Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([O:21]C(C)C)[C:18]([Br:25])=[CH:17][C:16]=2[F:26])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:2].S(=O)(=O)(O)O>>[CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([OH:21])[C:18]([Br:25])=[CH:17][C:16]=2[F:26])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=1)[CH3:2]
Reactant: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC(C)C)c(Br)cc1F
Agent: O=S(=O)(O)O
Product: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Br)cc1F

Procedure:
using 2-ethoxy-1-(4-bromo-2-fluoro-5-isopropoxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone with concentrated sulphuric acid during 2 minutes at 0° C. there is obtained 2-ethoxy-1-(4-bromo-2-fluoro-5-hydroxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 160°-161° C.
Reaction SMILES: I[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]([C:18]12[CH2:25][CH2:24][CH2:23][N:22]1[CH2:21][CH2:20][CH2:19]2)#[CH:17].Cl>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:19]1[C:18]2([C:16]3[O:8][C:7]4[C:2](=[N:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=3)[N:22]([CH2:23][CH2:24][CH2:25]2)[CH2:21][CH2:20]1
Reactant: Oc1cccnc1I
Reactant: C#CC12CCCN1CCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1cnc2cc(C34CCCN3CCC4)oc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-Iodo-3-pyridinol (902 mg, 4.1 mmol), copper(I) iodide (116 mg, 0.61 mmol), bis(triphenylphosphine)palladium(II) chloride (119 mg, 0.17 mmol) and triethylamine (570 mL, 4.1 mmol) were combined in DMF (4.5 mL) and stirred for one hour. 7a-Ethynyl-hexahydro-1H-pyrrolizine(460 mg, 3.4 mmol) in DMF (1.2 mL) was added dropwise and the mixture was heated at 60° C. for 18 h. The reaction mixture was allowed to cool to ambient temperature and 2 N aqueous HCl was added. The heterogeneous mixture was washed with Et2O (2×), basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The CH2Cl2 extracts were combined, dried (MgSO4) concentrated and chromatographed (silica gel; CHCl3 /MeOH, 96:4) to afford an amber oil which solidified upon storage at -20° C. (405 mg, 52%): mp 39-41° C.; 1H NMR (CDCl3, 300 MHz) δ 1.86-1.97 (m, 6H), 2.24-2.34 (m, 2H), 2.68-2.76 (m, 2H), 3.21-3.28 (m, 2H), 6.77 (s, 1H), 7.12 (dd, J=8.5, 5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 8.46 (d, J=5 Hz, 1H); MS (CI/NH3) m/z: 229 (M+H)+.
Reaction SMILES: C([Li])(C)(C)C.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=1[O:21][CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[O:30])[CH:24]=1.Cl>O1CCCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:29]([C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[OH:30])=[CH:16][C:15]=1[O:21][CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc(Br)ccc1OCc1ccccc1
Reactant: O=Cc1cccnc1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cccnc2)ccc1OCc1ccccc1
Reaction time: 2 h

