Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[N:10]=O.[S:12](=[O:16])(=[O:15])([OH:14])[OH:13]>[Pd].O>[S:12](=[O:14])(=[O:13])([OH:16])[OH:15].[NH2:10][C:3]1[CH:4]=[N:5][N:6]([CH2:7][CH2:8][OH:9])[C:2]=1[NH2:1]
Reactant: Nc1c(N=O)cnn1CCO
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1cnn(CCO)c1N

Procedure:
A solution of 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole (97 g) in a mixed solvent of sulfuric acid (34 ml) and water (2000 ml) was treated with 10% palladium on carbon (10 g) under a hydrogen atmosphere at room temperature for 4 days. After the catalyst was filtered off, the filtrate was concentrated in vacuo. The residue was triturated with methanol and dried in vacuo to give 4,5-diamino-1-(2-hydroxyethyl)pyrazole sulfuric acid salt (90.2 g) as a solid.
Reaction SMILES: [OH:1][C@@:2]([CH3:18])([C:16]#[CH:17])[CH2:3][CH2:4][C:5]1[C:6](=[O:15])[C:7]([CH3:14])=[C:8]([CH3:13])[C:9](=[O:12])[C:10]=1[CH3:11]>C(O)C>[C:2]([O:15][C:6]1[C:7]([CH3:14])=[C:8]([CH3:13])[C:9]([O:12][C:9](=[O:12])[CH3:8])=[C:10]([CH3:11])[C:5]=1[CH2:4][CH2:3][C@@:2]([CH3:18])([OH:1])[C:16]#[CH:17])(=[O:1])[CH3:3]
Reactant: C#C[C@](C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Solvent: CCO
Product: C#C[C@](C)(O)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O

Procedure:
By the same procedure described in Example 17, the title compound was prepared form (R)-2-[3-hydroxy-3-methyl-4-pentynyl]-3,5,6-trimethyl-2,5-cyclohexadiene-1,4-dione. mp 100°-103° C. (from ether-hexane): [α]D25 30 14.38° (C2H5OH): [α]D25 31 17.38°
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.F[C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][N:20]=1>O>[I:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([O:15][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)[CH:24]=1
Reactant: COc1ccc(CO)cc1
Reactant: Fc1cc(I)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(I)ccn2)cc1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
With cooling with ice, sodium hydride (60% oily, 4.93 g, 0.188 mmol) was added to a DMF (250 mL) solution of 4-methoxybenzyl alcohol (17.04 g), and stirred for 30 minutes. 2-Fluoro-4-iodopyridine (25.0 g) was added, and stirred at room temperature for 2 hours. Water was added to the reaction liquid, and extracted with diethyl ether. The organic layer was washed with saturated saline, and dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, then diisopropyl ether was added to the obtained residue, and the obtained solid was collected by filtration to obtain the entitled compound (26.15 g, 68%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:18]([NH:20][C@H:21]([C:27]([NH:29][C@H:30]([C:35]([NH:37][C@H:38]([C:40]([NH:42][C@H:43]([C:47]([NH:49][C@H:50]([C:66]([NH2:68])=[O:67])[CH2:51][CH2:52][CH2:53][CH2:54][NH:55]C(OCC1C=CC=CC=1)=O)=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[CH3:39])=[O:36])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:28])[CH2:22][CH2:23][C:24](=[O:26])[NH2:25])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C=CC=CC=1)=O.Br>C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:18]([NH:20][C@H:21]([C:27]([NH:29][C@H:30]([C:35]([NH:37][C@H:38]([C:40]([NH:42][C@H:43]([C:47]([NH:49][C@H:50]([C:66]([NH2:68])=[O:67])[CH2:51][CH2:52][CH2:53][CH2:54][NH2:55])=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[CH3:39])=[O:36])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:28])[CH2:22][CH2:23][C:24](=[O:26])[NH2:25])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: CCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(N)=O)C(C)C
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(N)=O)C(C)C

Procedure:
The protected hexapeptide (XV) (0.2 g, 0.2 mmol) was dissolved in TFA (5 ml) and treated with HBr gas over 1 hr. The mixture was evaporated in vacuo and triturated with Et2O (2×50 ml) to give (V) as a hydrobromide salt (0.13 g) RfH=0.14. This and a subsequent batch of product were purified by adsorption on to an ion exchange column (CM 25 Sephadex, Pharmacia) which was washed with 10-100 mmol NH4OAc at pH 7. The product was eluted with 100 mmol NH4OAc at pH 8.5. Lyophilisation and subsequent preparative HPLC [μBondapak ODS.; CH3CN: 50 mmol NH4OAc(aq) (15:85) gave (V) as an acetate salt (0.15 g) mp 253°-255° C. T.l.c. RfH=0.14, MH+ (FAB)=685.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2ccc(Cl)cc2)C1

