Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[C:15]([NH:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1)(=[O:17])[CH3:16].N1CCCC1.O>C(O)C>[CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=[C:23]1[C:22]2[C:26](=[CH:27][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[CH:20][CH:21]=2)[NH:25][C:24]1=[O:28])([CH3:3])[CH3:2]
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Solvent: CCO
Solvent: C1CCNC1
Solvent: O
Product: COc1cc(C)c(C=C2C(=O)Nc3cc(NC(C)=O)ccc32)cc1C(C)C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
A mixture of 5-isopropyl-4-methoxy-2-methylbenzaldehyde (0.25 g, 1.3 mmol), 6-acetamido-2-oxindole (0.25 g, 1.3 mmol) and pyrrolidine (0.54 ml, 6.5 mmol) in ethanol (4 ml) was held in a sealed tube at 100° C. for 12 hours. The reaction was cooled and then poured into water (100 ml). The solid which formed was removed by filtration, washed with water and then dissolved in ethyl acetate (200 ml). The ethyl acetate solution was dried over magnesium sulfate and concentrated. The resulting solid was triturated with dichloromethane/hexanes to afford 0.33 g (70%) of N-[3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-acetamide as a brownish yellow solid.
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)([N:32]3[CH2:31][CH2:30][N:29]([C:26]4[CH:25]=[CH:24][C:23]([C:22]([F:35])([F:36])[F:21])=[CH:28][CH:27]=4)[CH2:34][CH2:33]3)[C:3](=[O:12])[NH:4]2)=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.270 mmol), 1-(4-trifluoromethyl-phenyl)-piperazine (75 mg, 0.324 mmol) and DIPEA (42 mg, 0.324 mmol) In acetonitrile (3 mL) was stirred at room temperature for overnight. The crude was concentrated and the residue was purified with preparative HPLC to give 76 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-1,3-dihydro-indol-2-one as a white solid. MS: 520 (M+H)+. H1-NMR (400 MHz, CDCl3) δ 7.584 (s, 1H), 7.493 (d, 2H), 7.240 (d, 1H), 7.081 (t, 2H), 7.011 (t, 1H), 6.908 (d, 3H), 6.766 (d, 1H), 6.684 (d, 1H), 3.431 (d, 1H), 3.329-3.206 (m, 5H), 2.947 (t, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]([CH3:30])([CH3:29])[CH2:9][C:10]([OH:28])([C:24]([F:27])([F:26])[F:25])[CH2:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:21]([NH2:23])=O)[C:19]=3[CH:20]=2)[CH:7]=1.N1C(Cl)=NC(Cl)=NC=1Cl.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]([CH3:29])([CH3:30])[CH2:9][C:10]([OH:28])([C:24]([F:26])([F:27])[F:25])[CH2:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:21]#[N:23])[C:19]=3[CH:20]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2c(C(N)=O)cccc2[nH]1)C(F)(F)F
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2c(C#N)cccc2[nH]1)C(F)(F)F
Reaction time: 3 h
Yield: 36.2 %

