Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][NH:4]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(N(CC)CC)C.Br[C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:11]1[C:12]2[C:7](=[CH:6][CH:5]=[N:4][CH:3]=2)[CH2:8][CH2:9][N:10]1[C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: c1cc2c(cn1)CNCC2
Reactant: CCOC(=O)c1cccc(Br)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(N2CCc3ccncc3C2)c1
Temperature: 95 °C
Yield: 5.7 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-2,7-naphthyridine dihydrochloride (41.4 mg, 0.20 mmol), cesium carbonate (326 mg, 1.0 mmol), and triethylamine (0.056 mL, 0.40 mmol) in 2.0 mL dioxane was warmed until the amine starting material had dissolved. The reaction filtrate was transferred into another reaction vial and the following added: a spatula portion of cesium carbonate, ethyl 3-bromobenzoate (0.032 mL, 0.20 mmol), palladium acetate (2.2 mg, 0.01 mmol) plus catalytic Pd2(dba)3, and RAC-BINAP (6.2 mg, 0.01 mmol). The reaction was heated at 95° C. for 17 hours, filtered, and evaporated to an oil. The oil was chromatograph eluting with CHCl3/EtOAc to give the title compound as a light yellow oil (3.2 mg, 6%). 1H NMR (CDCl3) δ: 8.46 (s, 1H), 8.39 (d, J=5.0 Hz, 1H), 7.66 (dd, J=2.3, 1.5 Hz, 1H), 7.54 (dt, J=7.5, 1.2 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.16 (dd, J=8.4, 1.9 Hz, 1H), 7.12 (d, J=5.0 Hz, 1H), 4.46 (s, 2H), 4.39 (q, J=7.1 Hz, 2H), 3.62 (t, J=5.9 Hz, 2H), 3.01 (t, J=5.7 Hz, 2H), 1.38-1.44 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:6]([F:10])=[C:5]([F:11])[C:3]=1[NH2:4].[Br:12]Br.C(=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[C:8]([F:9])=[C:7]([Br:12])[C:6]([F:10])=[C:5]([F:11])[C:3]=1[NH2:4]
Reactant: BrBr
Reactant: Nc1c(F)c(F)cc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1c(F)c(F)c(Br)c(F)c1F
Reaction time: 2 h

