Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([C:6]1[N:7]([C:11]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]3[C:12]=2[NH:13][CH:14]=[N:15]3)[CH:8]=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5].[C:21]1([CH3:47])[CH:26]=[CH:25][C:24]([C:27]([O:29][C@@H:30]2[C@@H:34]([CH2:35][O:36][C:37]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)=[O:38])[O:33][C@H:32](Cl)[CH2:31]2)=[O:28])=[CH:23][CH:22]=1>CC#N.C(Cl)Cl>[CH2:2]([C:6]1[N:7]([C:11]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:32]2[O:33][C@H:34]([CH2:35][O:36][C:37]([C:39]3[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=3)=[O:38])[C@@H:30]([O:29][C:27]([C:24]3[CH:23]=[CH:22][C:21]([CH3:47])=[CH:26][CH:25]=3)=[O:28])[CH2:31]2)[CH:8]=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Reactant: CCCCc1nccn1-c1nc(Cl)nc2nc[nH]c12
Agent: [Na]
Solvent: CC#N
Solvent: ClCCl
Product: CCCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1

Procedure:
The sodium salt of 6-(2-butylimidazol-1-yl)-2-chloropurine (0.139 g, 0.5 mmol) in dried CH3CN (10 mL) was treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (0.334 g, 0.86 mmol) in CH2Cl2 (10 mL) by general method 2. Sampling of the reaction mixture showed traces of α-nucleoside by 1H NMR (500 MHz) (1:24). Volatiles were evaporated in vacuo, and the residue was chromatographed (25 g silica gel, EtOAc/hexanes, 3:7→EtOAc) to give the β-anomer (274 mg, 86%) with traces of the α-anomer. Recrystallization (EtOAc/hexanes) gave 6-(2-butylimidazol-1-yl)-2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]purine: UV (MeOH) max 223, 241, 287 nm (∈ 29 900, 33 400, 13 200), min 230, 265 nm (∈ 28 100, 7500); 1H NMR (500 MHz, CDCl3) δ 8.51 (s, 1H), 8.26 (s, 1H), 7.98 (d, J=8.0 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.09 (s, 1H), 6.60 (t, J=6.9 Hz, 1H), 5.80 (br s, 1H), 4.78-4.81 (m, 1H), 4.66-4.70 (m, 2H), 3.31 (t, J=7.8 Hz, 2H), 2.97-3.00 (m, 2H), 2.46 (s, 3H), 2.37 (s, 3H), 1.80 (quint, J=7.4 Hz, 2H), 1.50 (sext, J=7.4 Hz, 2H), 0.97 (t, J=7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 166.05, 165.98, 154.13, 153.17, 151.43, 147.92, 144.71, 144.39, 142.18, 129.87, 129.53, 129.35, 129.31, 128.91, 126.38, 126.20, 122.70, 120.33, 85.20, 83.57, 74.94, 63.87, 38.61, 30.70, 30.07, 22.64, 21.79, 21.66, 13.91; HRMS 771/z 629.2270 (MH+[C33H34ClN6O5=629.2279]).
Reaction SMILES: [NH2:1][C:2]1([C:9]([OH:11])=O)[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][CH2:5]2.N[C:13]1([CH2:20]O)[CH2:18]C2C[CH:14]1CC2.NO.C(Br)C(C)C>CN(C=O)C>[CH2:14]([NH:1][C:2]1([CH2:9][OH:11])[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][CH2:5]2)[CH:13]([CH3:20])[CH3:18]
Reactant: NC1(C(=O)O)CC2CCC1C2
Reactant: NC1(CO)CC2CCC1C2
Agent: NO
Solvent: CN(C)C=O
Solvent: CC(C)CBr
Product: CC(C)CNC1(CO)CC2CCC1C2

