Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1.C(N(CC)CC)C.Cl[C:33]([O:35][CH3:36])=[O:34]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:36][O:35][C:33]([O:1][CH:2]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)=[O:34]
Reactant: COC(=O)Cl
Reactant: Cc1cccc(C#CC(O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)OC(C#Cc1cccc(C)n1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the Compound of Example 39 (50 mg, 0.15 mmol), triethylamine (65 μL, 0.45 mmol) and 4-dimethylaminopyridine (10 mg, 0.07 mmol) in 3 mL of CH2Cl2 cooled at 0-5° C., methyl chloroformate (23 μL, 0.30 mmol) was added dropwise. The reaction mixture was stirred at r.t. overnight. Afterwards, it was evaporated to dryness and purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 8:2 affording the title product (0.28 g) as a brown oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[CH:11]=1)[CH3:9])(C)(C)C.Cl>O1CCOCC1>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[O:16][C:12]1[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cnccn2)c1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1cccc(Oc2cnccn2)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 85.2 %

Procedure:
A mixture of (S)-{1-[3-(pyrazin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.33 g, 4.2 mmol), dioxane (20 mL) and HCl (4.2 mL, 4N) was stirred at 50° C. for 5 h and concentrated in vacuo. CH2Cl2 (50 mL) was added and the reaction mixture was basified with NaOH (5N) followed by extraction with CH2Cl2 (2×50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated to give the title compound (0.77 g, 85% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][C:20]#[CH:21].[Sn](Cl)(Cl)(Cl)Cl>>[C:1]([C:5]1[CH:10]=[C:9]([C:16](=[O:22])[CH2:17][CH2:18][CH2:19][C:20]#[CH:21])[CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: C#CCCCC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: C#CCCCC(=O)c1cc(C)c(O)c(C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
To a solution of 2-tert-butyl-6-methylphenol (1.2 g, 7.3 mmol) in methylene chloride (28 ml, 1.1 equiv.), stirred under argon at -78° C., is added 5-hexynoyl chloride (1.0 g) followed by tin tetrachloride (0.93 mL, 1.1 equiv.). After stirring 30 minutes at -78° C., the reaction is warmed to -50° C. and stirred 5 minutes more. The mixture is then quenched with 1N HCl/ether. The product is extracted from 1N HCl with 3 portions of ether, and the ether layers are combined and washed with water. The resulting ether layer is dried (MgSO4), filtered, and concentrated in vacuo to give 2.14 g crude product. The product is flash chromatographed on silica gel using 10% EtOAc in hexane to give 0.97 g 2-t-butyl-4-(5-hexynoyl)-6-methylphenol. Crystallization from hexane gives crystals, mp 63°-64° C.
Reaction SMILES: [Cl-:1].[Cl:2][CH2:3][C:4]1[NH:9][C:8](=[O:10])[NH:7][C:6](=[O:11])[CH:5]=1>C(O)(=O)C>[Cl:1][C:5]1[C:6](=[O:11])[NH:7][C:8](=[O:10])[NH:9][C:4]=1[CH2:3][Cl:2]
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Reactant: [Cl-]
Solvent: CC(=O)O
Product: O=c1[nH]c(CCl)c(Cl)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Sulfulyl chloride (120 ml) was added dropwise to a suspension of 163 g of 6-chloromethyluracil in 500 ml of acetic acid at room temperature for 20 minutes and stirred at the same temperature for 3 hours. The reaction mixture was poured into ice water (500 ml) and the resulting crystals were collected by filtration to give 182.3 g of 5-chloro-6-chloromethyluracil (yield 92%). The physical properties of this compound are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[N:7][CH:8]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[N:7][CH:8]=1
Reactant: COC(=O)/C=C/c1cncc(OC)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cncc(OC)c1
Reaction time: 5 h
Yield: 96.1 %

Procedure:
In Parr apparatus, a mixture of 1 g (5.33 mmol) of methyl (2E)-3-(5-methoxypyridin-3-yl)prop-2-enoate in 20 mL of MeOH and 0.1 g of 10% Pd/C is hydrogenated at 7 bar for 5 hours. The reaction mixture is then filtered through Whatman GF/F paper and concentrated under reduced pressure. 1 g of methyl 3-(5-methoxypyridin-3-yl)propanoate is thus obtained in the form of a wax, which is used without further purification in the following step.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14]1[N:19]([CH:20]([CH2:22][CH3:23])[CH3:21])[C:18](=[O:24])[CH:17]=[C:16]([C:25]([F:28])([F:27])[F:26])[N:15]=1.[Cl:31]N1C(=O)CCC1=O>ClCCl>[F:30][C:2]([F:29])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:11])([F:10])[F:12])=[CH:5][C:4]=1[NH:13][C:14]1[N:19]([CH:20]([CH2:22][CH3:23])[CH3:21])[C:18](=[O:24])[C:17]([Cl:31])=[C:16]([C:25]([F:26])([F:27])[F:28])[N:15]=1
Reactant: CCC(C)n1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCC(C)n1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)c(Cl)c1=O
Yield: 28 %

