Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H]1COC(=O)N1C(=O)[CH2:15][C@@H:16]([C:22]1[CH:49]=[CH:48][C:25]([O:26][CH2:27][C:28]2[CH:29]=[C:30]([NH:34][S:35]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)C1C=CC=CC=1.[OH:51]O.[Li+].[OH-].Cl.C1[CH2:60][O:59]CC1>O>[F:46][C:44]([F:45])([F:47])[C:41]1[CH:40]=[CH:39][C:38]([S:35]([NH:34][C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[CH2:27][O:26][C:25]2[CH:48]=[CH:49][C:22]([C@@H:16]([C:17]3[CH:21]=[CH:20][O:19][N:18]=3)[CH2:15][C:60]([OH:59])=[O:51])=[CH:23][CH:24]=2)(=[O:37])=[O:36])=[CH:43][CH:42]=1
Reactant: O=C(C[C@@H](c1ccc(OCc2cccc(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)c2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OO
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C[C@@H](c1ccc(OCc2cccc(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)c2)cc1)c1ccon1
Reaction time: 1 h

Procedure:
To a solution of the oxazolidinone (32.1) (17.0 mg, 0.0241 mmol) dissolved in THF (2 mL), was added a 30% hydrogen peroxide solution (27.0 μL, 0.241 mmol) followed by a 2 M LiOH solution (60.0 μL, 0.121 mmol). The resulting slurry was stirred for one hour. The reaction mixture was then diluted with water and acidified with hydrochloric acid to pH 3. The mixture was then extracted with EtOAc (1×20 mL), and the organic layer was washed with an acidic sodium sulfite solution (2×15 mL) and brine (1×15 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 32 (6.00 mg). MS ESI (pos.) m/e: 547.0 (M+H). 1H NMR (400 MHz, CD3CN) δ ppm 8.32 (1 H, d, J=1.6 Hz), 7.81 (2 H, d, J=8.2 Hz), 7.69 (2 H, d, J=8.2 Hz), 7.04-7.23 (5 H, m), 6.95 (1 H, d, J=7.8 Hz), 6.79 (2 H, d, J=9.0 Hz), 6.15 (1 H, d, J=1.6 Hz), 4.91 (2 H, s), 4.44 (1 H, t, J=7.8 Hz), 3.08 (1H, dd, J=16.4, 8.2 Hz), 2.83 (1 H, dd, J=16.4, 7.4 Hz). 6.28 Example 33
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].[Cl:8][CH2:9][CH2:10][CH2:11][C:12]#N.Cl.CC[O:17]CC>>[Cl:8][CH2:9][CH2:10][CH2:11][C:12](=[O:17])[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOCC
Reactant: CCCCCBr
Reactant: N#CCCCCl
Agent: Cl
Agent: [Mg]
Product: CCCCCC(=O)CCCCl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the Grignard reagent prepared from a mixture of amyl bromide (226.59 g.; 1.5 moles) and magnesium (36.48 g.; 1.5 moles) in ether (1000 ml.) is added, dropwise, during one hour, 4-chlorobutyronitrile (155.34 g.; 1.5 moles). Stirring is continued for an additional one hour. The reaction mixture is poured into a mixture of finely crushed ice (1000 g.) and concentrated hydrochloric acid (750 ml.). The ether layer is separated quickly and discarded. The aqueous layer is heated on a steam bath for one hour to hydrolyze the intermediate imine and cause the separation of the ketone as an oil. After cooling, the oil is extracted with ether and the combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed under vacuum and the residual oil is distilled to give 69.0 g. (26%) of colorless oil, b.p. 115°-117°/14 mm.; pmr (CDCl3) δ 0.90 (3H,t), 3.56 (2H,t,CH2Cl).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.CN.CC(O)=O.[BH3-][C:19]#[N:20].[Na+]>CO>[CH3:19][NH:20][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=Cc1cc2ccccc2o1
Agent: CN
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.2 %

