Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]3[C:22]([OH:30])=[C:23]([C:27](=[O:29])[CH3:28])[CH:24]=[CH:25][CH:26]=3)=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:31](OCC)(=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]3[C:22]4[O:30][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][C:27](=[O:29])[C:23]=4[CH:24]=[CH:25][CH:26]=3)=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(/C=C/c2ccc(OCCCCc3ccc(F)cc3)cc2)c1O
Product: CCOC(=O)c1cc(=O)c2cccc(/C=C/c3ccc(OCCCCc4ccc(F)cc4)cc3)c2o1
Yield: 65 %

Procedure:
Following the process described in example 1 (point A), starting from 3'-[(E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethen-1-yl]-2'-hydroxy-acetophenone and diethyl oxalate, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform, 8:2 (65% yield).
Reaction SMILES: [Br:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1.C(O)C.Cl>O.[Fe].C(O)C.O>[Br:1][C:2]([F:16])([F:17])[C:3]([F:14])([F:15])[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)C(F)(F)Br)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(OC(F)(F)C(F)(F)Br)cc1
Temperature: 25 °C
Yield: 37.7 %

Procedure:
The product of the previous reaction, 4-(2bromotetrafluoroethoxy)nitrobenzene (20.0 g, 0.069 mole), is added to a 50 percent by volume solution of ethyl alcohol in water (30.0 g) and powdered iron filings (11.0 g, 0.20 mole) in a 250 ml 3-necked round bottomed flask fitted with a nitrogen padded reflux condenser and a dropping addition funnel. The mixture is purged thoroughly with nitrogen, and brought to reflux. A solution of concentrated HCl (1.3 ml, 0.0156 mole) in 8 ml ethanol/water (1:1 by volume) is added slowly drop wise over 30 minutes. The resulting reaction mixture is refluxed for 3 hours, then cooled to room temperature. The mixture is filtered and the solids are washed twice with dilute KOH (10 ml each, 0.01M), just enough to make the flitrate up to pH 7. The solids are then washed with acetone (25 ml) and the acetone wash is added to the flitrate. The flitrate phase-separates, and the lower phase is removed and distilled on a rotary evaporator (2.0 mm Hg (2.66 kPa), 100° C.) to recover the pure product (7.47 g, 0.026 mole, 37 percent yield) as a water white oil in greater than 99 percent purity.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[CH2:27](Br)[CH2:28][CH3:29]>>[ClH:1].[CH2:27]([N:12]1[CH2:13][CH2:14][C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[C@H:10]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=2)[CH2:11]1)[CH2:28][CH3:29]
Reactant: CCCBr
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CNCC[C@H]2c2ccc(F)cc2)cc1
Agent: Cl
Product: CCCN1CC[C@@H](c2ccc(F)cc2)[C@H](COc2ccc(C(C)(C)C)cc2)C1

Procedure:
trans-1-propyl-4-(4-fluorophenyl)-3-(4-t-butylphenoxy-methyl)-piperidine hydrochloride M.p. 221.1° C. was prepared exactly as described in example 1 from trans-4-(4-fluorophenyl)-3-(4-t-butylphenoxymethyl)-piperidine hydrochloride and propyl bromide by refluxing for 96 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:13]([NH:15][CH:16]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:17]([C:19]1[O:20][CH:21]=[C:22]([C:24](O)=[O:25])[N:23]=1)[OH:18])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CN([P+](ON2N=[N:63][C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][C:57]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.NC1C=CC=CC=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH3:37][CH:36]([CH3:38])[CH2:35][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13](=[O:14])[NH:15][CH:16]([CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH:17]([OH:18])[C:19]1[O:20][CH:21]=[C:22]([C:24](=[O:25])[NH:63][C:58]2[CH:57]=[CH:62][CH:61]=[CH:60][CH:59]=2)[N:23]=1
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)NC(CCc1ccccc1)C(O)c1nc(C(=O)O)co1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)NC(CCc1ccccc1)C(O)c1nc(C(=O)Nc2ccccc2)co1
Reaction time: 0.03 h