Procedure:
2,3,5,6-Tetrafluoroaniline (25.0 g, 0.15 mol) is dissolved in methanol (100 mL) and treated with elemental bromine (28.4 g, 0.17 mol) by dropwise addition at room temperature. Solid sodium bicarbonate (15 g, 0.18 mol) is added portionwise and the resulting mixture stirred for an additional 2 hours. The reaction mixture is partitioned between Et2O (500 mL) and water (1000 mL). The organic layer is dried (MgSO4) and evaporated by a rotary evaporator to give 2,3,5,6-tetrafluoro-4-bromoaniline (m.p. 59–60° C.).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:27]1([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([CH2:42]Br)[CH:36]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([O:34][CH2:33][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:36][C:37]=1[CH2:42][N:9]1[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])=[N:8]1
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: Clc1ccc(OCc2ccccc2)cc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2cc(OCc3ccccc3)ccc2Cl)n1)c1c(F)cccc1F
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for as preparation see Intermediate 9) (0.790 g, 3.54 mmol) in THF (30 ml) was added 1.0 M lithium bis(trimethylsilyl)amide in THF (3.54 ml, 3.54 mmol). The reaction mixture was stirred for 30 min. To the reaction mixture was added 3-(bromomethyl)-4-chlorophenyl phenylmethyl ether (1.11 g, 3.56 mmol) in THF (10 ml). The reaction was stirred overnight, under nitrogen at ambient temperature. The solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and water (70 ml). The phases were separated and the organic phase washed with brine (70 ml). The phases were separated and the organic phase was evaporated in vacuo. The sample was loaded in dichloromethane and purified on silica (2×100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an off-white gum (1.03 g);
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[O:12][CH2:13][P:14](=[O:21])([O:18]CC)[O:15]CC.C[Si](I)(C)C.CO>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[O:12][CH2:13][P:14](=[O:15])([OH:21])[OH:18]
Reactant: CCOP(=O)(COc1ccccc1-c1nc2ccccc2s1)OCC
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CO
Product: O=P(O)(O)COc1ccccc1-c1nc2ccccc2s1
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a stirred solution of diethyl 2-(2-benzthiazolyl)phenoxymethylphosphonate (0.2 g, 0.53 mmol) dissolved in dry dichloromethane (2.7 ml) under an atmosphere of nitrogen was added trimethylsilyl iodide (0.31 ml). The red solution was stirred for 2 h then methanol (4.3 ml) was added. After 2 h the solvent was removed under reduced pressure and then water (3.5 ml) was added to the residue. The mixture was concentrated under reduced pressure. Water (2 ml) was added and the mixture was concentrated under reduced pressure. This was repeated four times. The residue was washed finally with water then acetone to give 2-(2-benzthiazolyl)phenoxymethylphosphonic acid (0.13 g, 77%) δH (270 MHz, DMSO) 8.43 (1H, d, J 8 Hz), 8.04 (2H, m), 7.53 (2H, m), 7.44 (2H, m), 7.21 (1H, t, J 8 Hz), 4.4 (2H, d, J 12 Hz), δP (109.7 MHz, DMSO) 14.4
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH3:34])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([O:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO.Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH3:34])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc2c(c1)cc(C(=O)N1CCN(c3ccccc3C(C)(C)C)CC1)n2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc2cc(OCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A mixture of methyl [(2-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1-methyl-1H-indol-5-yl)oxy]acetate obtained in Example 30 (470 mg), 1 M sodium hydroxide solution (5 mL), methanol (50 mL), and tetrahydrofuran (50 mL) was stirred at room temperature for 2 h. 1 M hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (455 mg, 100%) as crystals.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([N:15](C)[C:16](=O)OC(C)(C)C)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCO.Cl>[CH3:16][NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: CCCCCCCCc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCCCCCCCc1ccc(NC)cc1
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of the product of Step A (0.14 g; 0.44 mmol) in 60% TFA in CH2Cl2 (5 ml) was stirred for 30 min at room temperature and the mixture was diluted to 5 ml with EtOH and a few drops of concentrated HCl was added. This was evaporated to dryness under reduced pressure, kept in vacuo for 1 h and the residue was partitioned between saturated NaHCO3 (5 ml) and Et2O (15 ml). The organic phase was dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc 9:1) to give the title compound (0.055 g; 57%), as a creamy solid. 1H-NMR (CDCl3) 7.01 (d, 2H, J=8.2 Hz); 6.55 (d, 2H, J=8.2 Hz); 3.55 (broad s, 1H); 2.81 (s, 3H); 2.49 (t, 2H, J=7.9 Hz); 1.56 (m, 2H); 1.28 (m, 10H); 0.88 (t, 3H, J=6.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=[C:5]([O:17][CH3:18])[N:4]=1.CN(CCN(C)C)C.C([Li])CCC.Cl[C:33]([O:35][CH3:36])=[O:34]>CCOCC>[C:33]([C:7]1[CH:6]=[C:5]([O:17][CH3:18])[N:4]=[C:3]([O:2][CH3:1])[C:8]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])([O:35][CH3:36])=[O:34]
Reactant: COC(=O)Cl
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(OC)n1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: COC(=O)c1cc(OC)nc(OC)c1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 34.5 %