Procedure:
aa) 10 ml of tert.butyl lithium solution (1.4M in hexane) are added dropwise at -70° within 10 minutes to 4.1 g of 4-(benzyloxy)-3-methoxy-bromobenzene dissolved in 40 ml of tetrahydrofuran. After stirring at -70° for 2 hours. 1 ml of pyridine-3-carbaldehyde is added within 5 minutes. The reaction mixture is stirred at -70° for 1 hour and at 0° for 2 hours, and poured into 100 ml of 1N hydrochloric acid. The mixture is extracted three times with 50 ml of ether each time. The combined ether phases are washed with 100 ml of 1N hydrochloric acid and 20 ml of water. The combined aqueous phases are made alkaline with aqueous ammonia solution and extracted three times with 100 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated. There is obtained alpha-[4-(benzyloxy)-3 -methoxyphenyl]-3-pyridinemethanol as an oil.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:34])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[CH2:25][CH3:26])[C:5]1=[O:33])[CH:2]=[CH2:3].[CH3:35][Mg]Br>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:34])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])([CH3:35])[CH3:31])[CH2:25][CH3:26])[C:5]1=[O:33])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCCC(C)=O)C1=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCCC(C)(C)O)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-7-oxooctan-3-yl)piperidin-2-one prepared above in Step C (122 mg, 0.244 mmol) in THF (2.4 mL) was added 1.4 M methylmagnesium bromide in toluene and THF (75:25) (522 μL, 0.731 mmol) at 0° C. Then the reaction was allowed to warm to rt and stirred for 2 h. The reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure and purification of the residue by chromatography on silica gel (12 g SiO2, 30% and 40% EtOAc/Hex) provided the title compound as a colorless foam.
Reaction SMILES: [CH3:1][C:2]1[C:21]([CH3:22])=[CH:20][C:5]2[NH:6][C:7]([C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:18]C)[CH:16]=4)[NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1[C:21]([CH3:22])=[CH:20][C:5]2[NH:6][C:7]([C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=4)[NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: COc1ccc2[nH]nc(-c3nc4cc(C)c(C)cc4[nH]3)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc2nc(-c3n[nH]c4ccc(O)cc34)[nH]c2cc1C
Yield: 71.1 %

Procedure:
A solution of 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole [34 mg, Example 235(b)] at 0° C. was treated with a solution of boron tribromide in dichloromethane (0.30 mL, 1M). The mixture was then heated at reflux temperature for 4 hours, then cooled and then treated dropwise with water. The pH was adjusted to between 7 and 8 by the addition of saturated aqueous sodium bicarbonate solution and this mixture was then extracted twice with ethyl acetate. The combined extracts were washed with brine, then dried over magnesium sulfate and then evaporated. The pale yellow solid residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and triethylamine (99:1, v/v) to yield 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-ol (23 mg) as a white solid. LC-MS (METHOD B): RT=2.19 minutes; 279 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:25]=1B(O)O>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:25]=1[C:2]1[CH:21]=[CH:20][CH:19]=[C:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=2)[CH:3]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Reactant: COc1cccc(OC)c1B(O)O
Product: COC(=O)CCc1ccc(OCc2cccc(-c3c(OC)cccc3OC)c2)cc1

Procedure:
The title compound was synthesized in the same manner as in Example 22 from methyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate and 2,6-dimethoxyphenylboronic acid. colorless oil (yield 93%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].[N+](C1C=CC(OC2C=CC=CC=2)=CN=1)([O-])=O>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccccc1O
Agent: O=[N+]([O-])c1ccc(Oc2ccccc2)cn1
Product: COc1ccccc1Oc1ccc([N+](=O)[O-])cc1
Yield: 99.8 %

Procedure:
Compound 430A (7.34 g, 100%) was prepared from 1-fluoro-4-nitro-benzene (4.23 g, 30.0 mmol) and 2-methoxy-phenol (3.72 g, 30.0 mmol) by a route analogous to that used for the preparation of compound 429B. It is a bright yellow solid.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([OH:26])/[CH:22]=[CH:23]/[CH2:24][OH:25].CCCCCC.CCOC(C)=O.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:25][CH2:24]/[CH:23]=[CH:22]/[CH2:21][OH:26])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC/C=C/CO
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: OC/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Trityl chloride (500 mg; 1.81 mmol), TEA (0.277 ml; 1.99 mmol) and DMAP (8.8 mg; 0.072 mmol) in dry DCM (5 ml) was added with a syringe to a solution of the diol (10) (800 mg; 9.07 mmol) in DCM (15 ml). The mixture was stirred at room temperature for 1 hour and 30 minutes, then other TrCl, TEA and DMAP (half quantities than before) were added. The reaction was stirred at the same temperature until TLC (Hexane/EtOAc 50:50) showed complete disappearance of Trityl chloride. After 1.5 hours water (20 ml) was added and the reaction was stirred for few minutes, then the phases were separated. The organic layer was washed with water (25 ml) and brine (25 ml). The solvent was dried over MgSO4 and evaporated to afford a crude oil which was purified by flash chromatography using Hexane/EtOAc 50:50 as eluent which gave the title compound as a colourless oil, 637 mg, 71%. Rf: 0.72 in Hexane/EtOAc 50:50 (UV/PMA).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[F:12][C:13]1[CH:18]=[C:17]([CH:19]=[CH:20][N+:21]([O-])=O)[CH:16]=[CH:15][C:14]=1[O:24][CH3:25]>C(OCC)(=O)C>[F:12][C:13]1[CH:18]=[C:17]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:15][C:14]=1[O:24][CH3:25]
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc(CCN)cc1F
Reaction time: 1 h