Procedure:
To a stirred solution of 2-benzofurancarboxaldehyde (2.22 g, 15.2 mmole) in MeOH (5 mL) was added 2 M methylamine in MeOH (15 mL), HOAc (0.86 mL, 15 mmole), and NaBH3CN (1.0 g, 15.9 mmole). The reaction was stirred for 18 h at RT then concentrated under vacuum. The remaining residue was taken up in Et2O, and the solution was washed with 1 N NaOH then brine, dried (Na2SO4), and concentrated to dryness. Purification by flash chromatography on silica gel (5% (5% NH4OH in MeOH)/CHCl3) gave the title compound (1.23 g, 50%) as a pale yellow oil: MS (ES) m/e 162.4 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([CH:10](O)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1>>[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([CH:10]([Cl:3])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1

Procedure:
Forty-two milliliters of thionyl chloride were gradually added to 75 g of 4,4'-dichlorobenzhydrol. When the addition was complete, the reaction was heated on a steam bath for 2 hours. The excess thionyl chloride was removed in vacuo. One hundred milliliters of carbon tetrachloride were added, and the solvent was again evaporated. The carbon tetrachloride treatment was repeated and upon evaporation the resulting oil was crystallized from peotroleum ether to provide 65.3 g of the desired sub-titled intermediate, m.p. 63° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7](B3OC(C)(C)C(C)(C)O3)[CH:8]=[CH:9][C:2]1=2.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[C:28]2[CH3:32])[N:23]=[N:24][CH:25]=1>>[ClH:19].[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:20]3[CH:21]=[C:22]([CH2:26][N:27]4[CH:31]=[CH:30][N:29]=[C:28]4[CH3:32])[N:23]=[N:24][CH:25]=3)[CH:8]=[CH:9][C:2]1=2
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: CC1(C)OB(c2ccc3sccc3c2)OC1(C)C
Product: Cc1nccn1Cc1cc(-c2ccc3sccc3c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=307.3 (M+H+), was prepared from 2-benzo[b]thiophen-5-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: FC(F)(F)C([NH:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH:16]([CH3:18])[CH3:17])[CH:13]=2)[C@H:8]([OH:19])[CH2:7]1)=O.C([O:25]C1C=C(C=CC=1)C=O)(C)C.C(O)(=O)CC(O)=O.C([O-])(=O)C.[NH4+]>C(O)C.CO.C(Cl)Cl>[NH2:5][CH:6]([C:14]1[CH:9]=[CH:10][CH:11]=[C:12]([O:15][CH:16]([CH3:17])[CH3:18])[CH:13]=1)[CH2:7][C:8]([OH:19])=[O:25]
Reactant: CC(C)Oc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)C[C@H]2O
Reactant: CC(C)Oc1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: O=C(O)CC(=O)O
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CC(C)Oc1cccc(C(N)CC(=O)O)c1
Yield: 62 %

Procedure:
Step AU (2). A solution of 3-isopropoxybenzaldehyde (77 g, 470 mmol), malonic acid (52 g, 496 mmol) and ammonium acetate (65 g, 844 mmol) in 1.0 L of ethanol was refluxed at 120° C. for 24 h. The solvent was evaporated in vacuo. The residue was purified using silica-gel column chromatography with (100% EtOAc, then 30% methanol/methylene chloride) to afford 65 g (62% yield) of 3-amino-3-(3-isopropoxyphenyl)propanoic acid as a white solid. LC-MS (M+H)+=224.14. 1H NMR (300 MHz, DMSO-d6) δ 1.2-1.3 (d, 6H) 2.4-2.5 (m, 2H) 4.2-4.4 (m, 1H) 4.5-4.7 (m, 1H) 6.8-6.9 (m, 1H) 6.9-7.0 (m, 2H) 7.2-7.3 (m, 1H).
Reaction SMILES: [OH:1][C:2](=[C:17]1[C:22](=[O:23])[CH2:21][C:20]([CH3:25])([CH3:24])[CH2:19][C:18]1=[O:26])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]CC1C=CC=CC=1)=[O:8]>CO.[Pd]>[OH:1][C:2](=[C:17]1[C:18](=[O:26])[CH2:19][C:20]([CH3:24])([CH3:25])[CH2:21][C:22]1=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC1(C)CC(=O)C(=C(O)CCCCC(=O)OCc2ccccc2)C(=O)C1
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(=O)C(=C(O)CCCCC(=O)O)C(=O)C1
Yield: 97.8 %