Procedure:
A solution 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-4-carboxylic acid amide (95 mg, 0.21 mmol) in 1 mL of DMF was reacted with cyanuric chloride (46 mg, 0.25 mmol). After 3 hours, the mixture was treated with sodium bicarbonate, extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give 33 mg of the title product as off-white solid (36% yield).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][C:9]=1[O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1>CCOCC>[Br:7][C:8]1[CH:17]=[CH:16][C:11]([CH2:12][OH:13])=[CH:10][C:9]=1[O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: COC(=O)c1ccc(Br)c(OC2CCCCO2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1ccc(Br)c(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a suspension of LiAlH4 (0.72 g, 19.04 mmol) in anhydrous Et2O (90 mL) was slowly added a solution of methyl 4-bromo-3-(tetrahydropyran-2-yloxy)benzoate (4.0 g, 12.69 mmol) in anhydrous Et2O (10 mL). The mixture was stirred at room temperature for 2 h and then cautiously quenched with Na2SO4.10H2O (until gas evolution ceases). The solids were filtered off and washed with Et2O (100 mL). The combined organic fractions were then dried (Na2SO4) and concentrated in vacuo. The pale yellow residue was purified by flash column chromatography [SiO2, Et2O/n-hexane (7:3)] to give 4-bromo-3-(tetrahydropyran-2-yloxy)benzyl alcohol as a colourless oil (3.21 g, 88%). δH (270 MHz, CDCl3) 1.54-1.76 (m, 3H), 1.82-2.12 (m, 3H), 3.54-3.64 (m, 1H), 3.8-3.94 (m, 1H), 4.61 (d, J=4.9, 2H), 5.52 (m, 1H), 6.85 (dd, J=7.9, 1.5, 1H), 7.13 (d, J=2.0, 1H), 7.49 (d, J=7.9, 1H), Nb. ArCH2OH too broad to be observed; LC-MS (APCI+): tR=3.84 min, m/z 306.11 (C12H1581BrO4+H3O+), 304.13 (C12H1579BrO4+H3O+); HPLC: tR=2.34 min (96%); HRMS (FAB+) Found 289.02646; C12H16O381Br requires 289.02624.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][C:19]([NH:25][CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]=1[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][O:42]C2CCCCO2)=[CH:34][CH:33]=1.Cl>CO>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][C:19]([NH:25][CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]=1[C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][CH2:41][OH:42])=[CH:36][CH:37]=1
Reactant: NC(=O)C1(NCCC(F)(F)F)CCN(C(=O)c2cc(-c3ccc(OCCCOC4CCCCO4)cc3)c(-c3ccc(F)cc3Cl)s2)CC1
Agent: Cl
Solvent: CO
Product: NC(=O)C1(NCCC(F)(F)F)CCN(C(=O)c2cc(-c3ccc(OCCCO)cc3)c(-c3ccc(F)cc3Cl)s2)CC1
Reaction time: 2 h
Yield: 174.5 %

Procedure:
0.7 g of the compound obtained in stage 18A) and 3 ml of 2N ethereal hydrochloric acid are added to 15 ml of methanol. After 2 hours at AT, concentrating to dryness, taking up the residue in ether and then filtering, 0.57 g of the expected compound is obtained.
Reaction SMILES: [OH-].[K+].COC([CH:7]1[C:9]([CH2:11][CH2:12][CH2:13][C:14]([O:18][CH3:19])([CH3:17])[CH2:15][CH3:16])([CH3:10])[O:8]1)=O.Cl.P(=O)(O)(O)O>O>[CH3:19][O:18][C:14]([CH3:17])([CH2:15][CH3:16])[CH2:13][CH2:12][CH2:11][CH:9]([CH3:10])[CH:7]=[O:8]
Reactant: CCC(C)(CCCC1(C)OC1C(=O)OC)OC
Agent: Cl
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: O
Product: CCC(C)(CCCC(C)C=O)OC
Reaction time: 0.5 h

Procedure:
180 g Potassium hydroxide dissolved in 800 ml water was added over 2 h to 810 g 3-(4-methoxy-4-methyl-hexyl)-3-methyl-oxirane-2-carboxylic acid methyl ester at a temperature of 0° C. to 5° C. Then 36 g KOH dissolved in 150 ml water was added in portions till the colour change from orange to beige persisted. The mixture which had pH 11 was then acidified at 0° C. by the addition of HCl 32% (300 ml, added over 30 minutes), followed by diluted phosphoric acid till pH 3 was reached. The phases were separated and the aqueous phase extracted with tert.-butyl methyl ether. The combined organic phases were washed with concentrated NaCl solution prior to evaporating the solvent. The very viscous oil which remained (780 g) was added dropwise over a period of 3 h to 300 ml PEG 200 which was kept at 160° C. Thereby the product distilled off. After the addition, steam was injected for about 30 minutes to distil off any steam-volatile product. The two phases of the distillate were separated and the aqueous phase extracted with tert.-butyl methyl ether. The combined organic phases were washed with KHCO3 and NaCl. Evaporation of the solvent afforded 380 g of a faintly yellow oil which was distilled over a 60 cm Sulzer column to give 338 g 6-methoxy-2,6-dimethyl-octanal (bp. 65°-66° C./0.3 Torr=0.399 mbar).
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C@H:8]([N:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18])[C@@H:9]2[CH3:14].Br>>[ClH:1].[OH:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C@H:8]([N:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18])[C@@H:9]2[CH3:14]
Reactant: CCCCCN(CCC)[C@H]1CCc2c(OC)cccc2[C@H]1C
Agent: Br
Agent: Cl
Product: CCCCCN(CCC)[C@H]1CCc2c(O)cccc2[C@H]1C