Procedure:
62.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 4-chloro-benzoic acid to give (R)-3-[(4-chloro-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester. Yellow oil. MS 339.3 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:47][N:48]([C:53](=[O:64])[C@H:54]([NH:62][CH3:63])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[NH:49][C:50](=[O:52])[CH3:51].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([C@@H:10]([C:11](=[O:13])[N:62]([C@H:54]([CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:53]([N:48]([CH3:47])[NH:49][C:50](=[O:52])[CH3:51])=[O:64])[CH3:63])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N(C)NC(C)=O
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 2(R)-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (0.18 g, 0.53 mmol) in methylene chloride (5 ml) was added 1-hydroxy-7-azabenzotriazole (0.072 g, 0.53 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10 g, 0.53 mmol) and the mixture was cooled to 0° C. Then acetic acid N'-methyl-N'-((2R)-2-(methylamino)-3-phenylpropionyl)hydrazide (0.11 g, 0.44 mmol) and diisopropylethylamine (0.098 ml, 0.57 mmol) were added and the mixture was stirred at room temperature overnight. Then methylene chloride (50 ml) was added and the mixture was washed with water (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (MgSO4), filtered, concentrated in vacuo and chromatographed on silica gel (40 g) with ethyl acetate to give 0.14 g (57%) of N-((1R)-1-(N-[(1R)-2-(N'-acetyl-N-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:12]([CH:26]=[O:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:29]([C:32]1[CH:37]=[CH:36][C:35]([Mg]Br)=[CH:34][CH:33]=1)([CH3:31])[CH3:30]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[C:12]([CH:26]([C:35]3[CH:36]=[CH:37][C:32]([CH:29]([CH3:31])[CH3:30])=[CH:33][CH:34]=3)[OH:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc([Mg]Br)cc1
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C=O)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Product: CC(C)c1ccc(C(O)c2c(C3CCCC3)nc3c(c2I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C3)cc1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-2-cyclopentyl-4-iodo-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-iso-propylphenylmagnesium bromide. The product is obtained as a diastereomic mixture, which is used directly in the next step.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([NH:25]C(=O)OC(C)(C)C)=[CH:21][CH:20]=2)[N:9]=1.Cl>CO.O1CCOCC1>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[N:9]=1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]carbamate (1.09 g, 2.35 mmol) was dissolved in methanol (5 mL) and 4M hydrogenchloride in dioxane (5 mL) was added. The solution was stirred at room temperature overnight, then the mixture evaporated to a dark brown oil and dissolved in ethyl acetate (10 mL). Water (5 mL) was added followed by the addition of sodium bicarbonate solution until neutral pH was achieved (˜2 mL). The phases were separated and the organic phase washed with water (10 mL). The organic layer was dried over magnesium sulphate and evaporated to a pale yellow foam (805 mg).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:6]([CH:16]1[CH2:18][CH2:17]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=[O:14])=[O:5]>CO.[Pd].C(OCC)(=O)C>[CH:16]1([N:6]2[C:7]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:13]([OH:14])[C:3](=[O:2])[C:4]2=[O:5])[CH2:18][CH2:17]1
Reactant: COC(=O)C(=O)N(c1ccccc1[N+](=O)[O-])C1CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1c(=O)n(C2CC2)c2ccccc2n1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of N-cyclopropyl-N-(2-nitro-phenyl)-oxalamic acid methyl ester (45.0 g, 0.17 mol, 1.0 equiv) in methanol (400 mL) was added palladium on carbon (4.52 g, 0.0043 mol, 0.025 equiv; 10% Pd/C; [CAS RN 7440-05-3]) and the reaction mixture stirred under an atmosphere of hydrogen (1.2 bar) at rt for 2 h. The reaction mixture was diluted with ethyl acetate (400 mL), filtered over Celite® and the solvent mixture removed by evaporation under reduced pressure to give 31.2 g (84%) of the title compound as a light yellow solid. MS (ISN): 219.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH:11]([OH:20])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2].[CH3:26][Si:27]([CH3:30])([CH3:29])Cl.Cl[SiH3]>C1(C)C=CC=CC=1>[C:21]([C:7]1[CH:8]=[C:9]([CH:11]([O:20][Si:27]([CH3:30])([CH3:29])[CH3:26])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(C(O)CCc2ccccc2)cc(C(C)(C)C)c1O
Reactant: C[Si](C)(C)Cl
Agent: [SiH3]Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(CCc2ccccc2)O[Si](C)(C)C)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a nitrogen-purged 250 mL three-neck round-bottom flask were added 141 grams (0.41 mole) of the 2,6-di-t-butyl-4-(1-hydroxy-3-phenylpropyl)phenol produced in step (A) of this example, 100 mL of toluene, and 54.3 grams (0.50 mole) of trimethylchlorosilane. The addition of the chlorosilane produced a several degree exotherm. The mixture was allowed to stir overnight at ambient temperature. After this time, the reaction mixture was washed with water (3×200 mL), dried with sodium sulfate, and filtered. Removal of the hexane gave 148.9 grams of desired product (87.1 percent).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N+:10]([CH3:13])([O-:12])=[O:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:6][CH:5]([C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=1)[CH2:13][N+:10]([O-:12])=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])CC(O)c1cccc(O)c1
Reaction time: 2 h
Yield: 90 %