Procedure:
A dichloromethane (10 ml) solution of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-sec-butyl-6-trifluoromethyl-4(3H)-pyrimidinone (430 mg, 0.96 mmol) and N-chlorosuccinimide (141 mg, 1.06 mmol) was heated under reflux for 4 hours. After completion of the reaction, the solvent was evaporated under a reduced pressure, the resulting residue was suspended in ether (20 ml) and then the solid deposited was filtered. The resulting filtrate was washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure. By purifying the thus obtained residue by a silica gel column chromatography (toluene), 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-sec-butyl-5-chloro-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 59] was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[CH:7]=[N:6]2.COC1C=C2C(N=CC(=O)N2)=CC=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:8]1[CH:7]=[N:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2[nH]c(=O)cnc2c1
Agent: COc1ccc2ncc(=O)[nH]c2c1
Product: COc1ccc2nc(Cl)cnc2c1
Yield: 35 %

Procedure:
A mixture of 6-methoxyquinoxalin-2(1H)-one and 7-methoxyquinoxalin-2(1H)-one (5.67 g, 32.20 mmol) was refluxed in phosphorus oxychloride (120 mL) for 1 h. The reaction was concentrated and quenched by addition of ice, then basified with sodium carbonate, and extracted with ethyl acetate (3×200 mL). The organic layers were combined and concentrated in vacuo. The crude product was absorbed onto sodium sulfate and purified by column chromatography (0 to 5% ethyl acetate/hexanes) to afford 2-chloro-6-methoxyquinoxaline (2.21 g, 11.36 mmol, 35% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.69 (s, 1 H), 7.88 (d, J=9.32 Hz, 1 H), 7.43 (dd, J=9.32, 2.77 Hz, 1 H), 7.37 (d, J=2.77 Hz, 1 H), 3.95 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([NH2:22])=[O:21])[CH2:15]3)[CH2:10][CH:9]=2)=[CH:4][C:3]=1[NH:23][C@@H:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])[CH3:25]>[Pd].C(O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C@@H:14]3[CH2:19][CH2:18][CH2:17][C@@H:16]([C:20]([NH2:22])=[O:21])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:23][C@@H:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])[CH3:25]
Reactant: C[C@@H](Nc1cc(C2=CCN(C3CCCC(C(N)=O)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: C[C@@H](Nc1cc(C2CCN([C@@H]3CCC[C@@H](C(N)=O)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
A mixture of the 3-(4-(4-chloro-3-((R)-1-(2,4-dichlorophenyl)ethylamino)phenyl)-5,6-dihydropyridin-1(2H)-yl)cyclohexanecarboxamide (0.154 g, 0.20 mmol), palladium on carbon (Pd/C) (10% by weight, 0.05 g) in ethanol (7 mL) containing concentrated hydrochloric acid (4 drops) in a Paar shaker flask was hydrogenated at 25 psi for 1 h. The reaction mixture was diluted with ethanol, and filtered through Celite. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash chromatography (SiO2, 5% triethylamine in ethyl acetate) to separate the desired isomer as a white solid (0.038 g, 0.075 mmol, 25%). 1H NMR (400 MHz, CD3OD) δ 7.45-7.41 (m, 2H), 7.26 (dd, J=2.0, 8.4 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 6.57 (d, J=8.0 Hz, 1H), 6.21 (s, 1H), 4.99 (dd, J=6.8, 13.2 Hz, 1H), 3.76-3.71 (m, 1H), 3.53-3.52 (m, 3H), 3.20-3.12 (m, 2H), 2.99-2.93 (m, 1H), 2.71-2.65 (m, 1H), 2.47 (d, J=11.6 Hz, 1H), 2.35 (d, J=13.2 Hz, 1H), 2.18-2.10 (m, 2H), 1.99-1.82 (m, 6H), 1.68-1.74 (m, 1H), 1.64-1.51 (m, 6H); MS: (ES) m/z calculated for C26H33Cl3N3O [M+H]+508.2. found 508.4.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:25]([CH2:26][CH2:27][C@:6]12[CH3:7])[C@:19]1([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:14](=[CH:15][C@@H:16]([OH:28])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[CH3:29][Si:30]([CH3:33])([CH3:32])Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:25]([CH2:26][CH2:27][C@:6]12[CH3:7])[C@:19]1([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:14](=[CH:15][C@@H:16]([O:28][Si:30]([CH3:33])([CH3:32])[CH3:29])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)OC[C@]12CC[C@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@]12CC[C@H](O[Si](C)(C)C)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12