Procedure:
cis-5-Methoxy-1-methyl-2-(N-n-pentyl-N-n-propyl-amino) tetralin hydrochloride (500 mg; 1.5 mmol) was heated in aqueous 48% HBr (3 ml) for 2 hours at 120° C. under N2. The mixture was evaporated and the residue was made alkaline with diluted NaHCO3 and extracted 3 times with ether. After drying (Na2SO4) and evaporation the product was precipitated as hydrochloride salt. Yield: 290 mg (60%) NMR (CDCl3), δ0.86 (t, 6H) δ1.17 (d, 3H), δ3.23-0.60 (m, 27H) δ5.36 (s, 1H phenolic) δ6.90 (m, 3H), MS (70 eV) m/z 289 (33%), 161 (100%), 232 (82%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:15][CH3:16])[C:6]([C:17]([OH:19])=[O:18])=[C:5]([C:20]([F:23])([F:22])[F:21])[N:4]=1.S(Cl)(Cl)=O.[CH2:30](O)[CH3:31]>>[F:25][C:2]([F:24])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:15][CH3:16])[C:6]([C:17]([O:19][CH2:30][CH3:31])=[O:18])=[C:5]([C:20]([F:22])([F:21])[F:23])[N:4]=1
Reactant: CCO
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)O)c1OCC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1OCC

Procedure:
This material was obtained from product of Example 14 and ethanol according to the following general procedure: A 5.0 g portion of the acid product of Example 14 was refluxed with excess thionyl chloride until the reaction was completed. Excess thionyl chloride was removed in vacuo. The residual acid chloride was refluxed with an excess of appropriate alcohol (ethanol in this Example) for 2-4 hours and concentrated to give the desired product. The crude product was purified by a wash with 20% K2CO3 and isolated as a solid (20.3% yield), mp 28°-30° C.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]([C:12]([OH:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[N:52]([CH2:53][CH2:54][CH:55]=[O:56])[C:51]([CH:57]([CH3:59])[CH3:58])=[C:50]([C:60]([NH:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[O:61])[C:49]=2[C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[CH:44][CH:43]=1>C1COCC1.O.CC(O)=O>[F:41][C:42]1[CH:43]=[CH:44][C:45]([C:48]2[N:52]([CH2:53][CH2:54][C@@H:55]([OH:56])[CH2:1][C:2]([O:4][C@@H:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]([OH:25])([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:3])[C:51]([CH:57]([CH3:59])[CH3:58])=[C:50]([C:60]([NH:62][C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)=[O:61])[C:49]=2[C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[CH:46][CH:47]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC=O
Reactant: CC(=O)O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)CC(=O)O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of S-(−)-2-Hydroxy-1,2,2-triphenylethyl acetate (40.2 g) in 300 mL anhydrous THF at −10 to 0° C. was added a solution of LDA prepared by reaction of diisopropylamine (46.5 mL) with 2.5 M n-BuLi/hexanes (97 mL) in 300 mL anhydrous THF at −5 to 0° C. After stirring at 0° C. for 30 min the mixture was cooled to −78° C. Then, a solution of 5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide 1 (50 g) in 280 mL anhydrous THF was added dropwise and maintained at −78° C. for 30 min. After adding 25 mL AcOH and 250 mL water the mixture was allowed to warm to room temperature. The layers were separated and the organic layer was washed and dried. After evaporation of the solvent the crude product was obtained (94 g). Analytical data are consistent with that from the prior art.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[OH-].[Na+].O1CCOCC1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:18]1([S:24]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)C[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To a stirred solution of L-asparagine (Aldrich) (10 g, 76 mmol), NaOH (3.4 g, 85 mmol), H2O (50 mL), and dioxane (50 mL) at 0° C. was added PhSO2Cl (10.6 mL, 84 mmol). After 1 min, NaOH (3.4 g) in H2O (50 mL) was added and the reaction mixture stirred for 30 min. The reaction mixture was then concentrated to remove the dioxane then washed with EtOAc. The aqueous phase was then cooled to 0° C. and acidified to pH 5.0 with conc. HCl to effect product precipitation. The resulting solid was collected by filtration, washed with H2O (20 mL) and dried at 50° C. under vacuum to give N-phenylsulfonyl-L-asparagine (1-1) as a white solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.CON(C)[C:18]([C:20]1[S:24][CH:23]=[N:22][CH:21]=1)=[O:19]>C1COCC1>[CH3:14][O:13][C:10]1[N:11]=[CH:12][C:7]([C:18]([C:20]2[S:24][CH:23]=[N:22][CH:21]=2)=[O:19])=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)cn1
Reactant: CON(C)C(=O)c1cncs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cncs2)cn1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A n-BuLi solution (1.89 mL, 3.03 mmol, 1.6 M solution in hexane) was slowly added to a −78° C. solution of 5-bromo-2-methoxypyridine (0.392 mL, 3.03 mmol) in dry THF (10 mL). After addition, stirring was continued for an additional 40 minutes and N-methoxy-N-methylthiazole-5-carboxamide (0.600 g, 3.48 mmol, Intermediate 11: step a) dissolved in THF (10 mL) was slowly added. The mixture was stirred at −78° C. for 10 minutes then warmed to 0° C. and stirred for 1 hour. The cold solution was quenched with saturated aqueous NH4Cl and warmed to room temperature. H2O was added and layers were separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts washed with brine, dried (Na2SO4), filtered, evaporated in vacuo, preabsorbed onto silica gel and chromatographed (CH2Cl2/EtOAc) to provide product. The pure white solid title compound was precipitated from MeOH, filtered and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28]C)=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:30]#[N:31])=[C:13]([CH3:34])[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Li+].[OH-].C(O)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:30]#[N:31])=[C:13]([CH3:34])[CH:12]=2)=[O:10])=[CH:35][CH:36]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3C)c(C#N)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCCc2ccc(Cl)cc2)ccc1Oc1cc2c(cc1C#N)C(C(=O)O)CCO2
Reaction time: 48 h
Yield: 32.6 %

