Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10](Br)=[CH:11][CH:12]=1)[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccccc2F)nc1

Procedure:
A mixture of 1000 mg (3.87 mmol) of 3-(6-bromopyridin-3-yl)propionic acid ethyl ester, 596.3 mg (4.26 mmol) of 2-fluorophenylboronic acid, 43.5 mg (0.19 mmol) of palladium acetate, 101.6 mg (0.38 mmol) of triphenylphosphane, 3.88 ml of a 1M sodium carbonate solution, 23 ml of toluene and 6 ml of ethanol was heated under reflux for 5 h and, after cooling, poured into water. The resulting mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and the residue was purified by chromatography (silica gel, n-heptane/ethyl acetate 5:1). Yield: 782 mg (74%).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43]>>[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH:43][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[S:27]([CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:29])=[O:28]
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: CN(C)CCNC(=O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 33.3 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27 mg, 0.30 mmol, 0.60M in DMF) were combined to give 20 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 601 [M+H]+.
Reaction SMILES: Br[C:2]1[NH:18][C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([OH:17])[CH:16]=3)[C:4]=2[CH:3]=1.ClCl.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:34][CH2:33]OCC1>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.Cl[Pd]Cl.[Fe+2]>[NH2:6][C:5]1[CH:4]=[C:3]([C:2]2[NH:18][C:5]3[N:6]=[CH:7][N:8]=[C:9]([O:10][C:11]4[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)[CH:2]=[CH:33][CH:34]=1
Reactant: Oc1cccc(Oc2ncnc3[nH]c(Br)cc23)c1
Reactant: C1COCCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: ClCl
Product: Nc1cccc(-c2cc3c(Oc4cccc(O)c4)ncnc3[nH]2)c1
Temperature: 80 °C
Yield: 50 %

Procedure:
5-(6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yloxyl)-phenol (14 mg, 0.0448 mmol) is mixed with 3-amninophenylboronic acid (13 mg, 0.0896 mmol), Pd(dppf)Cl2.CH2.Cl2 (7.5 mg, 0.009 mmol), and K3PO4 (19 mg, 0.0896 mmol) in anhydrous dioxane (0.8 mL) under an argon atmosphere. The mixture is heated to 80° C. for 18 hours, with stirring. The reaction is then cooled to ambient temperature and filtered through a pad of silica with 10% MeOH in DCM. The filtrate is concentrated and the resulting crude product is purified by reverse phase HPLC using a C18 column and 0-95% acetonitrile/water gradient to give 3-[6-(3-amino-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-phenol (7.1 mg, 50%); 1H NMR (500 MHz, DMSO): δ 8.27 (s, 1H), 7.29 (t, J=8.1 Hz, 1H), 7.20 (t, J=7.9 Hz, 1H), 7.10-7.17 (m, 2H), 6.68-7.08 (m, 4H), 6.52 (s, 1H); LC-ESMS observed [M+H]+ 319.1 (calculated for C18H14N4O2, 318.11).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=2)=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:39]([C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1)[CH2:40][CH2:41][CH2:42][CH3:43]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:39]([C@H:44]1[CH2:45][CH2:46][C@H:47]([C:50]([O:8][C:6]2[CH:7]=[C:2]([Cl:1])[C:3]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:14]=3)=[N:4][CH:5]=2)=[O:51])[CH2:48][CH2:49]1)[CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cc2Cl)cc1
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ncc(OC(=O)[C@H]3CC[C@H](CCCCC)CC3)cc2Cl)cc1

Procedure:
0.78 g (2.50 mmol) of 3-chloro-5-hydroxy-2-(4-octyloxyphenyl)pyridine, 0.52 g (2.50 mmol) of dicyclohexylcarbodiimide, 0.50 g (2.50 mmol) of trans-4-pentylcyclohexanecarboxylic acid and 0.01 g of 4-(N,N-dimethylamino)-pyridine are stirred at room temperature for 18 hours in 20 ml of dichloromethane. Filtration, evaporation to dryness and chromatographic purification (silica gel/ hexane:ethyl acetate 8:2) and recrystallization from acetonitrile give 0.28 g of 3-chloro-2-(4-octyloxyphenyl)pyridin-5-yl trans-4-pentylcyclohexanecarboxylate. ##STR26##
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:13])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)=[O:2].Cl.[NH:15]1[CH2:18][CH:17]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:16]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCOC(C)=O>[CH:1]([C:3]1[C:4]([CH3:13])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([N:15]1[CH2:18][CH:17]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:16]1)=[O:10])=[O:2]
Reactant: N#Cc1ccc(C2CNC2)cc1
Reactant: Cc1cc(C)c(C(=O)O)cc1C=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 5-formyl-2,4-dimethylbenzoic acid (compound 151.3, 500 mg, 2.81 mmol) in DCM (10 mL) 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 545 mg, 2.80 mmol), DIEA (1.4 mL, 8.41 mmol) and HBTU (1.60 g, 4.22 mmol) were added. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was diluted with 150 mL of EtOAc, then washed with 2×50 mL of NH4Cl (sat.) and 1×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/1) as eluent to furnish 480 mg (54%) of the title compound as a white solid.
Reaction SMILES: O.[OH-].[Li+].O.[OH:5][CH2:6][C:7]1([C:13]([O:15]CC)=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>CO>[OH:5][CH2:6][C:7]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C1(CO)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1(CO)CCOCC1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 54.4 %