Procedure:
2-Aminonorbornane-2-carboxylic acid was converted into 2-amino-2-(hydroxymethyl)norbornane as a diastereomeric mixture in a manner analogous to Method B1a. A solution of the amino alcohol (0.31 g, 2.16 mmol) and isobutyl bromide (0.23 ml, 2.16 ml) in DMF (3 mL) was heated at 90° C. for 92 h, then cooled to room temp. and partitioned between EtOAc (100 mL) and a saturated NaHCO3 solution (100 mL). The organic layer was washed with a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure to yield 2-(isobutylamino)-2-(hydroxymethyl)norbornane as a diastereomeric mixture (0.24 g, 55%): GC-MS m/z 197 (M+).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([N:6]([C:16](=[O:35])[CH:17]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:18](=[O:27])[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:5].[Li+].[OH-]>C1COCC1.O>[CH:21]1([CH2:20][CH2:19][C:18](=[O:27])[CH:17]([CH2:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[C:16]([N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:4]([CH3:5])[C:3]([OH:36])=[O:2])=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)C(C)N(Cc1ccc(OC)cc1)C(=O)C(CC1CCCCC1)C(=O)CCC1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)C(CC2CCCCC2)C(=O)CCC2CCCCC2)C(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 8 %

Procedure:
To a solution of methyl esters 59 (200 mg, 4.00 mmol) in THF/H2O (25 mL/4.5 mL) was added LiOH (1 M in H2O, 0.50 mL, 4.4 mmol) at 10° C. dropwise. The reaction mixture was stirred at ambient temperature for 12 h and THF was removed under reduced pressure. The aqueous layer was acidified to pH2 with 1 M HCl and extracted with CH2Cl2 (25 mL×3). The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (1:3 EtOAc/hexanes) to give the desired acids 60 (155 mg, 80%) as a white solid. IR (neat) 3199, 1719, 1648, 1612 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.18 (d, J=8.5 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 4.69 (d, J=17.5 Hz, 1H), 4.54 (q, J=7.0 Hz, 1H), 4.34 (d, J=17.0 Hz, 1H), 3.80 (s, 3H), 3.64 (dd, J=5.5, 8.5 Hz, 2H), 2.49 (dd, J=7.0, 8.5 Hz, 2H), 1.91 (ddd, J=6.0, 8.5, 14.0 Hz, 1H), 0.69-1.70 (m, 28H); LRMS (ESI) Calcd. for C29H43NO5 [M+H] 486, found 486.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=1>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:13]([F:18])[CH:12]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Product: Fc1cc(Br)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred mixture of phenylboronic acid (1.20 g, 9.85 mmol) and 4-bromo-2-fluorophenol (0.94 g, 4.92 mmol) in DCM (50.00 mL) was added cupric acetate (1.34 g, 7.39 mmol), powdered 4 A molecular sieves and TEA (3.43 mL, 24.6 mmol) at rt. The resulting mixture was then stirred at rt for 24 h at ambient atmosphere. The solvent was then removed under reduced pressure and the resulting residue was purified by flash chromatography (5% EtOAc in hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18](=[O:19])[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[OH:20])[CH:5]=[CH:6][C:7]=1[Cl:8].O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18](=[O:19])[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[O:20][C:22](=[O:24])[CH3:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]c2nccnc2c(O)c1-c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Oc1c(-c2ccc(Cl)c(Cl)c2)c(=O)[nH]c2nccnc12
Reaction time: 16 h

Procedure:
Crude 7-(3,4-dichlorophenyl)-8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (0.13 g) was heated in acetic anhydride (10 mL) for 3 hours and then allowed to cool and stored at ambient temperature for 16 hours. The reaction mixture was poured onto ice and water, stirred vigorously and extracted with ethyl acetate. The organic extract was washed with water and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:1) to give Compound B29 of Table B as a yellow solid (0.077 g).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([N:20]3[CH2:25][CH2:24][Si:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]3)=[C:15]([F:28])[CH:14]=2)[CH2:8]1)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+].O>CN(C=O)C>[N:29]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([N:20]3[CH2:21][CH2:22][Si:23]([CH3:26])([CH3:27])[CH2:24][CH2:25]3)=[C:15]([F:28])[CH:14]=2)[CH2:8]1)=[N+:30]=[N-:31]
Reactant: C[Si]1(C)CCN(c2c(F)cc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si]1(C)CCN(c2c(F)cc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To the Mesyl compound 18a (320 mg, 0.74 mmol) in DMF, NaN3 (63 mg, 0.97 mmol) is added and stirred at 60° C. for 2 h. Water (5 mL) is added and extracted with DCM (2×5 mL), dried and concentrated. The crude (300 mg) is used for further steps without purification.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[O:10][C:9]([CH2:13][OH:14])([CH2:11][OH:12])[C@@H:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:7]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:6]1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1>CN(C)C=O>[CH2:1]([O:4][CH:5]1[O:10][C:9]([CH2:11][O:12][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)([CH2:13][O:14][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[CH:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:2]=[CH2:3]
Reactant: COc1ccc(CBr)cc1
Reactant: C=CCOC1OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1OC(COCc2ccc(OC)cc2)(COCc2ccc(OC)cc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Temperature: 0 °C
Yield: 51.7 %