Procedure:
A solution comprised of 2-[2-(2-benzyloxycarbonylamino-4-methylvalerylamino)-1-hydroxy-4-phenylbutyl]oxazole-4-carboxylic acid (0.05 g, 0.096 mmol), provided as in Example 7, in DMF (5 mL) was stirred while PyBOP® (0.05 g, 0.096 mmol) and aniline (9 mg, 0.096 mmol) were added. The mixture was stirred for an additional 2 minutes and diisopropylethylamine (12.4 mg, 0.096 mmol) was added. The mixture was stirred for 2 hours at room temperature, poured into cold water 0° C. at and extracted with ethyl acetate (4×30 mL). The extracts were combined, dried (MgSO4) and then concentrated. The product was purified from the residue by flash chromatography eluting with 1:2 hexanes/ethyl acetate to provide benzyl 3-methyl-1-[2-hydroxy-1-phenethyl-2-(4-phenylcarbamoyloxazol-2-yl)ethylcarbamoyl]butylcarbamate (30 mg, 0.05 mmol) as a white solid. MS (ESI)) m/z=599 (M+1); 1H NMR (CDCl3): δ 0.8-1.05 (d, J=4 Hz, 6H), 1.35 (m, 1H), δ 1.55 (m, 1H), δ 2.00-2.15 (m, 2H), δ 2.62 (m, 2H), δ 2.80 (m, 2H), δ 3.65 (m, 2H), δ 4.11 (m, 1H1), δ 4.30 (m, 1H), δ 4.45 (m, 1H), δ 4.95 (s, 1H) 5.17 (s, 2H), δ 5.2 (d, J=4 Hz, 1H), δ 6.70 (d, J=5 Hz 1H), δ 7.1-7.45 (m, 15H) 7.7(d, J=4 Hz, 1H), δ 8.19 (s, 1H), δ 8.99 (s, 1H), (C34H38N4O6).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12]([OH:14])=[O:13])=[O:5])[CH3:2].C1N(CCS(O)(=O)=O)CCOC1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Cl-].[Mg+2].[Cl-].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[OH-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]1[C:12]([OH:14])=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)O
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)CCN1CCOCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)O
Yield: 67.7 %

Procedure:
A solution of (1R,2R)-4-oxo-cyclopentane-1,2-dicarboxylic acid monoethyl ester (example 1, step 1, 6.0 g) in an aqueous buffer (600 mL, 30 mM; 2-(N-morpholino)ethanesulfonic acid; 0.5 M D-glucose [10 equ.]; 2 mM Magnesium chloride) was adjusted to pH 6.4 at 35° C. Under stirring the reduction was started by the addition of the cofactor NADP (120 mg), the cofactor regeneration enzyme-glucose dehydrogenase (120 mg GDH 102 [Codexis]) and the reductase (1.2 g KRED-NADP-174 [Codexis]). During the 69 h reaction time at 35° C. the pH was kept at pH 6.5 by the addition of 1M NaOH. Afterwards the enzymes were denatured by adjusting to pH 2, adding a total of 300 mL ethyl acetate and a total of 60 g filter aid—Dicalite under stirring of at least 1.5 h. After filtration, two further extractions with 200 mL ethyl acetate, treatment of the combined organic phases with magnesium sulfate, evaporation and drying for 4 h on a high vacuum, 4.1 g of the title compound was isolated. MS: 201.07 (M−H)−; chiral GC: d.r.: 1.4:97.3:1.4: 0.0 [BGB-172 (BGB Analytik AG), 30 m*0.25 mm; 0.25 μm; H2; 2° C./min, 100° C. to 200° C.]. An additional extraction of the aqueous phase with further 200 mL ethyl acetate yielded after treatment with magnesium sulfate, evaporation and drying for 4 h on a high vacuum in 1.62 g of the title compound. MS: 201.07 (M−H)−; chiral GC: d.r.: 1.3:96.3:1.6:0.4. The summing up gave a total yield of 5.72 g (93.9%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CO.S(=O)(=O)(O)O.[C:21](=O)([O-])O.[Na+]>ClCCCl>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:21])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 68 %