Procedure:
Dissolve 3-hydroxybenzaldehyde (18.4 g, 15.07 mmol) in tetrahydrofuran (100 mL). Add nitromethane ((42 mL, 780 mmol), cool in an ice bath and add tetrabutylammonium fluoride (151 mL, 151 mmol, 1.0 M in tetrahydrofuran). Stir for 2 hours, dilute with ethyl acetate (200 mL), wash with water (3×500 mL) and saturated aqueous sodium chloride (200 mL). Extract the aqueous washes with diethyl ether (3×), wash with saturated aqueous sodium chloride, dry (magnesium sulfate), filter through a pad of silica gel, and concentrate. Suspend the residue in hot dichloromethane with 5% ethyl acetate, cool and filter solid. Purify filtrate using silica gel chromatography, eluting with 5:95 ethyl acetate:dichloromethane. Combine the solid from the dichloromethane tritutation with the purified filtrate to give the desired compound (24.88 g, 90% total yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH2:8]([NH2:11])[CH:9]=[CH2:10].[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:8]([NH:11][CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[CH:9]=[CH2:10]
Reactant: C=CCN
Reactant: O=Cc1ccoc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCNCc1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6.019 g (62.64 mmol) of 3-furaldehyde and 5.37 g (94.0 mmol) of allylamine in 100 ml of methanol was stirred at room temperature for 0.5 hours. To this reaction mixture, 4.74 g (125 mmol) of sodium borohydride was added portionwise under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into an aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 to ethyl acetate) to yield N-allyl-3-furylmethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:10][C:41](=[O:42])[C:40]([S:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH:30]([CH3:31])[CH3:32])=[C:44]([OH:45])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2cccc(Cl)c2)oc1=O
Yield: 70 %

Procedure:
The title compound was prepared by Method A using 3'-chloroacetophenone (3 g, 19.41 mmol), trimethylsilyl triflate (4.31 g, 19.41 mmol), triethylamine (3.92 g, 38.82 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]-propanedioic acid (3.0 g, 9.71 mmol). Isolated yield: 70% m.p. 177°-178° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.28 (d, 6H), 3.42 (m, 1H), 6.92 (d, 1H), 6.94 (s, 1H), 7.06 (t, 1H), 7.13 (t, 1H), 7.28 (d, 1H), 7.58 (t, 1H), 7.63 (t, 1H), 7.83 (d, 1H), 7.89 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=1)[O:29][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1
Reactant: COc1cccc(O)c1
Reactant: CC(=O)c1c(C)cc(Cl)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1cccc(Oc2cc(C)c(C(C)=O)c(C)c2)c1
Temperature: 100 °C
Yield: 72.9 %

Procedure:
To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (5.00 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mmol), 3-methoxyphenol (4.08 g, 32.9 mmol) in toluene (54.8 mL) was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (349 mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(4-(3-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (5.4 g) as yellow oil in 73% yield: 1H NMR (500 MHz, CDCl3) δ 7.24 (m, 1H), 6.68-6.66 (m, 3H), 6.57-6.56 (m, 2H), 3.79 (s, 3H), 2.48 (s, 3H), 2.22 (s, 6H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([CH2:6][C:7]2[CH:8]=[C:9]([C:22]3[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH2:29])[N:23]=3)[C:10]([NH:13][C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[N:11][CH:12]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[NH2:29][C:24]1[N:25]=[C:26]([CH3:28])[N:27]=[C:22]([C:9]2[CH:8]=[C:7]([CH2:6][N:4]3[CH2:5][CH:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:3]3)[CH:12]=[N:11][C:10]=2[NH:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:23]=1
Reactant: COc1ccc(Nc2ncc(CN3CC(N)C3)cc2-c2nc(C)nc(N)n2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Nc2ncc(CN3CC(NS(C)(=O)=O)C3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.9 %