Procedure:
Lithium aluminum hydride (200 mL of 1 M in diethyl ether) was placed in a 1 L round bottomed flask along with 300 mL of diethyl ether. Intermediate 81 was placed in the thimble of a soxhlet extractor atop this flask and the mixture refluxed for 24 hours. The mixture was cooled to ° 0 C and 50 mL of ethyl acetate added dropwise. After stirring for 1 hour, the mixture was quenched with 100 mL of 1 N KHSO4. The Organic layer was separated washed with sat. NaHCO3, sat. NaCl, and dried over MgSO4. Removal of the solvent gave product. LC-MS showed the product had the expected M+H+ of 170. It was used in the next step without purification.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C@H:7]([NH:16][C:17]([C:19]2([CH2:24][CH:25]([CH2:29][C:30]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:31])[C:26]([OH:28])=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[C:6]1=[O:37])([OH:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:44](Br)[CH3:45]>CN(C)C=O.O.ClCCl>[CH2:44]([O:2][C:1](=[O:3])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C@H:7]([NH:16][C:17]([C:19]2([CH2:24][CH:25]([CH2:29][C:30]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:31])[C:26]([OH:28])=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[C:6]1=[O:37])[CH3:45]
Reactant: O=C(O)CN1C(=O)[C@@H](NC(=O)C2(CC(CC(=O)NCCCO)C(=O)O)CCCC2)CCc2ccccc21
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)C2(CC(CC(=O)NCCCO)C(=O)O)CCCC2)CCc2ccccc21
Yield: 28576.1 %

Procedure:
800 mg of the 2-{[1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)amino]-4-oxobutyric acid (isomer mixture) obtained above according to Example 9 was dissolved in 15 ml dimethyl formamide (=DMF). 302.5 mg Cs2CO3 and 169 mg ethyl bromide were added to this receiving solution at room temperature with stirring. After stirring overnight, it was diluted with 42 ml water and 21 ml dichloromethane and the aqueous phase was extracted with dichloromethane. The solvent was largely evaporated at reduced pressure and the remaining residue was chromatographed (stationary phase: silica gel, mobile phase: EA (100%) to EE/MeOH 7:3 (v/v)). Drying the product fractions in an oil pump vacuum (5×10−2 mbar) yielded 241 g of the title compound as foam resin, MS: [M+H]+: 546; m/z: 453, 425, 379; 1H-NMR (CDCl3): 7.34-7.1, m, [4]; 4.82, 4.77, 4.34, 4.29, AB-Q-. [2]; 3.62, m, [2]; 3.37, m, [3].
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:11]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:10]=[C:9]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[S:8]1)=[N+]=[N-].CO.[ClH:34]>[Pd]>[ClH:34].[NH2:1][CH2:4][CH2:5][CH2:6][C:7]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:11]([C:12](=[O:17])[C:13]([CH3:16])([CH3:14])[CH3:15])[N:10]=[C:9]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[S:8]1
Reactant: CC(C)(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.1 %