Procedure:
To a solution of 4-hydroxy-3-nitrobenzoic acid (15.8 g, 86.3 mmol) in 1,2-dichloroethane (150 mL) were added methanol (14 mL) and conc. sulfuric acid (0.5 mL) and the mixture was heated to 80° C. and stirred. Methanol (9 mL) was added on the way and the mixture was stirred for 21 hours. The reaction mixture was added to a saturated aqueous sodium hydrogencarbonate solution (400 mL) and extracted with chloroform. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give methyl 4-hydroxy-3-nitrobenzoate as a yellow solid (11.5 g, 68%).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH:5]=[CH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[CH3:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH2:15]([N:3]([CH2:1][CH3:2])[CH2:4][CH:5]=[CH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:10][CH:9]=1)[CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC=CCc1ccc(N)cc1
Solvent: ClCCl
Product: CCN(CC)CC=CCc1ccc(NS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve 3.5 g (0.014 mole) N,N-diethyl-4-(4-aminophenyl)-2-buten-1-amine in 50 ml of methylene chloride, chill to about 0° C. To this slowly add 1.5 ml (0.019 mole) of methanesulfonyl chloride. Stir at room temperature 1 hr and then wash with 2×50 ml of 10% NaOH. Wash the sodium hydroxide extracts with 1×100 ml of ether and then acidify to pH 10 with concentrated HCl. Extract with 2×100 ml methylene chloride and dry the methylene chloride extracts over Na2SO4. Evaporate to dryness to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH:18]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[C:32]([CH:41]=O)[CH:31]=3)=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[C:32]([CH2:41][NH:17][CH2:16][CH2:15][N:12]4[CH2:11][CH2:10][N:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)[CH2:14][CH2:13]4)[CH:31]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Reactant: O=Cc1cc(-c2ccc(C3CCCCC3)cc2)n(-c2ccccc2)n1
Product: COc1ccc(N2CCN(CCNCc3cc(-c4ccc(C5CCCCC5)cc4)n(-c4ccccc4)n3)CC2)cc1
Yield: 89.1 %

Procedure:
Compound 47 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 5-(4-cyclohexylphenyl)-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[C:13]([O:14][C:15]3[C:20]=1[CH:19]=[CH:18][C:17](=[O:21])[CH:16]=3)=[CH:12][C:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([OH:30])=[O:29])=[CH:10][CH:9]=2)(=O)=O.[C:33]12(C3C=C(B(O)O)C=CC=3OCC3C=CC=CC=3)[CH2:42][CH:37]3[CH2:38][CH:39]([CH2:41][CH:35]([CH2:36]3)[CH2:34]1)[CH2:40]2.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.CCCCCC>[C:33]12([C:15]3[CH:16]=[C:17]([C:7]4[C:8]5[C:13]([O:14][C:15]6[C:20]=4[CH:19]=[CH:18][C:17](=[O:21])[CH:16]=6)=[CH:12][C:11]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([OH:30])=[O:29])=[CH:10][CH:9]=5)[CH:18]=[CH:19][C:20]=3[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:40][CH:39]3[CH2:38][CH:37]([CH2:36][CH:35]([CH2:41]3)[CH2:34]1)[CH2:42]2
Reactant: O=C(O)c1ccccc1-c1ccc2c(OS(=O)(=O)C(F)(F)F)c3ccc(=O)cc-3oc2c1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1-c1ccc2c(-c3ccc(Cc4ccccc4)c(C45CC6CC(CC(C6)C4)C5)c3)c3ccc(=O)cc-3oc2c1
Temperature: 82.5 °C