Procedure:
The starting diol [((3S,4S,5R)-6-allyloxy-3,4,5-tris-benzyloxy-2-hydroxymethyl-tetrahydro-pyran-2-yl)-methanol (I-1b: 10 g, 19.208 mmol) was dissolved in N,N-dimethylformamide (70 mL) and cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 1.69 g, 42.3 mmol) was added and the reaction was allowed to stir at 0° C. for 1 hour before the addition of 1-bromomethyl-4-methoxy-benzene (5.96 mL, 40.3 mmol). The reaction was then heated to 60° C. overnight. The mixture was cooled down to room temperature and the reaction was quenched with water and extracted with ethyl acetate (2 times). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The reaction was then chromatographed over silica gel (eluting with a gradient of 0 to 80% ethyl acetate in heptane) yielding 7.55 g (52% yield) of product (I-1c). MS 778.8 (M+NH4+; positive mode).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=3[CH:31]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:35])=O.ClC(Cl)C.C(=O)(O)[O-].[Na+]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:35])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=3[CH:31]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)c1nc(O)c2cc(Oc3ccc4oc(N(C)C)nc4c3)ccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCCOC(=O)c1nc(Cl)c2cc(Oc3ccc4oc(N(C)C)nc4c3)ccc2c1O
Temperature: 120 °C
Yield: 58.1 %

Procedure:
A mixture of 7-(2-dimethylamino-benzooxazol-5-yloxy)-1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester (364 mg, 0.83 mmol), phosphorus oxychloride (92 μL, 1.00 mmol) and dichloroethane (4.5 mL) was stirred at 120° C. in a CEM microwave apparatus for thirty minutes. The mixture was then stirred with saturated sodium bicarbonate for fifteen minutes at ambient temperature. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (220 mg): MS: (+) m/z 456.32 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=3[S:16](=[O:27])(=[O:26])[CH2:15][CH2:14]2)[CH:3]=1.[O:28]1[CH2:31][C:30]([CH2:34][NH2:35])([CH2:32][NH2:33])[CH2:29]1>>[NH2:33][CH2:32][C:30]1([CH2:34][NH:35][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=4[S:16](=[O:26])(=[O:27])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:31][O:28][CH2:29]1
Reactant: NCC1(CN)COC1
Reactant: COc1ccc2c(c1)S(=O)(=O)CCN(c1cc(Cl)c3cc(Cl)ccc3n1)C2
Product: COc1ccc2c(c1)S(=O)(=O)CCN(c1cc(NCC3(CN)COC3)c3cc(Cl)ccc3n1)C2

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6-dichloroquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 3-13) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 503, 1H NMR (400 MHz, CD3OD) δ ppm 8.23 (s, 1 H), 7.88 (d, J=8.59 Hz, 1 H), 7.73 (d, J=8.84 Hz, 1 H), 7.65-7.51 (m, 2 H), 7.21 (dd, J=8.34, 2.78 Hz, 1 H), 6.30 (s, 1 H), 5.26 (brs, 2 H), 4.76-4.60 (m, 6 H), 4.56 (brs, 1 H), 3.91 (s, 2 H), 3.85 (s, 3 H), 3.69 (brs, 2 H), 3.52 (s, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][S:10][C:11]#[N:12].[BrH:14].C(O)(=O)C.O>C(O)(=O)C>[Br:14][C:11]1[S:10][CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:12]=1
Reactant: N#CSCC(=O)c1ccccc1F
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccccc1-c1csc(Br)n1
Temperature: 130 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-oxoethyl thiocyanate (4.20 g, 21.5 mmol) in acetic acid (40 ml) was added a solution of 25% hydrogen bromide/acetic acid (40 ml), and the mixture was stirred at 130° C. for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (3.41 g, 61.4%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:14])=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([F:8])=[CH:6][CH:7]=1.CC(O)=O.[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[CH2:20]>CO>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:19][CH2:20][NH:1][C:2]1[C:3]([F:14])=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: C=Cc1ccccn1
Reactant: COC(=O)Cc1c(F)ccc(N)c1F
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Cc1c(F)ccc(NCCc2ccccn2)c1F