Procedure:
A solution of 4-androstene-3β,17β,19-triol 17,19-diacetate, trimethylchlorosilane and pyridine in toluene is refluxed for 24 hours. The solid is removed by filtration and the filtrate reduced to dryness under vacuum. The oil is crystallized from hexane to yield 3β-trimethylsiloxy-4-androstene-17β,19-diol 17,19-diacetate. This produce is refluxed one hour with 1 equivalent of sodium bicarbonate in 10% aqueous methanol. The solution is poured onto water. The solid which forms is filtered, dried, and crystallized from ether-hexane to yield 3β-trimethylsiloxy-4-androstene-17β,19-diol 17-acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:17][CH2:16]2)=[C:11]([CH:18]=[C:19]2[C:23]([CH3:25])([CH3:24])[O:22][C:21]([CH3:27])([CH3:26])[C:20]2=[O:28])[CH:10]=1.[OH-:29].[Li+]>CO.OO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:17][CH2:16]2)=[C:11]([CH:18]2[C:19]3([C:20](=[O:28])[C:21]([CH3:27])([CH3:26])[O:22][C:23]3([CH3:24])[CH3:25])[O:29]2)[CH:10]=1
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3Cl)ccc2C2CC2)C1=O
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(-c3ccc(Cl)cc3Cl)ccc2C2CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 429.9 %

Procedure:
To a solution of 4-[1-(2′,4′-dichloro-4-cyclopropylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (20.0 g, 0.048 mol) in methanol (800 ml) at 35° C. is added 50% aqueous hydrogen peroxide (4.80 ml, 0.072 mmol), followed immediately by 2M lithium hydroxide (4.80 ml, 9.60 mmol) solution. The mixture is stirred at this temperature for a further 2 hours, then allowed to cool to room temperature. Then reaction mixture is quenched with 10% sodium metabisulfite (negative KI-starch indicator test) then diluted with diethyl ether. Most of the methanol is removed under vacuum, and the crude mixture is partitioned between distilled water and diethyl ether. The aqueous phase is further extracted with diethyl ether (×2), then all organics are combined and washed with saturated sodium bicarbonate (×2) then brine. After drying over magnesium sulfate the suspension is filtered and the filtrate concentrated in vacuo to afford 2-(2′,4′-dichloro-4-cyclopropylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxa-spiro[2.4]heptan-7-one (17.80 g) as an orange foam. This material is of sufficient purity to use directly in the next step without further purification.
Reaction SMILES: Cl.[CH2:2]([C@@H:9]1NC(C)(C)N(C)C1=O)[C:3]1[CH:8]=CC=C[CH:4]=1.[CH:18]([CH:20]=[CH2:21])=[O:19].C=CC(=C)C>C[N+]([O-])=O.O>[CH3:8][C:3]1[CH2:2][CH2:9][C@@H:20]([CH:18]=[O:19])[CH2:21][CH:4]=1
Reactant: C=CC=O
Reactant: CN1C(=O)[C@H](Cc2ccccc2)NC1(C)C
Agent: Cl
Solvent: C=CC(=C)C
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CC1=CC[C@H](C=O)CC1
Temperature: 0 °C
Reaction time: 7 h
Yield: 84 %