Procedure:
To a solution of lithium hydroxide monohydrate (4.46 Kg) in methanol (44 liters) and water (11 Kg) was added ethyl 4-hydroxymethyl-tetrahydropyran-4-carboxylate (8.0 Kg) The mixture was refluxed for 30 minutes, then solvent removed under reduced pressure. The mixture was cooled to 20° C., methyl tert-butyl ether (14.8 Kg) added, stirred for 10 minutes, and allowed to settle. The top organic layer was separated. This was repeated twice more, then the remaining mixture cooled to -10° C., and a solution of 31% hydrochloric acid (13 Kg) in water (3 Kg) added, maintaining the temperature below 5° C. The mixture was extracted several times with tetrahydrofuran, and the combined organic phases dried over magnesium sulfate. Approximately 90% of the tetrahydrofuran was removed, and the remaining solution added to a mixture of hexane (64.5 Kg) and methyl tert-butylether (23.7 Kg) with stirring. The precipitated solid material was filtered off and dried under reduced pressure at 60° C., to give 4-hydroxymethyl-tetrahydropyran-4-carboxylic acid (3.7 Kg), the compound of Formula (9a).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[N:10]12[CH2:17][CH2:16][C:13]([C:18]([O:20]CC)=O)([CH2:14][CH2:15]1)[CH2:12][CH2:11]2>C1COCC1>[N:10]12[CH2:11][CH2:12][C:13]([C:18]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=3)([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=3)[OH:20])([CH2:14][CH2:15]1)[CH2:16][CH2:17]2
Reactant: Cc1cccc([Mg]Br)c1
Reactant: CCOC(=O)C12CCN(CC1)CC2
Solvent: C1CCOC1
Product: Cc1cccc(C(O)(c2cccc(C)c2)C23CCN(CC2)CC3)c1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A solution of 3-methylphenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1484 g, 0.810 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.1806 g, 69.4%). EI-MS m/z 322(M+H+) Rt (1.54 min).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25]#[CH:26])[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CON(C)[C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[C:31]1([C:30](=[O:37])[C:26]#[C:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:20]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C#Cc1cccc(OCc2ccccc2)c1
Reactant: CON(C)C(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: O=C(C#Cc1cccc(OCc2ccccc2)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 57 %

Procedure:
Place lithium hexamethyldisilazane (15 mL of a 1M solution in tetrahydrofuran, 15 mmol) and tetrahydrofuran (75 mL) under an argon atmosphere and cool with an ice-water bath. Add, by dropwise addition, a solution of 3-benzyloxyphenylacetylene (3.13 g, 15 mmol) in tetrahydrofuran. Stir at 0° C. for 45 minutes, then add, by dropwise addition, N-methoxy-N-methylbenzamide (2.45 mL, 16 mmol). Remove the cooling bath and stir at room temperature for 1 hour. Partition between ethyl ether and water, separate the organic phase and dry (MgSO4). Filter and evaporate the solvent in vacuo to yield a crude solid. Recrystallize (hexane/ethyl acetate) to yield 2.67 g (57%) of the title compound; mp 75°-77° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:27][CH2:26][C:20]2([NH:24][NH:23][C:22](=[O:25])[CH2:21]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:27][CH2:26][C:20]2([N:24]([CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[NH:23][C:22](=[O:25])[CH2:21]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)NN2
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)NN2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 39 %

Procedure:
4-Fluorobenzylbromide (0.37 mL, 2.97 mmol) was added dropwise to a solution of 84AF15 (289 mg, 1.13 mmol) in dry DMF (50 mL) at rt. The mixture was stirred at rt for 6 days under argon atmosphere. The solvent was removed by evaporation under reduced pressure and the residue partitioned between chloroform and water. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane, afforded the desired compound (160 mg, 39%).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[OH:1][CH:2]([CH2:3][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: C1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(O)CN1CCCCC1
Yield: 70.8 %