Procedure:
A solution of 402 mg (2.0 mmol) of methyl 3-amino-2,6-difluorophenylacetate (prepared in step 3 of example 24) in 15 mL of MeOH was treated with 1.1 mL (20.0 mmol) of HOAc and 0.28 mL (2.6 mmol) of 2-vinylpyridine. The reaction mixture was stirred at reflux for 16 h. The mixture was cooled and the acetic acid was removed in vacuo. The residue was dissolved in EtOAc and washed with saturated NaHCO3 (4×5 mL), water (1×10 mL) and brine. Column chromatography (1:4 EtOAc/Hex) afforded methyl 3-(2-pyridylethyl)amino-2,6-difluorophenylacetate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].II>C(OCC)C.C1(C)C=CC=CC=1.[Zn]>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[OH:12]
Reactant: O=C1CCc2c(F)cc(F)cc21
Reactant: CCOC(=O)CBr
Agent: II
Agent: [Zn]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(O)CCc2c(F)cc(F)cc21
Reaction time: 24 h
Yield: 110.7 %

Procedure:
A mixture of 4,6-difluoro-1-indanone (12.6 g, 0.08 mol), ethyl bromoacetate (19.0 g, 0.11 mol, Aldrich), activated zinc powder (7.5 g, 0.11 mol, Aldrich; Org. Syn., Coll. Vol. 6, 290, 1988) and a few crystals of iodine in diethyl ether:toluene (1:1, 300 mL) was heated at 30-35° C. under a nitrogen atmosphere for 24 h. A few more crystals of iodine were added, the temperature was adjusted to 40-45° C., and the mixture was kept at that temperature for an additional 24 h. The reaction mixture was filtered and concentrated in vacuo. The residue was treated with a mixture of diethyl ether (450 mL), concentrated ammonium hydroxide (135 mL) and water (135 mL). The aqueous phase was separated and extracted with diethyl ether. The combined organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo to give 22.7 g of crude Ethyl 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetate which was Chromatographed on silica gel with dichloromethane:hexanes (9:1) as eluent gave 12.7 g (66%) of a yellow oil; NMR (CDCl3): d 6.67-6.88 (m, 2H), 4.22 (q, 2H), 3.02 (m, 1H), 2.75 (2m's, 3H), 2.31 (m, 2H), 1.28 (t, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:20])[S:8]([C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[OH-].[Na+].CN(C)[CH:25]=[O:26]>O>[CH3:6][N:7]([CH3:20])[S:8]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:25]=[O:26])=[CH:16][NH:17]2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: CN(C)S(=O)(=O)c1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)S(=O)(=O)c1ccc2c(C=O)c[nH]c2c1
Reaction time: 0.25 h
Yield: 54 %

Procedure:
Phosphorus oxychloride (0.76 ml, 0.008 mol) was slowly added at 0° C. under nitrogen atmosphere to anhydrous N,N-dimethyl formamide (3.8 ml), 0.05 mol). The mixture was stirred for 15 minutes and a solution of 6-(N,N-dimethyl aminosulfonyl)indole (1.74 g, 0.0078 mol) in anhydrous N,N-dimethylformamide (4 ml) was added dropwise below 2° C. The reaction mixture was allowed to stand at room temperature for 20 h and diluted with water (10 ml). The solution was neutralized (pH 8) with 10% aqueous solution of sodium hydroxide. The mixture was cooled and the precipitated solid was collected by filtration and was recrystallized from ethanol to yield 1.05 g (54%) of the entitled product (mp 250–252° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[C:17]([NH:21][C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[Cl:30])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][N:13](C)[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].N[C:32]1[CH:33]=[N:34][CH:35]=C[CH:37]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[C:17]([NH:21][C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[Cl:30])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][NH:13][C:14]1[CH:35]=[N:34][CH:33]=[CH:32][CH:37]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: Nc1cccnc1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1cccnc1)C(=O)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Yield: 104.4 %