Procedure:
Benzyl 6-hydroxy-6-(4,4-dimethyl-2,6-dioxocyclo-hexylidene)-hexanoate (1.50 g, 4.19 mmol) was hydrogenated over Pd/C (10%) (150 mg) in MeOH (20 ml) at room temperature for 10 hours. The catalyst was filtered off, and the filtrate was evaporated, yielding 6-hydroxy-6-(4,4-dimethyl-2,6-dioxocyclohexylidene)-hexanoic acid (1.10 g, 98%);
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]([NH2:17])[CH2:6][C:7]([F:16])([F:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(NC(C)C)(C)C.[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>ClCCl.O>[CH3:2][O:3][C:4](=[O:18])[C@@H:5]([NH:17][C:32]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:33])[CH2:6][C:7]([F:16])([F:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COC(=O)[C@@H](N)CC(F)(F)Cc1ccccc1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.5 %

Procedure:
To a mixture of (S)-2-amino-4,4-difluoro-5-phenyl-pentanoic acid methyl ester hydrochloride (2.50 g, 8.94 mmol) and diisopropyl amine (22.3 mmol, 2.89 g) in dry dichloromethane (40 mL) under N2 is added drop wise morpholine carbonyl chloride (13.4 mmol, 2.0 g). The mixture is stirred at room temperature for 15 hours, and then diluted with water (50 mL). The aqueous layer is extracted with dichloromethane (30 mL). The organic layers are dried over magnesium sulfate and then concentrated in vacuum. Purification over 110 g silica gel, eluting with EtOAc:Heptane (1:1, then 2:1) affords (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-5-phenyl-pentanoic acid methyl ester (2.82 g, 88.5%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[CH:10][S:11][C:4]=2[S:3]1(=[O:13])=[O:12].[CH2:14]([N:21]=[C:22]=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[S:11][CH:10]=[CH:9][C:5]=2[C:6]=1[C:22](=[O:23])[NH:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1C(=O)Cc2ccsc2S1(=O)=O
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(O)=C(C(=O)NCc2ccccc2)c2ccsc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature for 3 hours under nitrogen with 0.61 g (4.6 mmol) of benzylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml of methylene chloride. The combined organic phases are dried over sodium sulfate, whereupon the solvent is distilled off. For purification, the product is recrystallized from ca 40 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-benzylcarbamoyl-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide of melting point 176°-177° C.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]2[CH2:15]Br.[OH:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:13])([F:12])[F:14])[CH:7]=[C:6]2[CH2:15][O:25][CH2:26][C:27]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: C[Si](C)(C)CCOCn1nc2c(CBr)cc(C(F)(F)F)cc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3c(Br)n(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Bromo-7-(bromomethyl)-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (140 mg, 0.29 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (75 mg, 0.26 mmol) were combined in dimethylformamide (2 mL) and cooled to 0° C. The reaction was treated with sodium hydride (14 mg, 0.57 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (10%→20% ethyl acetate/hexanes) gave 101 mg (50%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 7.86 (s, 1H), 7.44 (s, 1H), 7.14-7.18 (m, 5H), 5.26 (s, 2H), 4.68 (s, 2H), 3.69 (m, 2H), 3.44 (s, 2H), 3.38-3.41 (m, 2H), 2.98-3.02 (m, 2H), 2.11-2.14 (m, 2H), 1.72-1.77 (m, 2H), 1.41 (s, 9H), 0.74-0.77 (m, 2H), 0.10 (s, 9H). Mass spec.: 700.11 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.C(=O)([O-])[O-].[K+].[K+]>>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:18]3[O:20][CH2:19]3)=[CH:11][CH:10]=2)[N:5]=1
Reactant: ClCC1CO1
Reactant: Cc1cc(C)nc(-c2ccc(O)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(C)nc(-c2ccc(OCC3CO3)cc2)n1

Procedure:
4,6-dimethyl-2-(4-hydroxyphenyl)-pyrimidine is reacted with epichlorohydrin in the presence of potassium carbonate analogously to Example 5b). After working up, 4,6-dimethyl-2-[4-(2,3-epoxypropoxy)-phenyl]-pyrimidine is obtained which, after recrystallisation from isopropanol, has a melting point of 88°-90°.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[O:4][C:3]1=[O:9].[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([Cl:19])[CH:12]=1.ClC1C=C(NC(=O)C(C)CCC(O)=O)C=CC=1C#N>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[Cl:19][C:13]1[CH:12]=[C:11]([NH:10][C:5](=[O:8])[CH2:6][CH2:7][CH:2]([CH3:1])[C:3]([OH:4])=[O:9])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: CC1CCC(=O)OC1=O
Agent: CC(CCC(=O)O)C(=O)Nc1ccc(C#N)c(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CCC(=O)Nc1ccc(C#N)c(Cl)c1)C(=O)O
Yield: 39 %

