Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1
Reactant: CC1CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of 46.72 g (0.166 mole) of (rac)-2-chloro-9-cyclopentyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one in 1000 mL of dimethylformamide was added 81.32 g (0.25 mole) of cesium carbonate, followed by 70.88 g (0.499 mole) of methyl iodide. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed four times with water, once with brine and dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure to give 45 g of (rac)-2-chloro-9-cyclopentyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1). This material was used subsequent steps without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:18]C(C)([O-])C.[K+].CI.O>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1c2cc(Br)ccc2CC12CCC(O)CC2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 94 %

Procedure:
A mixture of isomers of 6′-bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 5 Step 2, 12.7 g, 43.0 mmol) was dissolved in THF (210 mL) under N2 and cooled to 0° C. Potassium tert-butoxide (5.79 g, 51.6 mmol) was added portionwise and the mixture was stirred at 0° C. for 25 min. Methyl iodide (4.30 mL, 68.8 mmol) was added. The cooling bath was removed, and the mixture was stirred at r.t. Additional potassium tert-butoxide (0.483 g, 4.30 mmol) was added twice, after 2 h and 3 h respectively, and then the mixture was stirred for 2 h. Water (100 mL) was added and the resulting solution was partitioned between aq. NaCl solution (200 mL), and EtOAc (200 mL). The aq. phase was extracted with another portion of EtOAc (100 mL). The combined organic phases were dried (MgSO4) and evaporated to give 12.5 g (94% yield) of a mixture (approx. 80:20) of:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][SH:14].[Na]>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:13]([S:14][CH:13](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: SCc1ccccc1Cl
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2)c2ccccc2Cl)c2ccccc2Cl)cc1

Procedure:
A solution of 4-fluorophenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-fluorostyryl 2-chlorobenzylsulfide. The title compound was obtained in 74% yield following oxidation. 1HNMR (CDCl3) δ 4.55 (2H, s), 6.66 (1H, d, JH,H=11.94), 7.20-7.65 (8H aromatic+1H ethylenic).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:32][CH:31]2[N:17]([C:18](=[O:44])[N:19]([CH3:43])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]3[C:28]([C:34]([NH:36][S:37]([CH:40]4[CH2:42][CH2:41]4)(=[O:39])=[O:38])=[O:35])([NH:29][C:30]2=[O:33])[CH2:27]3)[CH2:16]1.C[C:46]1[N:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1.[C:55](=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:55][C:48]1[CH:47]=[CH:46][N:51]=[CH:50][C:49]=1[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:32][CH:31]2[N:17]([C:18](=[O:44])[N:19]([CH3:43])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]3[C:28]([C:34]([NH:36][S:37]([CH:40]4[CH2:41][CH2:42]4)(=[O:39])=[O:38])=[O:35])([NH:29][C:30]2=[O:33])[CH2:27]3)[CH2:16]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1-c1cnccc1C
Temperature: 25 °C
Yield: 21.1 %

Procedure:
A solution of 51 (17.3 mg, 0.025 mmol), 6-methylpyridine-3-boronic acid (5.9 mg, 0.028 mmol), tetrakistriphenylphosphine palladium (8.2 mg, 0.005 mmol) and sodium carbonate (5.8 mg, 0.055 mmol) in DMF (2 mL) were warmed to 90° C. for 20 h. Then, the reaction mixture was cooled down to room temperature and the solvent was evaporated. The residue was purified by HPLC to yield 3.7 mg (21%) of the title product 52 as a white powder. m/z=703 (M+H)+; 1H-NMR (CDCl3): 10.6 (bs, 1H), 8.8 (s, 1H), 8.12 (d, J=9.1 Hz, 1H), 7.97 (d, J=6.3 Hz, 1H), 7.9 (d, J=9.0 Hz, 1H), 7.54 (d, J=6.3 Hz, 1H), 7.3 (d, J=9.0 Hz, 1H), 7.21 (d, J=9.1 Hz, 1H), 6.68 (br s, 1H), 5.87 (br s, 1H), 5.74 (dd, J=17.3 Hz, 8.3 Hz, 1H), 5.16 (t, J=10.4 Hz, 1H), 4.74 (dd, J=9.4 Hz, 7.3 Hz, 1H), 4.11-3.98 (m, 4H), 3.69-3.55 (m, 2H), 3.27-3.10 (m, 1H), 3.02-2.89 (m, 1H), 2.83 (s, 3H), 2.58-2.35 (m, 3H), 2.50 (s, 3H), 2.29-2.13 (m, 1H), 2.11-1.92 (m, 2H), 0.75-1.76 (m, 9H).
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:15])[CH3:14])[CH2:10][C:9]1=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([O:15][C:23](=[O:25])[CH3:24])[CH3:14])[CH2:10][C:9]1=[O:16])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(O)CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(C)CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-(t-butyldimethylsilyl)-4-(2-hydroxypropyl)-2-azetidinone (2.46 g) id dissolved in 20 ml CH2Cl2 cooled to 0° and treated with 0.90 g pyridine and 0.080 g of acetyl chloride (added dropwise). The reaction mixture is stirred at 0° for 15 min, allowed to warm to r.t. during the next 15 min and then worked up by dilution with CH2Cl2 and washing with water, drying and evaporating. The residue on chromatography on silica gel gives 1-(t-butyldimethylsilyl)-4-(2-acetoxypropyl)-2-azetidinone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([N+:16]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CN(C)C=O.[Pt]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([NH2:16])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Agent: [Pt]
Solvent: CN(C)C=O
Product: Nc1cc(OCc2ccccc2)ccc1O
Reaction time: 12 h