Procedure:
To a 0° C. solution of 5 (32 mg, 0.12 mmol) in CH3NO2/H2O (95/5 v/v, 1.0 M) was added acrolein (1.0 mL, 15 mmol), and isoprene (0.50 mL, 5 mmol). The solution was stirred at 0° C. for 7 hr, then directly placed onto a silica gel column and eluted with 3% Et2O/pentane, affording the title compound as a colorless oil in 84% yield (745 mg, 89% ee). Product ratios were determined by GLC (Bodman Γ-TA column, 35° C., 0.25° C./min gradient, 23 psi) t4=84.1 min, 85.3 min. 1H NMR, 13C NMR, and IR data were consistent with previously reported values (see Ishihara et al. (1998), supra). The absolute configuration was determined by oxidation to 4-methyl-3-cyclohexene-1-carboxylic acid and correlation of the optical rotation to the reported value; see Poll et al. (1985) Tetrahedron Lett. 26:3095-3098. To the aldehyde (255 mg, 2 mmol) was added a solution of isobutylene in THF (2.0 M, 30 mL) followed by tBuOH-H2O (5/1, 20 mL), KH2PO4 (840 mg, 6 mmol), and NaClO2 (540 mg, 6 mmol). The heterogenous mixture was stirred for 4 hr, then partitioned between EtOAc and H2O. The organic extract was washed with brine, dried (MgSO4), and concentrated. The white solid was purified by silica gel chromatography (20% EtOAc/hex): [α]D20=+89®=4.0, 95% EtOH). Literature [α]D20=−107 ®=4, 95% EtOH) for (S)-4-methyl-3-cyclohexene-1-carboxylic acid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=O>C1COCC1>[CH3:7][C:8]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9]1
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CNc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a 1M of LAH (30 mL) in THF was added 2b (630 mg, 3.88 mmol) in portion. The reaction mixture was stirred at rt for 2 h, then refluxed for 1 h. The reaction mixture was quench with 1 part of H2O (10-mL), one part of 15% NaOH (5 mL) and another part of H2O (5 mL). The aqueous layer was extracted with EtOAc. The EtOAc layer was dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure to afford 2c (320 mg, 56%) as an oil. MS (ES) m/z 150 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19](=O)[CH2:20][CH2:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1ccc(CNC(=O)CCCC[Si](C)(C)C)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1ccc(CNCCCCC[Si](C)(C)C)cc1
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a suspension of 2.5 g of lithium aluminum hydride in 100 ml of anhydrous tetrahydrofuran was added dropwise a solution of 5.0 g of N-[(4-butylphenyl)methyl]-5-(trimethylsilyl)pentanamide in tetrahydrofuran. The resulting mixture was heated at reflux for 16 hours. The mixture was cooled, and the complex was decomposed by the cautious portionwise addition of sodium sulfate decahydrate. The mixture was stirred for 1/2 hour and then filtered. The solid was washed with tetrahydrofuran, and the filtrate was dried with anhydrous magnesium sulfate and filtered. The filtrate was evaporated to dryness and gave 4.53 g of the desired product as a colorless liquid, in 95% yield.
Reaction SMILES: [CH2:1]1N2CCN(CC2)C1.[CH3:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][NH:31]4)=[CH:27][CH:26]=3)[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18]>C(=O)(OC)OC.CN(C=O)C>[CH3:1][N:31]1[C:32]2[C:28](=[CH:27][CH:26]=[C:25]([C:22]3[N:21]=[C:20]([C:12]4[CH:13]=[N:14][C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[C:10]([CH3:9])[CH:11]=4)[O:24][N:23]=3)[CH:33]=2)[C:29]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30]1
Reactant: C1CN2CCN1CC2
Reactant: Cc1cc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cnc1OC(C)C
Solvent: COC(=O)OC
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(-c3ccc4c(CCC(=O)O)cn(C)c4c3)no2)cnc1OC(C)C
Temperature: 90 °C
Yield: 53.2 %