Procedure:
To a stirred suspension of 1.00 g (2.15 mmol) of 9-(trifluoromethane-sulfonyloxy)-6-(2-carboxyphenyl)xanthen-3-one, 0.80 g (2.20 mmol) of 3-(1-adamantyl)-4-benzyloxyphenylboronic acid [1H NMR (300 MHz, CDCl3) δ 1.77, 2.26 (2 s, 12, AdCH2), 2.07 (s, 3, AdCH), 5.21 (s, 2, CH2), 7.06 (d, J=8.2 Hz, 1, ArH), 7.3-7.5 (m, 5, ArH), 8.03 (d, J=7.8 Hz, 1, ArH), 8.19 ppm (s, 1, ArH)], 0.32 g (0.28 mmol) of Pd[P(C6H5)3]4 and 0.26 g (6.1 mmol) of LiCl in 20 ml of DME was added under Ar 3 ml of 2.0 M aq. Na2CO3. The reaction mixture was heated at reflux (80-85° C.) overnight, at which time the reaction was complete. The mixture was extracted with EtOAc. The extract was washed with brine and water, dried (MgSO4), filtered, and concentrated. Flash column chromatography (10% EtOAc/hexane) yielded a pale red (0.60 g, 44%): Rf0.45 (40% EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ 1.74, 2.19 (2 s, 12, AdCH2), 2.06 (s, 3, AdCH), 5.17 (s, 2, CH2), 6.55 (dd, J=8.0, 2.0 Hz, 1, ArH), 6.68 (d, J=8.0 Hz, 1, ArH), 6.8-7.7 (m, 16, ArH), 8.05 ppm (d, J=8.0 Hz, 1, ArH).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17]C)(=[O:5])[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>ClCCl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(O)cccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (26.3 g, 0.1 mol) in dichloromethane (250 ml) was cooled to -78° under nitrogen, and boron tribromide (75 g, 0.3 mol) added slowly. The solution was stirred overnight, warming gradually to room temperature, then quenched with water. The organic solution was separated and evaporated to give the crude product, which was used immediately without further purification.
Reaction SMILES: C(O[CH2:10][C@@H:11]([O:30]S(C)(=O)=O)[C@@H:12]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO.O.O>[F:20][C:18]1[CH:19]=[C:14]([CH2:13][C@H:12]([NH:22][C:23](=[O:24])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C@@H:11]2[CH2:10][O:30]2)[CH:15]=[C:16]([F:21])[CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@@H](COC(=O)c1ccccc1)OS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@@H]1CO1

Procedure:
Mesylate 30 was dissolved in methanol/water at 0° and a solution of sodium hydroxide in water was added. After all of the starting material was consumed, the reaction was extracted and the residue purified using silica gel chromatography to obtain epoxide 31 as a white solid, m.p.=99°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[C:4]([C:10]2([OH:21])[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.Cl[C:24]1[N:29]=[C:28]([N:30]([CH:40]2[CH2:42][CH2:41]2)[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:27]2=[N:43][CH:44]=[C:45]([C:46]#[N:47])[N:26]2[N:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:22][C:3]1[C:2]([NH:1][C:24]2[N:29]=[C:28]([N:30]([CH:40]3[CH2:42][CH2:41]3)[CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:27]3=[N:43][CH:44]=[C:45]([C:46]#[N:47])[N:26]3[N:25]=2)=[CH:7][C:6]([C:8]#[N:9])=[CH:5][C:4]=1[C:10]1([OH:21])[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2cc(C#N)cc(N)c2Cl)C1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C4(O)CN(C(=O)OC(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 100 °C
Yield: 54.4 %