Procedure:
To a solution of 2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (1.0 g, 4.9 mmol) in ethanol (25 mL) was added piperidine (0.46 g, 5.4 mmol). The resulting reaction mixture was heated at reflux for 1 hour. After this time, TLC analysis showed no starting material remaining so the mixture was concentrated to afford the title product as oil (1.0 g). The titled product structure was confirmed by LC/MS analysis. MS m/z: 289.21 [M+H]+. The resulting hydroxylamine was dissolved in ethanol (20 mL) and to which was added hydrazine (0.86 g, 7.36 mmol). The resulting reaction mixture was stirred at ambient temperature for over night. After this time, TLC analysis showed no starting material remaining so the mixture was concentrated to afford the title product as oil (0.4 g). MS m/z: 159.2 [M+H]+. The crude was used as such for the next step transformation.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.O[CH2:12][NH:13]C(=O)C(F)(F)F>>[CH:1]1[C:10]2[C:5](=[C:6]([NH:13][CH3:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: c1ccc2cnccc2c1
Reactant: O=C(NCO)C(F)(F)F
Product: CNc1cccc2cnccc12

Procedure:
Isoquinoline is reacted with N-(hydroxymethyl)trifluoroacetamide in acid followed by reduction to afford isoquinolin-5-yl-methylamine. Carbamylation using aminotetralin as described above, produces aminotetralin-derived ureas in which L═CH2 (methylene) (Scheme 7).
Reaction SMILES: OC1C(C)=NC([Br:9])=CN=1.O[C:11]1[C:16]([CH2:17][CH3:18])=[N:15][C:14]([Br:19])=[CH:13][N:12]=1>>[Br:9][C:11]1[C:16]([CH2:17][CH3:18])=[N:15][C:14]([Br:19])=[CH:13][N:12]=1
Reactant: Cc1nc(Br)cnc1O
Reactant: CCc1nc(Br)cnc1O
Product: CCc1nc(Br)cnc1Br

Procedure:
By replacing the 2-hydroxy-3-methyl-5-bromopyrazine used in Step A of Preparation 87 by an equivalent quantity of 2-hydroxy-3-ethyl-5-bromopyrazine and following substantially the same procedure, there is obtained 2,5-dibromo-3-ethylpyrazine.
Reaction SMILES: [Sn](Cl)[Cl:2].[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:15]=1[C:16]#[N:17])([O-])=O>Cl.C(O)C>[ClH:2].[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:14]2[NH:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:4]=[C:16]([NH2:17])[C:15]=2[CH:18]=1
Reactant: Cl[Sn]Cl
Reactant: N#Cc1cc(C(F)(F)F)ccc1Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: NC1=Nc2ccccc2Nc2ccc(C(F)(F)F)cc21
Yield: 89.9 %

Procedure:
Add a solution of tin(II) chloride (567 mg, 3 mmol) in 12 N hydrochloric acid (1.8 mL) to a solution of 2-(2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile (307 mg, 1 mmol) in ethanol (10 mL). Reflux for 24 hours, then concentrate under vacuum, add water and filter. Wash the resulting solid with water and dichloromethane then dry under vaccum to yield the titled compound as a yellow solid (282 mg, 90%): mp 334–336° C.; 1H NMR (DMSO-d6) δ 7.05–7.19 (m, 4H), 7.34 (d, 1H), 7.86 (dd, 1H), 7.87 (s, 1H), 8.79 (s, 1H), 9.26 (s, 1H), 9.75 (s, 1H), 12.40 (s, 1H). MS (ESI/neg) m/z (rel intensity) 276.1 (100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][C:3]=1[OH:10].[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[C:36](OC)(OC)(OC)[CH3:37]>CCO.CC(=O)OCC>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]2[N:1]=[C:36]([CH3:37])[O:10][C:3]=2[CH:4]=1
Reactant: Cc1cc(N)c(O)cc1Br
Reactant: COC(C)(OC)OC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc2cc(C)c(Br)cc2o1
Temperature: 90 °C

Procedure:
A mixture of 2-amino-5-bromo-4-methylphenol (42) (290 mg), trifluoromethanesulfonic acid Ytterbium (III) salt (20 mg, 1% mol) and trimethyl orthoacetate (216 μl, 1.5 eq.) in 2 ml EtOH was heated at 90° C. for 2 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine, dried over Na2SO4, concentrated to dryness. The resulting brown solid was dissolved in DCM and subjected to silica gel column purification using 0-60% B (A: hexane; B: 50% EA in hexane) to furnish 148 mg 6-bromo-2,5-dimethylbenzoxazole (48) as pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][CH2:9][OH:10])[CH:7]=1
Reactant: Nc1ccc(F)c(CC(=O)O)c1
Solvent: C1CCOC1
Product: Nc1ccc(F)c(CCO)c1
Temperature: 50 °C
Yield: 58.9 %

