47 (d, J=8.4 Hz, 1 H), 7.42 (dd, J=8.4, 2.0 Hz, 1 H), 3.76 (q, J=7.3 Hz, 1 H), 3.68 (s, 3 H), 1.52 (d, J=7.3 Hz, 3 H).
Reaction SMILES: [CH3:1][C:2]([CH3:40])([CH3:39])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:15]=[C:16]([N:20]4[CH2:24][CH2:23][C:22]([CH2:26][O:27]C(=O)C)([CH3:25])[CH2:21]4)[CH:17]=[CH:18][CH:19]=3)[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4].C([O-])(=O)C.CO.O>CCN(CC)CC>[OH:27][CH2:26][C:22]1([CH3:25])[CH2:23][CH2:24][N:20]([C:16]2[CH:15]=[C:14]([C:11]3[N:12]=[C:13]4[C:5]([C:3](=[O:4])[C:2]([CH3:39])([CH3:1])[CH3:40])=[CH:6][NH:7][C:8]4=[N:9][CH:10]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:21]1
Reactant: CC(=O)OCC1(C)CCN(c2cccc(-c3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)c2)C1
Agent: CC(=O)[O-]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(CO)CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c2)C1
Yield: 15 %

Procedure:
1-{2-[3-(3-Hydroxymethyl-3-methyl-pyrrolidin-1-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared following a similar procedure but using acetic acid 1-{3-[7-(2,2-dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-3-methyl-pyrrolidin-3-ylmethyl ester as starting material. In this reaction, the acetate was hydrolysed at the same time of the second step of the SEM hydrolysis by heated at reflux the hydrolysis intermediate in a 8/1/1 mixture of MeOH, H2O, and Et3N over the weekend. The product was obtained in 15% yield after SiO2 chromatography (hexanes/EtOAc 0-30% EtOAc).