Procedure:
Methyl 7-(4-((4-chlorophenethyl)carbamoyl)-2-methylphenoxy)-6-cyanochroman-4-carboxylate (0.0063 g, 0.0125 mmol) was taken up in 0.5 ml THF and treated with aqueous 1.0 molar LiOH (0.0250 ml, 0.0250 mmol) at ambient temperature. After 48 hours, the reaction was neutralized with acetic acid and concentrated in vacuo. Purification of the crude material by preparative thin layer chromatography using 5% MeOH/DCM with 1% HOAc as the mobile phase provided the title compound (2 mg, 38%). MS (apci) m/z=491.1 (M+H).
Reaction SMILES: [CH2:1](Br)[CH3:2].[Br:4][C:5]1[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:4][C:5]1[C:12]([O:13][CH2:1][CH3:2])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: CCBr
Reactant: COc1ccc(C=O)c(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1c(OC)ccc(C=O)c1Br
Temperature: 35 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
Ethyl bromide (2.88 g, 26.4 mmol) was added to a mixture of 2-bromo-3-hydroxy-4-methoxybenzaldehyde (5.08 g, 22 mmol) and potassium carbonate (4.56 g, 33 mmol) in anhydrous DMF (50 mL) at room temperature under nitrogen. The reaction mixture was stirred at 35° C. for 18 h, diluted with EtOAc (150 mL), washed with water (2×50 mL), brine, dried over Na2SO4 and concentrated to give crude product as a white solid. Purification by silica column chromatography (eluant: 30% EtOAc in Hexanes) to generate 5.65 g (99% yield) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm) 10.26 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 4.08 (q, J=7.1 Hz, 2H), 3.95 (s, 3H), 1.46 (t, J=7.0 Hz, 3H); MS (ESI) m/z=261 (M+1, positive).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([OH:17])[CH2:13][O:14][CH2:15][CH3:16])=[N:8][CH:9]=1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][C:30]=3[CH3:35])[N:27]=[CH:28][C:21]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([O:17][C:20]2[C:21]3[CH:28]=[N:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][C:30]=4[CH3:35])[C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:13][O:14][CH2:15][CH3:16])=[N:8][CH:9]=1
Reactant: Cc1cnccc1-n1ncc2c(Cl)ncnc21
Reactant: CCOC[C@H](O)C(=O)Nc1ccc(Cl)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ccncc1C)C(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.6 %