Procedure:
50 g. 4-benzyloxy-2-nitrophenol [U.S. Pat. No. 4,603,2091] (Compound XXII) is dissolved in 100 mL dimethylformamide to give a yellow solution which is shaken in the presence of 5% platinum on charcoal under 40 psi pressure of hydrogen. After 12 hours, the reduction is colorless and is filtered through diatomaceous earth to remove the catalyst. The clear filtrate is diluted to 800 mL with ethyl acetate and is washed three times with 500 mL water. The organic layer is evaporated to yield a clear oil, which is triturated with cold methanol and filtered to give 4-benzyloxy-2-aminophenol as a gray solid (Compound XXIII).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:5]=1)(O)=[O:2].S(Cl)([Cl:25])=O>>[ClH:25].[Cl:25][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cn(-c2cnc3ccccc3c2)c2ccccc12
Product: Cl
Product: O=C(Cl)c1cn(-c2cnc3ccccc3c2)c2ccccc12

Procedure:
10 cm3 of thionyl chloride are added at 22° C. under an argon atmosphere to 1 g (2.3 mmol) of 3-carboxy-1-(quinol-3-yl)-1H-indole. After stirring at reflux for 1.5 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated twice with 10 cm3 of dimethoxyethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1 g of 3-chlorocarbonyl-1-(quinol-3-yl)-1H-indole hydrochloride in the form of an orange-coloured solid which is used directly in the following step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[O:8])[CH:2]=1.S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22].[OH-].[NH4+]>>[Cl:15][C:10]1[CH:11]=[CH:12][C:13]([N+:21]([O-:23])=[O:22])=[CH:14][C:9]=1[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:8]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1cccnc1)c1ccccc1Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=C(c1cccnc1)c1cc([N+](=O)[O-])ccc1Cl
Yield: 94.2 %

Procedure:
To a mixture of o-chlorophenyl 3-pyridyl ketone (10.0 g, 0.460 mol) and concentrated sulfuric acid at 0° C. is added dropwise a mixture of 90% nitric acid (2.40 ml) and concentrated sulfuric acid (6.0 ml). The resultant mixture is stirred one hour at 0° C., poured onto ice and neutralized with 30% ammonium hydroxide. Filtration and drying affords the title compound as a solid (11.4 g, 94.2%) which is identified by mass spectral analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]([O:20]CC)=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+].O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([F:17])([F:15])[F:16])[N:11]=[C:10]([C:18]([OH:20])=[O:19])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n(CC(F)(F)F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(-c2ccc(F)cc2)n(CC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.54 g ethyl 5-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylate (1.7 mmol) and 0.21 g lithium hydroxide monohydrate (5.09 mmol) in 5 ml THF, 5 ml MeOH, and 2 mL water was stirred at room temperature for 2 h. The reaction was acidified with 1N HCl, was extracted with methanol/dichloromethane, dried over Na2SO4 and evaporated to provide 5-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylic acid as a white solid. LCMS (method A) 289.2 (M+H), 287.3 (M−H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([CH2:9][C:10](OC)=[O:11])#[N:8]>>[N:1]1([C:10](=[O:11])[CH2:9][C:7]#[N:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC#N
Reactant: C1COCCN1
Product: N#CCC(=O)N1CCOCC1
Temperature: 55 °C
Yield: 90.2 %