Procedure:
Borane-THF complex (1M, 11.8 mL, 11.8 mmol) was added to a solution of (5-amino-2-fluoro-phenyl)-acetic acid (1.00 g, 5.91 mmol) in dry THF (10 mL), under argon, over 20 min. Once the effervescence had ceased, the reaction mixture was heated to 50° C. for 2 h. The mixture was left to cool and then concentrated in vacuo. The residue was re-dissolved in DCM (25 mL) and treated with MeOH (2 mL). The mixture was stirred vigorously and then concentrated in vacuo. The residue was dissolved in MeOH (25 mL) and re-concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to afford the title compound (0.54 g, 59%). LCMS (Method 3): Rt: 0.41 min, m/z 156 [MH+].
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:18])[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[N:8]2[CH2:13][CH2:12][CH2:11][S:10][C:9]=12)([O-])=O.[C:19](O)(=[O:21])[CH3:20]>[Zn]>[C:19]([NH:1][C:4]1[C:5](=[O:18])[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[N:8]2[CH2:13][CH2:12][CH2:11][S:10][C:9]=12)(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: CCCn1c(=O)c([N+](=O)[O-])c2n(c1=O)CCCS2
Agent: [Zn]
Product: CCCn1c(=O)c(NC(C)=O)c2n(c1=O)CCCS2
Yield: 79 %

Procedure:
Zinc powder (1,21 g) was added to a solution of 9-nitro-7-propyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (1 g) in acetic acid (10 ml) and the mixture was refluxed for 4 hours. An insoluble material was removed by filtration, and the filtrate was concentrated to obtain syrup. The syrup was purified by column chromatography on silica gel. The resulting crude crystals were recrystallized from methylene chloride-hexane to give colorless needles (0.83 g, 79%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][CH:6]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[N:15]([CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][CH:6]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ccc2[nH]cc(CCCBr)c2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCc1c[nH]c2ccc(Cl)cc12

Procedure:
A mixture of 3-(3-bromopropyl)-5-chloro-1H-indole (0.730 g; 2.68 mmol) and sodium azide (0.522 g; 8.03 mmol) was stirred in DMF (5 mL) for 18 hours and was then concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. After separation, the organic layer was dried over magnesium sulfate and the volatiles were evaporated under reduced pressure to give quantitatively 3-(3-azidopropyl)-5-chloro-1H-indole as an oily residue which was used without purification in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Br:23])=[C:20]([CH3:22])[CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:33][C:34](=O)[NH:35][C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]3=[O:48])=[CH:38][C:37]=2[F:49])=CC=1)([O-])=O>>[F:49][C:37]1[CH:38]=[C:39]([N:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]2=[O:48])[CH:40]=[CH:41][C:36]=1[NH:35][C:34]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Br:23])=[C:20]([CH3:22])[CH:21]=2)=[O:16])[CH2:9]1)=[O:33]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(C(=O)NC[C@H]2CCNC2)sc1Br
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)NC[C@H]2CCN(C(=O)Nc3ccc(-n4ccccc4=O)cc3F)C2)sc1Br

Procedure:
57.3 Using general method H, 5-bromo-4-methyl-thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(5-bromo-4-methyl-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. White solid. MS 530.8 ([M−H]−)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)/[C:7]1=[O:22])=[O:5])[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[N:31][C:32]([O:34][Si](C)(C)C)=[CH2:33])[CH:27]=[CH:28][CH:29]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:33][C:32](=[O:34])[NH:31][CH:30]2[C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=2)[C:7]1=[O:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C(=O)/C(=C\C2CCCC2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)NC(=O)CC2C1CCCC1
Yield: 52 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-cyclopentylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.32 g, 1.00 mmol) was reacted with 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b, in toluene to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclopentyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as an off-white foam (Yield 0.26 g, 52%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]([C:31](=[O:33])[CH3:32])[CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C:10]2[CH:34]=[CH:35][C:36](Br)=[CH:37][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39]B(O)O.[F-].[Cs+]>O1CCOCC1.ClCCl.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.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]([C:31](=[O:33])[CH3:32])[CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C:10]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)(C)C)c2cc(Br)ccc21
Reactant: CB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)(C)C)c2cc(C)ccc21
Yield: 29.6 %

Procedure:
Combine tert-butyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.438 g, 0.719 mmol), methylboronic acid (0.086 g, 1.44 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.059 g, 0.072 mmol) and cesium fluoride (0.328 g, 2.16 mmol) in dioxane (2.5 mL) in a 10 mL microwave vessel and irradiate this mixture at 110° C. for 80 min. Dilute the cooled mixture with dichloromethane and filter through Celite®. Remove the filtrate solvent under reduced pressure and purify the residue first using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to afford the title compound as a white solid (0.116 g, 30%).