Procedure:
The product of Example 27 (1 g, 3.93 mmol) was dissolved in Et2O (35 mL) and TMEDA (1.7 mL, 1.18 mmol) and cooled to -78° C. n-Butyllithium (4.75 mL, 11.87 mmol) was added dropwise and the reaction was allowed to stir for 15 minutes at -78° C. before warming to -10° C. for 2.5 hours. The solution was cooled back to -78° C. and methyl chloroformate (0.6 mL, 7.8 mmol) dissolved in Et2O (4.5 mL) was added dropwise. The reaction was held at -78° C. for 10 minutes and then warmed to -10° C. and allowed to stir for 1.5 hours before quenching with NH4Cl (sat). The reaction mixture was extracted 3× with EtOAc. The organics were combined, washed with brine, dried over MgSO4, concentrated in vacuo. The residue was purified by column chromatography using hexane/ethyl acetate as eluant (gradient 9/1 to 4/1) to provide 0.423 g (34%) of tert-butyl N-(4-carbomethoxy-2,6-dimethoxy-3-pyridyl)carbamate as a white solid. Electrospray Mass Spec: 312.8 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[N:5].BrCC1C=CC=C(C#N)C=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2([C:28]3=[CH:29][C:30]4[O:34][CH2:33][O:32][C:31]=4[CH:35]=[C:27]3[O:26][CH2:25]2)[C:17]1=[O:36]>>[O:36]=[C:17]1[C:18]2([C:28]3=[CH:29][C:30]4[O:34][CH2:33][O:32][C:31]=4[CH:35]=[C:27]3[O:26][CH2:25]2)[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]1[CH2:2][CH2:3][C:4]#[N:5]
Reactant: N#CCCBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: N#Cc1cccc(CBr)c1
Product: N#CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 44 and making non-critical variations using 3-bromopropionitrile to replace α-bromo-m-tolunitrile, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propanenitrile was obtained (86%) as a colorless solid: mp 200-202° C.; 1H NMR (300 MHz, DMSO-d6) δ7.32 (ddd, J=7.6, 7.4, 1.2 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.15 (d, J=6.7 Hz, 1H), 7.04 (ddd, J=7.4, 7.4, 1.0 Hz, 1H), 6.66 (s, 1H), 6.24 (s, 1H), 5.89 (d, J=2.2 Hz, 2H), 4.69 (ABq, J=9.3 Hz, 2H), 4.10-3.88 (m, 2H), 2.95 (t, J=6.5 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.1, 155.8, 148.8, 142.2, 141.9, 132.3, 129.3, 124.1, 123.7, 120.1, 119.1, 109.8 103.6, 101.9, 93.7, 80.3, 57.9, 35.9, 16.2; MS (ES+) m/z 335.1 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([OH:22])=O)[CH2:3][CH2:2]1.Cl.Cl.[CH3:25][C@H:26]1[CH2:31][C@H:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:29][CH2:28][NH:27]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:27]2[CH2:28][CH2:29][C@@H:30]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:31][C@@H:26]2[CH3:25])=[O:22])[CH2:2][CH2:3]1
Reactant: C[C@H]1C[C@H](N2CCCC2)CCN1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)O
Agent: Cl
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CC[C@@H](N2CCCC2)C[C@@H]1C

Procedure:
The title compound was prepared from 5-cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid (Example 181A) and (trans)-2-methyl-4-pyrrolidin-1-yl-piperidine dihydrochloride (example 199B) in direct analogy to the general procedure used in example 150. MS: 461.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:7]=2)[CH:3]=1.[CH3:43][N:44]([Sn](CCCC)(CCCC)CCCC)[CH3:45]>C1(C)C=CC=CC=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.Cl[Pd]Cl>[CH3:43][N:44]([CH3:45])[C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:7]=2)[CH:3]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)N(C)C
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(N(C)C)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 120 °C

Procedure:
(±)-tert-Butyl 4-((1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (150 mg, 0.226 mmol), trans-dichlorobis(tri-o-tolylphosphine)palladium (II) (17.79 mg, 0.023 mmol), and dimethylaminotri-n-butyltin (0.28 mL, 0.905 mmol) were combined in toluene (1.5 mL) in a microwave tube and sealed. After flushing the mixture with nitrogen, the mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated, dissolved in ethyl acetate, washed with water and brine, concentrated and purified by flash chromatography on silica gel (15-30% EtOAc/Hex) to afford 115 mg (80.8%) as yellow oil. 1H-NMR (CDCl3, 500 MHz) δ 7.81 (s, 1H), 7.30 (m, 2H), 6.97 (m, 2H), 6.84 (s, 1H), 5.54 (s, 1H), 5.59 (m, 2H), 4.94 (q, J=5 Hz, 1H), 3.6-3.75 (m, 2H), 3.54 (m, 2H), 3.43 (d, J=10 Hz, 1H), 3.31 (d, J=10 Hz, 2H), 3.00-3.10 (m, 2H), 2.81 (s, 6H), 2.03-2.12 (m, 2H), 1.85-1.95 (m, 2H), 1.43 (d, J=10 Hz, 3H), 1.41 (s, 9H), 0.85-0.90 (m, 2H), −0.09 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 171.1, 161.3 (d, J=975 Hz), 155.0, 147.0, 143.4, 139.2, 134.1, 128.9, 123.5, 120.9, 115.4, 115.1, 114.9, 97.2, 81.5, 79.3, 74.4, 67.0, 60.4, 41.9, 41.2, 32.3, 28.5, 27.9, 26.9, 23.1, 21.1, 17.8, 17.6, 14.3, 13.7, −1.36; Mass spec.: 627.60(MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Cl[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:21][C:20]([F:23])([F:22])[C:16]1[N:15]=[C:14]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1CCCc2cc(Oc3cccc(C(F)(F)F)n3)ccc21
Temperature: 120 °C
Yield: 61.3 %