Procedure:
A solution of 30 mg (0.06 mmol) of ethyl 2-[2,4-dichloro-5-(2-chloro-4,6-difluorophenylamino) benzoyl]-3-dimethylaminoacrylate and 15 mg (0.16 mmol) of 3-aminopyridine in 2 ml of toluene were heated at 150° C. for 7 hours. Concentration resulted in 33 mg of the desired product, which were employed without further purification in the next stage.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH:3]([NH:16][CH2:17][C:18]1[C:23]([N+:24]([O-])=O)=[CH:22][N:21]=[C:20]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:19]=1)[C:4]([N:6]([CH3:15])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].C(O)C>[Pd].C(OCC)(=O)C>[NH2:24][C:23]1[C:18]([CH2:17][NH:16][CH:3]([CH:2]([CH3:34])[CH3:1])[C:4]([N:6]([CH3:15])[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])=[CH:19][C:20]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:21][CH:22]=1
Reactant: CC(C)C(NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C(=O)N(C)CCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)C(NCc1cc(Oc2ccccc2)ncc1N)C(=O)N(C)CCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 3,N-dimethyl-2-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-N-phenethyl-butyramide (2.1 g, 1.38 mmol), 10% Pd on carbon (2 g), ethanol (75 mL) and ethyl acetate (75 mL) were shaken under a hydrogen atmosphere (50 psi). After 2 hours, the hydrogen was evacuated and the bottle was purged with nitrogen. The resulting mixture was filtered through glass fiber filter paper and the solvent evaporated under low pressure to yield a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1Br.[Li]CCCC.C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1
Reactant: Cc1cccc(C)c1Br
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Product: Cc1cccc(C)c1B1OC(C)(C)C(C)(C)O1
Reaction time: 1 h

Procedure:
To a solution of 35.0 g (0.19 mol) of 2,6-dimethylbromobenzene cooled to −78° C., 76 ml (0.19 mol) of 2.5 M nBuLi in hexanes was added for 40 min. The resulting mixture was stirred at this temperature for 1 h, then 35.2 g (0.19 mol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added. The resulting mixture was stirred overnight at room temperature and then evaporated to dryness. The residue was poured into 500 ml of water, crude product was extracted with 3×200 ml of ethyl acetate. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. Yield 19.5 g (53%) of yellow crystalline solid. Anal. calc. for C14H21BO2: C, 72.44; H, 9.12. Found: C, 72.78; H, 9.45. 1H NMR (CDCl3): δ 7.12 (t, J=7.7 Hz, 1H, 4-H), 6.94 (d, J=7.7 Hz, 2H, 3, 5-H), 2.40 (s, 6H, 2, 6-Me), 1.38 (s, 12H, Bpin).
Reaction SMILES: [CH:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=C)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:31]=[O+][O-].C(N(CC)CC)C>ClCCl>[CH:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[O:31])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(C2CCCCC2)c1C(F)(F)F
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(C2CCCCC2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To a solution of 3-(5-cyclohexyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 75A, 0.015 g, 0.036 mmol) in dichloromethane (5.0 mL) at −78° C. was passed ozone from an ozone generator until the solution turned a deep blue. The reaction mixture was then purged with oxygen until the blue color disappeared and then with nitrogen for 5 minutes. The reaction mixture was allowed to warm to room temperature, and triethylamine (5.07 μl, 0.036 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes. Concentration under vacuum provided 3-(5-cyclohexyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde [0.014 g, 0.0.036 mmol, 98%] as a tan solid. The product had an HPLC ret. time=4.44 min. (condition B). LC/MS M+1=417.07.