Procedure:
A solution of 4-(5-((3-amino azetidin-1-yl)methyl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (106 mg, 0.269 mmol) and triethylamine (56.2 μL, 0.404 mmol) in DCM (2.7 mL) was treated with MsCl (20.85 μL, 0.269 mmol) and stirred at ambient temperature for 3 h. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated. The crude product was purified via flash chromatography (silica gel) with 100% DCM to 6% 2 M ammonia in MeOH/DCM to give N-(1-((5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)azetidin-3-yl)methanesulfonamide (10 mg, 7% yield) as yellow solid. m/z (ESI, +ve ion) 472.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.FC1C=CC([C:32]2([C:43]3[CH:48]=[CH:47][C:46](F)=CC=3)[CH2:37][CH2:36][CH2:35][N:34](CC(O)=O)[C:33]2=O)=CC=1.C1C2C(=CC=CC=2)CCN1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[CH2:33]1[C:32]2[C:37](=[CH:46][CH:47]=[CH:48][CH:43]=2)[CH2:36][CH2:35][N:34]1[C:14](=[O:16])[CH2:13][N:10]1[CH2:11][CH2:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:9]1=[O:17]
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Agent: c1ccc2c(c1)CCNC2
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCc2ccccc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 58D for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.31 (dt, J=4.4, 5.5, 4H), 7.22-7.11 (m, 3H), 7.06-6.94 (m, 5H), 4.75-4.53 (m, 2H), 4.27 (d, J=4.8, 2H), 3.82 (t, J=6.0, 1H), 3.65 (t, J=6.0, 1H), 3.52 (q, J=6.5, 2H), 2.91-2.67 (m, 4H); MS (DCI) m/z 447.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[CH2:16][C:15]4(OCC[O:18]4)[CH2:14][CH2:13][C:12]=3[N:11]([C:22]([NH:24][C@@H:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:26]([NH:28][CH3:29])=[O:27])=[O:23])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[CH2:16][C:15](=[O:18])[CH2:14][CH2:13][C:12]=3[N:11]([C:22]([NH:24][C@@H:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:26]([NH:28][CH3:29])=[O:27])=[O:23])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCC1(C2)OCCO1)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCC(=O)C2)C(C)(C)C
Yield: 91.1 %

Procedure:
A mixture of compound 63 (0.91 g) and p-toluenesulfonic acid (1.3 g) was heated in acetone and water at 50° C. until starting material was consumed. After evaporation of acetone, the residue was extracted between EtOAc and saturated sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography with 70% to 80% EtOAc/Hex to give (S)-3-(3,4-difluorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-5-oxo-4,5,6,7-tetrahydro-1H-indazole-1-carboxamide (0.75 g, 91% yield), which was reduced with sodium borohydride (1.0 equiv.) in MeOH to give compound 67 as a mixture of two diastereomers after purification with a preparative LC-MS. LCMS (+ESI) m/z=421.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[CH3:10][N:11]1[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[C:12]1B(O)O.[F-].[K+]>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]>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:12]2[N:11]([CH3:10])[C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[C:3]([F:9])[CH:4]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Product: Cn1c(C#N)ccc1-c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
4-Bromo-3-fluoroaniline (0.95 g, 5.0 mmol), 1-methyl-5-cyano-2-pyrroleboronic acid (1.35 g, 9.0 mmol), KF (0.96 g, 16.5 mmol), and Pd2(dba)3 (120 mg, 0.125 mmol) were added to a 50 mL round bottom flask under nitrogen. The flask was sealed and purged with nitrogen for 5 minutes. THF (12.5 mL) was added and the mixture was purged with nitrogen for an additional 5 minutes. A solution of tri-t-butylphosphine (10% wt in hexanes) (0.74 mL, 0.25 mmol) was added via syringe and the mixture was stirred vigorously at 25° C. for 16 hours. The mixture was diluted with 250 mL of EtOAc, filtered through a plug of silica gel, washed with 200 mL of EtOAc and concentrated to give a crude brown/black semi-solid. Purification via Isco chromatography (the Redisep® column, silica, gradient 5%-100% ethyl acetate in hexane) afforded 5-(4-amino-2-fluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile as a white solid (1.05 g, 98%).