Procedure:
A solution of 3-methyldihydro-2H-pyran-2,6(3H)-dione (876 mg, 6.84 mmol), 4-amino-2-chlorobenzonitrile (1044 mg, 6.84 mmol) and TEA (0.953 mL, 6.84 mmol) in toluene (10 mL) was stirred at 70° C. for 3 hr. To the reaction mixture was added brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by COOH-silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give a mixture (750 mg, 2.67 mmol, 39.1%) of 5-((3-chloro-4-cyanophenyl)amino)-2-methyl-5-oxopentanoic acid and 5-((3-chloro-4-cyanophenyl)amino)-4-methyl-5-oxopentanoic acid, as a colorless powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])=[C:15]([F:29])[CH:14]=2)[N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.CC[N:43]([CH:47]([CH3:49])[CH3:48])C(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[CH:47]1([NH:43][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[O:22])=[C:15]([F:29])[CH:14]=3)[N:3]=2)[CH2:49][CH2:48]1
Reactant: COc1cc(C(=O)N2CCOCC2)c(F)cc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCOCC2)c(F)cc1Nc1ncc(C(F)(F)F)c(NC2CC2)n1
Temperature: 100 °C
Yield: 32.9 %

Procedure:
To a solution of (4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)-(morpholino)methanone (120 mg, 0.28 mmol) in dioxane (2 mL) was added pTSA (52 mg, 0.28 mmol) and D4-cyclopropylamine (17 mg, 0.28 mmol). The mixture was heated to 100° C. for 2 hours. LSMS of crude sample indicated only 10% of desired material. DIPEA (100 μL, 0.56 mmol) and D4-cyclopropylamine (17 mg, 0.28 mmol) were added and the mixture was heated to 100° C. for one hour. After return to room temperature, DCM (20 mL) and saturated aqueous sodium bicarbonate solution (15 mL) were added. The separated organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by reversed phase HPLC to give (4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)-methanone (42 mg, 33%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=460 at 3.41 min. 1H NMR (400 MHz, CDCl3): δ 8.77 (d, J=12.8 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 6.91 (d, J=5.6 Hz, 1H), 5.48 (s, 1H), 3.92 (s, 3H), 3.80-3.74 (m, 4H), 3.69-3.67 (m, 2H), 3.44-3.43 (m, 2H).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2]1.[CH:19](=O)[CH2:20][CH2:21][CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[CH2:19]([N:9]1[CH2:10][CH2:11][C:6]2([CH2:1][CH2:2][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCC=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CCCCN1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (150 mg, 0.59 mmol) was dissolved in 10 ml of absolute dichloromethane and admixed with butyraldehyde (52 μl, 1 eq.). With ice bath cooling, 17 μl of glacial acetic acid (0.5 eq.) and sodium triacetoxyborohydride (137 mg, 1.1 eq.) were added. The mixture was stirred at RT for 16 h. Owing to incomplete reaction, butyraldehyde (52 μl, 1 eq.), glacial acetic acid (17 μl, 0.5 eq.) and sodium triacetoxyborohydride (137 mg, 1.1 eq.) were again added. After stirring at RT for a further 4 h, a little water was added and the reaction mixture was washed with saturated NH4Cl solution. The organic phase was dried over MgSO4 and freed from the solvent under reduced pressure. The product was obtained as a colorless oil.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: c1ccc(-n2nnc3c2CCNC3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(nnn2-c2ccccc2)C1
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A solution of 1-phenyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (17 mg, 0.085 mmol) and 2-chloro-3-(trifluoromethyl)benzoic acid (21 mg, 0.093 mmol) in DCM (8 mL) was treated with Et3N (35 μL, 0.25 mmol) followed by HATU (38 mg, 0.1 mmol). The reaction was stirred overnight, then concentrated to minimum volume and purified on 16 g SiO2 with 0-3.5% NH3 in MeOH/CH2Cl2 to give 32 mg (91%) of 5-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-1-phenyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine. MS (ESI): mass calcd. for C19H14ClF3N4O, 406.1. m/z found, 407.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.84-7.75 (m, 1H), 7.62-7.43 (m, 7H), 5.11 (q, J=16.5 Hz, 1H), 4.64-4.45 (m, 1H), 4.32 (dt, J=13.2, 5.4 Hz, 0.5H), 4.05-3.95 (m, 0.5H), 3.65-3.48 (m, 1H), 3.04 (t, J=5.9 Hz, 1H), 3.01-2.76 (m, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]3[C@H:18]4[C@H:28]([CH2:29][CH2:30][C@:13]23[CH3:14])[C@:26]2([CH3:27])[C@H:21]([CH2:22][C:23](=[O:31])[CH2:24][CH2:25]2)[CH2:20][CH2:19]4)=[O:11])[CH2:3][CH2:2]1.C(O)(C)C.C(N(CC)CC)C>O>[OH:31][C@@H:23]1[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@@H:21]([CH2:20][CH2:19][C@@H:18]3[C@@H:28]2[CH2:29][CH2:30][C@@:13]2([CH3:14])[C@H:15]3[CH2:16][CH2:17][C@@H:12]2[C:10]([O:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:11])[CH2:22]1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)OCCN3CCOCC3)CC[C@@H]12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)OCCN3CCOCC3)CC[C@@H]12
Yield: 72.3 %