Procedure:
A nitrogen inerted reactor equipped with reflux condenser, nitrogen inlet and mechanical stirring is charged with morpholine (1.2 mol), methyl cyanoacetate (1.0 mol) and MtBE (52 mL). The homogeneous solution is heated to ca. 55° C. and stirred at that temperature for 12 to 18 hours. MtBE (33 mL) is added over ca. 15 minutes, and the solution is slowly cooled below 50° C. where nucleation becomes evident. Additional MtBE (66 mL) is added over a 1-hour period. During this time, the reaction is allowed to cool to near ambient temperature. After complete MtBE addition, the reaction is cooled with stirring to ca. 0° C. The resulting precipitate is collected via filtration and the cake is washed with additional MtBE (ca. 40 mL). The solid is dried under vacuum at ca. 45° C. to provide 3-morpholin-4-yl-3-oxo-propionitrile (139 g). This material is used in subsequent steps without further purification.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1I.[Br-].[CH:17]1([Zn+])[CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>>[CH:17]1([C:5]2[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:4]=2[C:3]([OH:2])=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1I
Reactant: [Zn+]C1CCCC1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(C(F)(F)F)cc1C1CCCC1

Procedure:
In analogy to the procedure described for the synthesis of example B.10, the title compound was prepared from 2-iodo-4-trifluoromethyl-benzoic acid methyl ester and cyclopentyl zinc bromide followed by saponification with sodium hydroxide. MS (m/e): 257.0 (M−H).
Reaction SMILES: F[C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4](O)[CH:5]=[CH:6][C:7]=1[F:8].O[CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15]1.[H-].[Na+].[C:23](O)(=[O:25])C>C1COCC1.CO>[F:8][C:7]1[CH:2]=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=[CH:5][C:6]=1[O:25][CH2:23][CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15]1
Reactant: CN1CCCC(O)C1
Reactant: O=[N+]([O-])c1c(O)ccc(F)c1F
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCCC(COc2ccc([N+](=O)[O-])cc2F)C1
Temperature: 60 °C

Procedure:
Alternatively, the nitro derivative was prepared as follows: 3,4-Difluoronitro phenol (3 g, 18.7 mmol) and 3-hydroxy-1-methylpiperidine (2.5 g, 19.3 mmol) were dissolved in dry THF (100 mL) under nitrogen. Sodium hydride (60%, 1 g, 25 mmol) was slowly added under positive nitrogen pressure. The resulting light yellow solution was heated at 60° C. for 2.5 h. The dark-red solution was left to cool to room temperature and quenched with a solution of acetic acid (0.3 mL, 5.2 mmol) in methanol (10 mL). Solvent was removed under reduced pressure to yield an orange solid that was purified by column chromatography using DCM: MeOH (75: 25) as eluent to yield 3-(2-fluoro-4-nitro phenoxymethyl)-1-methylpiperidine as an orange oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CCO.C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCC#Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C#CCCC(=O)O)cc2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of methyl 5-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-4-pentynoate (243) (0.16 g, 0.38 mmol) in a mixture of EtOH (5 mL) and THF (5 mL) was added an aqueous solution of 1N NaOH (6 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Concentration gave a white residue, which was triturated with hot hexanes containing 1% MeOH to yield the title compound (244) as white solid (0.15 g, 95%), mp 233-234° C. 1H NMR (400 MHz, CH3OH-d6): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.29 (s, 2H), 1.94 (s, 2H), 1.98 (s, 2H), 2.50-2.60 (m, 2H), 2.60-2.70 (m, 2H), 6.68 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 7.07 (d, J=8.3 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H). LCMS (ESI): m/z 417 (M+H)+, 415 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:28].Br[C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>>[CH3:8][C:7]1[CH:6]=[C:5]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[CH:4]=[C:3]([CH3:28])[C:2]=1[O:1][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: Cc1cc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc(C)c1OC(C)(C)C(=O)OC(C)(C)C

Procedure:
Tert-butyl 2-(2,6-dimethyl-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoate is prepared from 3-(4-hydroxy-3,5-dimethylphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one according to general procedure D, using 15 equivalents of tert-butyl bromoisobutyrate and 15 equivalents of potassium carbonate added in portions of 3 equivalents in the course of the reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:24])[N:12]([CH3:23])[C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][CH:15]=1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[CH:32]=[C:33]([I:35])[S:34][C:27]=12>CN(C1C=CN=CC=1)C.BrC1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:26]2[CH:31]=[CH:30][N:29]=[C:28]3[CH:32]=[C:33]([I:35])[S:34][C:27]=23)[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:24])[N:12]([CH3:23])[C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][CH:15]=1
Reactant: Cn1c(Nc2ccccc2)ncc(-c2cc(F)c(O)cc2F)c1=O
Reactant: Clc1ccnc2cc(I)sc12
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Product: Cn1c(Nc2ccccc2)ncc(-c2cc(F)c(Oc3ccnc4cc(I)sc34)cc2F)c1=O