Procedure:
1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one (100 mg, 0.2255 mmol) was weighed into a flask and dissolved in 7 mL of MeOH.HCl (0.563 ml, 1.12 mmol) and Pd/C (23 mg 0.22 mmol) were then added. The reaction was stirred at ambient temperature under an atmosphere or H2 for 45 minutes. The reaction was then concentrated affording the desired product (97.4 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][F:11])=[N:6][CH:7]=1.[CH:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](OC2C=CC=CC=2)=[N:20][C:21]#[N:22])=[CH:14][CH:13]=1.COCCOC>CCOCC>[F:11][CH2:10][CH2:9][NH:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:19](=[N:20][C:21]#[N:22])[O:18][C:15]2[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=2)=[CH:3][CH:4]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1ccc(NCCF)nc1
Solvent: COCCOC
Solvent: CCOCC
Product: N#CN=C(Nc1ccc(NCCF)nc1)Oc1ccccc1
Reaction time: 18 h
Yield: 31 %

Procedure:
A stirred mixture of the product from Step 2 (0.0112 mol), diphenylcyanocarbonimidate (2.67 g, 0.0112 mol) and ethylene glycol dimethyl ether (25 ml) was kept under nitrogen for 18 hours at 24° C. The mixture was diluted with Et2O (25 ml) and the solid was collected by filtration to give 1.04 g, mp 157°-158° C. of the titled product. The filtrate was purified by silica gel chromatography with 2.5% MeOH--CHcl3 to give 0.39 g of additional product: MS m/z (relative intensity) 299 (M+, 100), 278 (23.5), 266 (24.4), 206 (37.7), 184 (42.6), 172 (68.3), 94 (95.4).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[C:20]([F:21])=[C:19]([OH:22])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[C:8]([F:23])[C:7]=2[F:24])[CH2:3][CH2:2]1.O[CH2:26][C@@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[C:20]([F:21])=[C:19]([O:22][CH2:28][C@@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH3:26])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[C:8]([F:23])[C:7]=2[F:24])[CH2:2][CH2:3]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Oc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3F)oc2c1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3F)oc2c1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-2,3-difluorophenyl)-7-fluoro-1,3-benzoxazol-6-ol (1.37 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (1.07 g) and triphenylphosphine (1.61 g) in THF (15 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 3.23 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (1.18 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].Cl.[CH3:12]O>O1CCOCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([O:10][CH3:12])=[O:9]
Reactant: N[C@H]1CCCC[C@H]1C(=O)O
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CCCC[C@@H]1N

Procedure:
To a solution of (1R,2S)-2-aminocyclohexanecarboxylic acid (0.13 g, 0.91 mmol) in methanol (5 mL) was added 4N HCl in dioxane (1 mL) and the reaction mixture was stirred at reflux overnight. The reaction mixture was concentrated in vacuo to afford an oil which was used directly for the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]([OH:19])[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Clc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.8 %