Procedure:
To a solution of 6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (5.0 g, 30.8 mmol) and 2-chloro-6-(trifluoromethyl)pyridine (5.87 g, 32.3 mmol) in ACN (100 mL) was added potassium carbonate (6.39 g, 46.2 mmol), and the reaction was heated at 120° C. in a sealed vessel overnight. The reaction was cooled, diluted with water (100 mL), and extracted with EtOAc (100 mL×3). Organics were dried (Na2SO4), and concentrated. Purification by silica gel chromatography (10-80% EtOAc/hexanes) gave 5.8 g (61%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 2.13-2.20 (2H, m), 2.67 (2H, t, J=6.2 Hz), 2.97 (2H, t, J=6.0 Hz), 7.07-7.14 (2H, m), 7.45 (1H, d, J=7.4 Hz), 7.89 (1H, t, J=8.0 Hz), 8.09 (1H, d, J=8.3 Hz). [M+H] calc'd for C16H12F3NO2, 308; found 308.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]=[C:14]1[NH:18][CH:17]([CH2:19]Cl)[CH2:16][S:15]1>CO>[CH3:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]=[C:14]1[NH:18][CH:17]([CH2:19][NH:2][CH3:1])[CH2:16][S:15]1
Reactant: CN
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC(CCl)CS1
Solvent: CO
Product: CNCC1CSC(=Nc2ccc([N+](=O)[O-])cc2C)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35 %

Procedure:
To a solution of methylamine in methanol (2.0M, 5 mL) was added 2-(2-methyl-4-nitrophenylimino)-4-(chloromethyl)-1,3-thiazolidine (prepared in a manner analogous to that described in Method C2a; 0.040 g, 0.140 mmol) and the resulting mixture was stirred at room temp for 72 h. The mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (5% MeOH/CH2Cl2) to give 2-(2-methyl-4-nitrophenylimino)-4-(N-methylaminomethyl)-1,3-thiazolidine as a solid (0.014 g, 35%).
Reaction SMILES: Br[CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[Cl:9][C:10]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=1[NH2:12].O(C1C=C(C=CC=1)CBr)C1C=CC=CC=1>>[Cl:9][C:10]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=1[NH:12][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([CH3:8])[CH3:7]
Reactant: Cc1ccc(N)c(Cl)c1
Reactant: CC(C)C(Br)C(=O)O
Agent: BrCc1cccc(Oc2ccccc2)c1
Product: Cc1ccc(N[C@H](C(=O)O)C(C)C)c(Cl)c1

Procedure:
N-(2-chloro-4-methylphenyl)valine is prepared as above from α-bromoisovaleric acid and 2-chloro-4-methylaniline and then reacted with m-phenoxybenzyl bromide, as above, to yield the m-phenoxybenzyl ester of N-(2-chloro-4-methylphenyl)valine. MS m/e 423 (M+, 4), 196 (100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)(=[O:36])=[O:35])=[CH:32][CH:33]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(OC)cc4)cc3)cc2C1=O

Procedure:
The compound of example 89 was prepared analogous to compound of example 77 by reaction of compound of example 6 with 4-methoxybenzene sulfonyl chloride. The compound of example 89 was used directly without isolation for the preparation of compound of example 90.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)(=O)=O.[CH3:19][O:20][C:21]([N:23]1[CH2:27][CH:26]=[CH:25][CH2:24]1)=[O:22].[Cl-].[Li+].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][O:20][C:21]([N:23]1[CH2:27][CH2:26][CH:25]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)[CH2:24]1)=[O:22]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: COC(=O)N1CC=CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C2CCN(C(=O)OC)C2)cc1
Temperature: 90 °C
Reaction time: 11 h