Procedure:
60% Sodium hydride in mineral oil (48.8 mg, 1.22 mmol) was added in one portion to (S)—N-(5-chloropyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H3) (199 mg, 0.81 mmol) in anhydrous THF (5 mL) cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-methylpyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate M1) (200 mg, 0.81 mmol) added portionwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm slowly to ambient temperature and stirred for 2 hours. 1M citric acid (2 mL) was added and the mixture extracted with ethyl acetate (2×20 mL). The organic extracts were washed with water (15 mL) and brine (15 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc to afford (2S)—N-(5-chloropyridin-2-yl)-3-ethoxy-2-[1-(3-methylpyridin-4-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxypropanamide (370 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 1.23 (3H, t), 2.34 (3H, s), 3.61-3.69 (2H, m), 4.06-4.14 (2H, m), 6.05 (1H, t), 7.49 (1H, d), 7.68 (1H, dd), 8.22 (1H, dd), 8.23-8.25 (1H, m), 8.44 (1H, s), 8.61 (1H, s), 8.63 (1H, dd), 8.69 (1H, s), 8.76 (1H, s); m/z (ESI+) (M+H)+=454; HPLC tR=1.93 min.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]#[CH:17]>C(N(CC)CC)C.[Cu]I.Cl[Pd](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>[Cl:8][C:7]1[C:2]([C:17]#[C:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: C#Cc1ccccc1F
Reactant: Clc1nccnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Fc1ccccc1C#Cc1nccnc1Cl
Temperature: 0 °C

Procedure:
49 mg (0.26 mmol) of copper(I) iodide and 179 mg (0.26 mmol) of bis(triphenyl-phosphine)palladium(II) chloride are added to a solution of 760 mg (5.10 mmol) of 2,3-dichloropyrazine in 27 ml of triethylamine and cooled to 0° C. Then 919 mg (7.65 mmol) of 2-fluoro-phenylacetylene are added dropwise, and the mixture is heated at 80° C. for 3 h. It is then filtered and concentrated. The residue is purified by preparative HPLC. 717 mg (60% of theory) of the title compound are obtained as pale beige crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Cl[C:11]1[N:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:17][C:14]1[CH:13]=[N:12][C:11]([O:1][C:2]2[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=2)=[N:16][CH:15]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: OCc1cccc(Oc2ncc(Br)cn2)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 23.2 %

Procedure:
3-Hydroxybenzyl alcohol (1.50 g, 12.1 mmol) and 2-chloro-5-bromopyrimidine (2.57 g, 13.3 mmol) were suspended in DMSO (20 mL), treated with cesium carbonate (4.35 g, 13.4 mmol) and heated to 110° C. After 16 h, the reaction mixture was cooled and partitioned between water (200 mL) and heptane:ethyl acetate (1:1, 200 mL). The organic layer was separated and the aqueous was extracted again with heptane:ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica (20-70% EtOAc:heptane) to afford the title compound (0.790 g, 23% yield) as a light yellow oil. MS (APCI) M+1=281.0; 1H NMR (400 MHz, CDCl3) δ ppm 4.74 (s, 2H) 7.08-7.14 (m, 1H) 7.20-7.23 (m, 1H) 7.25-7.30 (m, 1H) 7.43 (t, J=7.80 Hz, 1H) 8.57 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]4[NH2:24])[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:46]([O:48][CH3:49])=[O:47]>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]4[NH:24][C:46](=[O:47])[O:48][CH3:49])[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC[C@@H]4N)n3)c3cc(Cl)cnc32)cc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H]1CCCC[C@@H]1Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Cl)cc23)ncc1F
Reaction time: 0.58 h

Procedure:
To a mixture of (1S,2S)—N1-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)cyclohexane-1,2-diamine, 23b, (0.18 g, 0.35 mmol) in dichloromethane (4 mL) at room temperature was added iPr2NEt (0.12 mL, 0.70 mmol) followed by methyl chloroformate (0.03 mL, 0.37 mmol). After 35 minutes. the mixture was diluted with EtOAc, washed successively with aqueous saturated NH4Cl and aqueous saturated NaHCO3 and brine, dried over Na2SO4 filtered and concentrated in vacuo to provide the crude product sufficiently pure for use in the next reaction.