Procedure:
A solution of 4-bromochlorobenzene (20.0 g, 104 mmol) in 125 mL of dry tetrahydrofuran under nitrogen was cooled to -78° and 70 mL of 1.5M n-butyllithium in hexane was added dropwise over 20 minutes. After stirring another 10 minutes, 12.5 mL (104 mmol) of 3-bromobenzaldehyde was added dropwise and the reaction was stirred for another 10 minutes at -78°. Saturated aqueous ammonium chloride (100 mL) was added and the reaction was warmed to room temperature and extracted with 300 mL of ether. The ethereal layer was extracted with three 75 mL portions of 1M sodium bisulfite, 75 mL of 1M sodium hydroxide, 75 mL of water, and 75 mL of brine. The ether layer was dried over magnesium sulfate and the solvent removed to give 31.2 g of 3-bromo-4'-chlorobenzhydryl alcohol as a pale yellow solid. A portion was recrystallized from hexanes containing 5% ether to give white needles, m.p. 67°-68°. Calc. for C13H10Br C10: C, 52.47; H, 3.39; Br, 26.85; Cl, 11.91. Found: C, 52.25; H, 3.25; Br, 26.72; Cl, 12.09.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]([F:28])([CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:18]O.N1C=CC=CC=1>ClCCl>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][CH2:18][C:17]([F:28])([F:16])[CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)(=[O:10])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCC(F)(F)COC1CCCCO1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(OCC(F)(F)COC1CCCCO1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triflic anhydride (1.8 ml, 11 mmol) was added to a cold (0° C.) solution of 2,2-difluoro-3-tetrahydropyranyloxy-1-propanol 91.6 g, 10 mmol), pyridine (0.9 ml, 11 mmol) in anhydrous dichloromethane (50 ml). The mixture was stirred 1 h at 0° C. and, after usual work-up, the product was purified by flash chromatography on silica gel (ethyl acetate:hexane; 15:85) (2.6 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1B(O)O.[F-].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:34]4[C:33]([F:32])=[CH:38][CH:37]=[CH:36][C:35]=4[F:39])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: OB(O)c1c(F)cccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4c(F)cccc4F)cc3)oc2C)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (300 mg, 0.614 mmol) (see Ex. 2, part B), 2,6-difluorophenylboronic acid (0.921 mmol), potassium fluoride (88.6 mg, 1.84 mmol), palladium acetate (1.3 mg, 0.14 μmol), and 2-(dicyclohexylphosphino)biphenyl (4.3 mg, 12.3 μmol) were combined under N2, to which anhydrous THF (1.23 mL) was added. The yellow mixture was heated at reflux for 12 h. After cooling to room temperature, the mixture was partitioned between Et2O (20 mL) and 1M NaOH (10 mL). The layers were separated, and the aqueous phase was back-extracted with Et2O (10 mL). Combined organic phases were dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (25 g SiO2, 1:4 ethyl acetate:hexanes) to yield the desired product as an oil. 1H NMR (400 MHz, CDCl3) δ8.02 (d, J=8.0 Hz, 2H), 7.51 (d, J=8 Hz, 2H), 7.34-7.28 (m, 1H), 6.98-6.91 (m, 2H), 6.81-6.73 (m, 4H), 4.20 (q, J=6.8 Hz, 2H), 4.17 (t, J=6.6 Hz, 2H), 2.93 (t, J=6.6 Hz, 2H), 2.33 (s, 3H), 1.50 (s, 6H), 1.24 (t, J=6.8 Hz, 3H); MS (EI) 522.2 (M+H)+.
Reaction SMILES: CO.[C:3]([C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1)(=O)[CH2:4][CH2:5][CH3:6].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=2)=[CH:23][CH:22]=1.[B][B][B][B][B][B][B][B][B][B]>Cl>[F:35][C:20]([F:19])([F:34])[C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:28]=[CH:29][C:30]([NH:33][CH:3]([C:8]3[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=3)[CH2:4][CH2:5][CH3:6])=[CH:31][N:32]=2)=[CH:25][CH:26]=1
Reactant: Nc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: CCCC(=O)c1ccc(C(=O)OCC)cc1
Agent: Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CCCC(Nc1cnc(-c2ccc(C(F)(F)F)cc2)nc1)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
Methanol (0.70 mL) was added to a flask containing ethyl 4-butyrylbenzoate (82.8 mg, 0.376 mmol), 2-(4-(trifluoromethyl)phenyl)pyrimidin-5-amine (90.0 mg, 0.376 mmol) and decaborane (46.0 mg, 0.376 mmol) at room temperature under nitrogen. The resulting solution was stirred at room temperature overnight. The mixture was diluted with 1N HCl and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-35% ethyl acetate in heptane) gave ethyl 4-(1-(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-ylamino)butyl)benzoate (40.0 mg, 24%). 1H NMR (400 MHz, CDCl3, δ): 8.32 (d, J=8.19 Hz, 2 H), 8.07 (s, 2 H), 7.98-8.04 (m, 2 H), 7.63 (d, J=8.19 Hz, 2 H), 7.36-7.41 (m, 2 H), 4.38-4.43 (m, 2 H), 4.35 (q, J=7.02 Hz, 2 H), 1.75-1.91 (m, 2 H), 1.36 (t, J=7.02 Hz, 3 H), 1.20-1.52 (m, 2 H), 0.94 (t, J=7.32 Hz, 2 H). MS (M+1): 444.3.