Procedure:
In N,N-dimethylformamide (25 ml), methyl 4-trifluoromethanesulfonyloxybenzoate (1.05 g), 1-methoxycarbonyl-3-pyrroline (1.0 g), lithium chloride (0.51 g), palladium (II) acetate(53 mg) and tri(2-furyl)phosphine (100 mg) were dissolved, followed by the addition of diisopropylethylamine (2.8 ml). Under an argon gas atmosphere, the resulting mixture was stirred at 90° C. for 11 hours and then, at 100° C. for 7 hours. The residue obtained by distilling off the solvent under reduced pressure was added with dichloromethane and water. The organic layer so separated was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=9:1˜5:1). The purified product was dissolved in methanol (30 ml), followed by the addition of 10% palladium carbon (water content: about 50%, 186 mg) and ammonium formate (197 mg). The resulting mixture was heated under reflux for 2 hours. After the removal of the catalyst by filtration, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (10% ethyl acetate-toluene), whereby the title compound (241 mg, 25%) was obtained.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]([N:12]1[C:17](=[O:18])[CH2:16][O:15][CH:14]([C:19]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[CH2:27][CH2:26][CH2:25]3)=[O:20])[CH2:13]1)([CH3:11])[CH3:10].O.C(OCC)(=O)C>O1CCCC1>[OH:20][C:19]([O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][CH2:26][CH2:25]2)([CH:14]1[O:15][CH2:16][C:17](=[O:18])[N:12]([CH:9]([CH3:10])[CH3:11])[CH2:13]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)N1CC(C(=O)Oc2ccc3c(c2)CCC3)OCC1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)N1CC(C(O)(Oc2ccc3c(c2)CCC3)c2ccccc2)OCC1=O
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A solution of 2.7 g. of phenylmagnesium bromide in 20 ml. of tetrahydrofuran was added dropwise to a mixture of 3.03g. of 4-isopropyl-5-oxo-2-(1-oxo-5-indanyloxymethyl)morpholine in 100 ml of tetrahydrofuran with stirring at room temperature and the mixture thus obtained was stirred for 30 minutes. Then, after adding to the mixture a small amount of water, tetrahydrofuran was distilled off under reduced pressure. To the residue formed were added 100 ml. of ethyl acetate and 100 ml. of water to dissolve the residue and the ethyl acetate layer formed was recovered, washed twice each with 50 ml. of water and then 50 ml. of saturated aqueous sodium chloride aqueous solution, and then ethyl acetate was distilled off. The residue formed was adsorbed on a silica gel column prepared from 150 ml. of silica gel in chloroform and then eluted with ethyl acetate. After removing the first 10 ml. of the ethyl acetate eluate emerging from the column, 300 ml. of the subsequent ethyl acetate eluate was collected and dried to provide 2.93 g. (yield 77%) of oily 2-(1-hydroxy-1-phenyl-5-indanyloxymethyl)-4-isopropyl-5-oxomorpholine.
Reaction SMILES: CON(C)[C:4]([C:6]1[O:10][C:9]([CH3:11])=[N:8][C:7]=1[CH3:12])=[O:5].[CH3:14][CH:15]([Mg]Cl)[CH3:16]>>[CH3:14][CH:15]([C:4]([C:6]1[O:10][C:9]([CH3:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:16]
Reactant: CON(C)C(=O)c1oc(C)nc1C
Reactant: CC(C)[Mg]Cl
Product: Cc1nc(C)c(C(=O)C(C)C)o1

Procedure:
Starting with N-methoxy-N-methyl-2,4-dimethyl-5-oxazolecarboxamide and 2-propyl magnesium chloride and following the general method of Preparation 3, the title compound was obtained.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]([CH:13]([CH2:16][CH3:17])[CH2:14]O)[CH3:12]>C([O-])(=O)C([O-])=O.[Sn+4].C([O-])(=O)C([O-])=O.O>[C:1]([O:10][CH2:14][CH:13]([CH2:16][CH3:17])[CH2:11][CH3:12])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)O
Reactant: CCC(CC)CO
Agent: O=C([O-])C(=O)[O-]
Agent: [Sn+4]
Solvent: O
Product: CCCCCCCC(=O)OCC(CC)CC
Temperature: 10 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
187.2 g (1.3 mol) of caprylic acid, 214.0 g (2.09 mol) of 2-ethylbutanol and 0.14 g of tin oxalate (“Fascat 2001”) were heated to 160° C. under N2, during which water separation was observed. Once water separation had subsided, the mixture was heated to 210° C. in 10° C. steps. This temperature was then held for 3 h. Then, firstly the excess alcohol was removed by distillation and then the product was distilled at 8-12 mbar and 136-141° C. The product (225.6 g) was obtained as a clear liquid with an acid number of 0.47 and an OH number of 1.36.