Procedure:
DABCO (110 mg) was added to a solution of 3-[6-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E85) (100 mg) in dimethyl carbonate (3 mL) and DMF (2 mL). The resulting mixture was heated at reflux for 5 days. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was dissolved in iPrOH (3 mL) and water (3 mL). Sodium hydroxide (30 mg) was added to the mixture. The resulting mixture was heated at 90° C. for 1 hour. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[1-methyl-6-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E86) (55 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.24 (3H, s), 2.60 (2H, t), 2.95 (2H, t), 3.83 (3H, s), 5.41 (1H, m), 7.31 (1H, s), 7.74 (2H, m), 8.10 (1H, s), 8.29 (1H, d), 8.82 (1H, d), 12.10 (1H, br s). MS (ES): C23H24N4O4 requires 420; found 421.2 (M+H+).
Reaction SMILES: CN1C(=O)N(C)CCC1.[Li+].CC([N-]C(C)C)C.[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=1)(=[O:21])=[O:20].Cl[CH2:33][C:34]1[S:35][CH:36]=[CH:37][CH:38]=1.C1(C)C=CC=CC=1>CCCCCCC.C1COCC1.C1(CC)C=CC=CC=1.C1COCC1>[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([CH:28]([CH2:33][C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)[C:29]([OH:31])=[O:30])=[CH:26][CH:27]=1)(=[O:20])=[O:21]
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: ClCc1cccs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C(Cc2cccs2)C(=O)O)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
DMPU (50 mL, 413 mmol) was added to a solution of LDA (65 mL of a 1.8M solution in n-C7H16-THF-PhEt, 117 mmol) in anhydrous THF (250 mL) at −78° C. The mixture was stirred for 1 h to generate a cream precipitate. A solution of (4-methanesulfonylphenyl)acetic acid (12.00 g, 56 mmol) in anhydrous THF (120 mL) was added over 20 min. More anhydrous THF (30 mL) was added, then the thick yellow slurry was stirred for 1 h. The mixture was treated with a solution of 2-chloromethylthiophene (7.50 g, 57 mmol) and PhMe (5.20 g, 57 mmol) in anhydrous THF (20 mL), then stirring was continued at −78° C. for 20 min. The reaction mixture was then allowed to warm to 20° C. over 16 h, before being quenched with H2O (500 mL). The THF was removed under reduced pressure, then 12M HCl was added to adjust the pH to 2. The mixture was extracted with EtOAc (2×300 mL), then the extracts were washed with H2O (2×200 mL) and brine (2×100 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (IH-EtOAc, 3:2 containing 0.5% AcOH) furnished the title compound: m/z (ES+)=638.3 [2M+NH4]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:32][CH3:33])=[CH:4][C:5]([C:10]2[CH:27]=[CH:26][C:13]([O:14][CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:12]([C:28]([F:31])([F:30])[F:29])[CH:11]=2)=[N:6][C:7]=1[C:8]#[N:9].Cl.[N:35]([O-])=O.[Na+]>O1CCOCC1.O>[C:8]([C:7]1[C:2]2[N:1]=[N:35][N:32]([CH3:33])[C:3]=2[CH:4]=[C:5]([C:10]2[CH:27]=[CH:26][C:13]([O:14][CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[C:12]([C:28]([F:29])([F:30])[F:31])[CH:11]=2)[N:6]=1)#[N:9]
Reactant: CNc1cc(-c2ccc(OCCN(C)C(=O)OC(C)(C)C)c(C(F)(F)F)c2)nc(C#N)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(CCOc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoro-methyl)phenoxy)ethyl(methyl)carbamate (7.43 mmol, 3.46 g) was dissolved in 1M Hydrochloric Acid (14.87 mmol, 14.87 ml) and Dioxane (5 ml). Sodium nitrite (10.41 mmol, 0.718 g) in Water (5.00 ml) was added to the reaction mixture and it was stirred at room temperature for 1 hr. The acetonitrile was removed and the reaction taken up in dioxane/water. The reaction mixture was filtered and the solid washed with water to afford tert-butyl 2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl(methyl)carbamate. (2.82 g)
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH2:19][CH2:20][CH3:21])[N:13]=1>C(Cl)Cl>[CH2:19]([S:18][C:14]1[N:13]=[C:12]([N:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[C:3]([OH:2])[C:4]=3[CH:5]=[N:6]2)[CH:17]=[CH:16][N:15]=1)[CH2:20][CH3:21]
Reactant: CCCSc1nccc(-n2ncc3c(OC)cccc32)n1
Solvent: ClCCl
Product: CCCSc1nccc(-n2ncc3c(O)cccc32)n1
Temperature: -78 °C

Procedure:
4-Methoxy-1-(2-propylsulfanyl-pyrimidin-4-yl)-1H-indazole was dissolved in methylene chloride (100 mL), and the mixture was cooled to −78° C. and stirred. BBR3 (152.62 uL) was added, and the mixture was allowed to stir overnight at room temperature. The mixture was partitioned between water and methylene chloride, and the combined organic layers were washed with water, saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 1-(2-propylsulfanyl-pyrimidin-4-yl)-1H-indazol-4-ol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][CH3:11])[N:3]=1.[NH2:12][NH2:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:9]([S:8][C:4]1[N:3]=[C:2]([NH:12][NH2:13])[CH:7]=[CH:6][N:5]=1)[CH2:10][CH3:11]
Reactant: CCCSc1nccc(Cl)n1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCSc1nccc(NN)n1
Temperature: 80 °C
Yield: 47.9 %

Procedure:
4-Chloro-2-propylsulfanyl-pyrimidine (15.03 g), hydrazine (10.69 g) and potassium carbonate (15.37 g) were added to ethanol (150 mL) and the mixture was heated to 80° C. for three hours. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed (CH2Cl2/hexanes through silica) to give 7.036 g of (2-propylsulfanyl-pyrimidin-4-yl)-hydrazine.