Procedure:
A mixture of 5-(2,5-difluoro-4-hydroxyphenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.031 g, 0.093 mmol), 7-chloro-2-iodothieno[3,2-b]pyridine (0.025 g, 0.085 mmol; prepared according to the procedure of Ragan, J. A. Org. Proc. Res. 2003, 7, 676) and DMAP (0.010 g, 0.085 mmol) in bromobenzene (1.5 mL) under nitrogen was stirred at 150° C. for 6 days. The reaction was concentrated in vacuo to remove as much bromobenzene as possible and then purified directly by flash column chromatography, eluting with 20:1 CH2Cl2/MeOH. The product was obtained (10.5 mg; 21%) as a yellow solid. LRMS (APCI pos) m/e 589 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.C(OCC)C.[B:30](OC)([O:33]C)[O:31]C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[B:30]([OH:33])[OH:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(OCc2ccccc2)c(I)c1
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
A solution of 4-benzyloxy-3-iodobenzotrifluoride (15.07 g, 39.85 mmol) in tetrahydrofuran (200 ml) was cooled to −40° C. with stirring under nitrogen. 2M isopropylmagnesium chloride in diethyl ether (39.85 ml, 79.7 mmol) was added dropwise and the mixture stirred at −40° C. for 40 minutes, then cooled to −75° C. Trimethyl borate (8.3 g, 9.2 ml, 79.7 mmol) was added at −75° C. over 10 minutes and the reaction stirred and allowed to reach 0° C. over 1 h. 1M hydrochloric acid (200 ml) was added and the mixture stirred vigorously for 1 h.
Reaction SMILES: C[O:2][C:3](=[O:52])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[C:44](=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:72][C:73]([CH3:78])([CH3:77])[CH2:74][CH2:75][OH:76].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[C:44]([N:24]1[C@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=3[CH3:19])=[CH:8][CH:7]=2)[C:3]([OH:52])=[O:2])=[O:22])[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:76][CH2:75][CH2:74][C:73]([CH3:78])([CH3:77])[CH3:72])=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25]1)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(O)cc1)CO3
Reactant: CC(C)(C)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3ccccc3)O[C@@H](c3ccc(OCCC(C)(C)C)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-2-{[(3S,8S)-7-Benzoyl-3-(4-hydroxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (18 mg) was dissolved in DCM, triphenyl phosphine (5.9 eq.). 3,3-Dimethyl-butan-1-ol (excess) added and mixture cooled on ice. DIAD (5.1 eq.) was added and the reaction mixture stirred on ice for 10 minutes and rt for 16 hours. The reaction mixture was directly purified over silica (DCM-EtOAc 8:2 to DCM-EtOAc 6:4). The resulting residue was hydrolyzed according to General Procedure B and purified over silica (DCM to DCM+1% MeOH to DCM+7% MeOH) to give the title compound (11 mg). LCMS (m/z): 769.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:7](=[O:20])[C@@H:6]([CH3:21])[NH:5][C:4]=2[N:3]=1.[CH:22]1([CH2:26]Br)[CH2:25][CH2:24][CH2:23]1.[H-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:7](=[O:20])[C@@H:6]([CH3:21])[N:5]([CH2:26][CH:22]3[CH2:25][CH2:24][CH2:23]3)[C:4]=2[N:3]=1
Reactant: C[C@H]1Nc2nc(Cl)ncc2N(c2cccc(C#N)c2)C1=O
Reactant: BrCC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1C(=O)N(c2cccc(C#N)c2)c2cnc(Cl)nc2N1CC1CCC1
Temperature: 25 °C
Yield: 41 %

Procedure:
To a stirred solution of 3-[(7R)-2-chloro-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile (120 mg, 0.4 mmol) in anhydrous DMF (3 ml) was added cyclobutyl methyl bromide (119 mg, 0.8 mmol) at 0° C. under nitrogen. To the resulting solution was added sodium hydride (32 mg of 60% dispersion in oil, 0.8 mmol) at 0° C. The reaction was then allowed to warm up to rt in 20 min and then heated at 50° C. for 3 h. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (30 mL×3). The organic layers were combined, dried (Na2SO4) and evaporated to give a crude residue, which was then purified by silica gel flash chromatography (eluent: 2% methanol in dichloromethane) to give desired product (Yield: 41%). 1HNMR (300 MHz, CDCl3) δ 1.50 (d, J=6.9 Hz, 3H), 1.78-1.94 (m, 4H), 1.96-2.21 (m, 2H), 2.68-2.87 (m, 1H), 3.17 (q, J=6.9 Hz, 1H), 4.22-4.36 (m, 2H), 7.10 (s, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.58 (s, 1H), 7.66-7.78 (m, 1H) and 7.79-7.81 (m, 1H).