Procedure:
A mixture of tert-butyl 3-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxyazetidine-1-carboxylate (Example 647B) (37.4 mg, 0.116 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (49.2 mg, 0.139 mmol), DPPF (6.40 mg, 0.012 mmol), Cs2CO3 (75 mg, 0.231 mmol), XANTPIIOS (6.68 mg, 0.012 mmol), and palladium(II) acetate (7.78 mg, 0.035 mmol) in a microwave vial in dioxane (1 mL) was evacuated and backfilled with nitrogen for 3 times, then the mixture was heated in an oil bath at 100° C. for 3 hours. The reaction mixture was diluted with EtOAc, washed with water, brine, and dried over Na2SO4. Removal of the solvent and the crude material was purified by radial silica gel chromatography eluting with hexane containing 10 to 40% EtOAc to afford 40.5 mg of tert-butyl 3-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxyazetidine-1-carboxylate
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[Cl:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1[N:39]1[C:48](=[O:49])[C:47]2[C:42](=[C:43]([F:50])[CH:44]=[CH:45][CH:46]=2)[N:41]([CH3:51])[C:40]1=[O:52].CCO.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([N:39]2[C:48](=[O:49])[C:47]4[C:42](=[C:43]([F:50])[CH:44]=[CH:45][CH:46]=4)[N:41]([CH3:51])[C:40]2=[O:52])[C:24]=1[Cl:23])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Reactant: Cn1c(=O)n(-c2cccc(B3OC(C)(C)C(C)(C)O3)c2Cl)c(=O)c2cccc(F)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1c(=O)n(-c2cccc(-c3c(Cl)cc(C(N)=O)c4[nH]c5cc(C(C)(C)O)ccc5c34)c2Cl)c(=O)c2cccc(F)c21
Temperature: 90 °C
Yield: 12.5 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (30 mg, 0.079 mmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione [Intermediate 41] (40.6 mg, 0.094 mmol), EtOH (1 mL), toluene (1 mL) and 2 M aqueous Na2CO3 (0.13 mL, 0.26 mmol) was bubbled with nitrogen for 5 min. The mixture was treated with tetrakis(triphenylphosphine)palladium (7.3 mg, 6.29 μmol), and the reaction vessel was sealed and heated at 90° C. for 16 h. The cooled mixture was partitioned between EtOAc and water, and the organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel (12 g), eluting with MeOH-DCM containing 1% TEA (gradient from 0-5%). The resulting material was further purified using preparative HPLC (PHENOMENEX® Axia C18 30×100 mm), eluting with MeCN-water containing 0.1% TFA (gradient from 20-100%, 10 min, 30 mL/min) The appropriate fractions were treated with saturated aqueous NaHCO3 and concentrated. The residue was partitioned between EtOAc and water, and the organic phase was washed with brine, dried and concentrated to provide 3-chloro-4-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a white solid (6 mg, 11% yield). Mass spectrum m/z 587 (M+H—H2O)+. 1H NMR (400 MHz, chloroform-d) δ 10.46 (s, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.66-7.61 (m, 1H), 7.59-7.54 (m, 1H), 7.51-7.46 (m, 2H), 7.27-7.17 (m, 2H), 7.06-6.88 (m, 1H), 3.88 (dd, J=11.6, 8.0 Hz, 3H), 1.64 (s, 6H). 19F NMR (400 MHz, chloroform-d) δ −121.34.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]([OH:19])=O)[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:16]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1>>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:4]1[C:5]3[O:9][C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[N:7][C:6]=3[CH:16]=[C:2]([Cl:1])[CH:3]=1)=[O:19])[CH2:24]2
Reactant: O=C(O)c1cc(Cl)cc2nc(-c3ccccc3)oc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: Cl
Product: CN1C2CCCC1CC(NC(=O)c1cc(Cl)cc3nc(-c4ccccc4)oc13)C2
Yield: 49 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-5-chloro-2-phenyl-benzoxazole-7-carboxamide was prepared from 5-chloro-2-phenyl-benzoxazole-7-carboxylic acid and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using the method outlined in Step C of Example 7. This compound was obtained in 49% yield as a white solid: mp 199-201° C.; 1H NMR (300 MHz, CDCl3) δ 8.19 (dd, J=7.5, 2.1 Hz, 2H), 8.05 (d, J=2.1 Hz, 1H), 7.85 (d, J=2.1 Hz, 1H), 7.66-7.55 (m, 3H), 6.84 (d, J=7.8 Hz, 1H), 4.65-4.56 (m, 1H), 3.15 (d, J=10.5 Hz, 2H), 2.71-2.60 (m, 2H), 2.53 (s, 3H), 2.17-2.10 (m, 1H), 2.03 (d, J=6.6 Hz, 3H), 1.78 (br s, 1H), 1.60-1.52 (m, 1H), 1.41 (t, J=10.8 Hz, 2H), 1.16-1.10 (m, 2H); MS (ESI) m/z 410 [M+H]+.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Br[CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.O>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CCOC(C)=O>[OH:3][CH2:2][CH2:1][O:4][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: OCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(COCCO)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 35.7 %

Procedure:
Ethylene glycol (0.084 mL, 1.5 mmol) was added to NaH (38 mg, 1.52 mmol, 95% in oil) in THF (3 mL). 4-(Bromomethyl)benzonitrile (290 mg, 1.5 mmol) was added to the reaction, and the residual 4-(bromomethyl)benzonitrile was transferred to the reaction tube with additional THF (1 mL). (Bu)4NI (55 mg, 0.15 mmol) was then added, and the reaction was heated at 60° C. for 18 h and then rt for 4 h. H2O (2 mL) and EtOAc (2 mL) were added, and the layers were separated via pipette. The aqueous layer was extracted with EtOAc (1×1 mL), and the combined organic layers were concentrated. The crude product was purified on a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: 10% EtOAc/hexanes (fractions 1,2), 30% EtOAc/hexanes (fractions 3,4), 50% EtOAc/hexanes (fractions 5-7), and 75% EtOAc/hexanes (fraction 8) to give the title compound (95 mg, 36%). The product was characterized by 1H NMR (400 MHz) in CDCl3.