Procedure:
A solution of 17β(2'-morpholinoethoxycarbonyl)-5α-androstan-3-one (750 mg.) in the minimum volume of isopropanol was added to a stock solution (35 ml.) of chloroiridic acid/trimethyl phosphite complex preneutralised to pH5 with triethylamine (3 ml.). This solution, after being refluxed for 4.5 hours, was poured into water and extracted with chloroform. The chloroform solution was washed with water, dried (MgSO4) and filtered through a short column of florisil before evaporation to a gum (740 mg.). Purification by preparative t.l.c. (ethanol/chloroform 1:19) afforded title compound (545 mg.) as a white froth; [α]D + 37.8, (c 0.9%).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[C:42](Cl)([O:44]C(=O)OC(Cl)(Cl)Cl)Cl.[O:53]1[CH2:58][CH2:57][CH:56]([NH2:59])[CH2:55][CH2:54]1.C(=O)(O)[O-].[Na+]>ClCCl.C(N(CC)CC)C>[NH:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([NH:34][C:42]([NH:59][CH:56]3[CH2:57][CH2:58][O:53][CH2:54][CH2:55]3)=[O:44])=[CH:35][CH:36]=2)[N:22]=[CH:21]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC1CCOCC1
Reactant: Nc1ccc(CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CCOc2ccccc2-c2c[nH]cn2)cc1)NC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
4-(2-(2-(1-trityl-1H-imidazol-4-yl)phenoxy)ethyl)aniline (50.0 mg. 0.096 mmol) was dissolved in dichloromethane (DCM, 5 ml) and triethylamine (1 ml), and a solution of triphosgene (0.105 mmol) in DCM (5 ml) was then added to the solution at 0° C. The mixture was stirred at room temperature under N2 for 2 h. Next, tetrahydro-2H-pyran-4-amine (20.0 mg, 0.192 mmol) was added to the reaction solution, and the mixture was stirred at room temperature under N2 for overnight. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with DCM (3×15 ml). The DCM layer was dried over Na2SO4. The solvent was removed by distillation under the reduced pressure. The residue was dissolved in MeOH/AcOH (4:1, 4 mL) and heated at 80° C. for 2 h. The reaction mixture was basified with aqueous 10% NaOH and the aqueous layer extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography. Yield=78%. 1H NMR (MeOH-d4): 1.40-1.54 (m, 2H), 1.81-1.92 (m, 2H), 3.11-3.15 (m, 2H), 3.46-3.53 (m, 2H), 3.55-3.80 (m, 1H), 3.85-3.95 (m, 2H), 4.35 (t, 2H, J=6.6 Hz), 6.95-7.00 (m, 1H), 7.05-7.13 (m, 2H), 7.19-7.30 (m, 5H), 7.70 (s, 1H), 7.78 (d, 1H, J=7.8 Hz).