Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([NH2:11])[C@@H:9]([O:12][C:13](=[O:15])[CH3:14])[C@H:8]([O:16][C:17](=[O:19])[CH3:18])[C@@H:7]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:6]1)(=[O:3])[CH3:2].[CH:25]1[C:37]2[CH:36]([CH2:38][O:39][C:40]([N:42]=[C:43]=[S:44])=[O:41])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:43]([NH:42][C:40]([O:39][CH2:38][CH:36]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:37]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:41])=[S:44])[C@@H:9]([O:12][C:13](=[O:15])[CH3:14])[C@H:8]([O:16][C:17](=[O:19])[CH3:18])[C@@H:7]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
The amine from above (220 mg) was dissolved in pyridine (5 mL) and 9-Fluorenylmethoxycarbonyl isothiocyanate (180 mg, 0.65 mmol) and triethylamine (0.02 mL) was added. Then the resulting mixture was stirred at room temperature for 16 h. The solution was concentrated and the residue taken up in CH2Cl2 (20 mL) and diluted with saturated aqueous NaHCO3 (20 mL), then the resulting mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were dried (Na2SO4) and concentrated. Flash chromatography of the residue (EtOAc:hexanes 2:3) gave (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-(((9H-fluoren-9-yl)methoxy)carbonyl)thioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white foam (360 mg, 89% yield over two steps). 1H NMR (600 MHz, CDCl3) δ 2.06 (s, 3H), 2.07 (s, 3H), 2.12 (s, 3H), 2.14 (s, 3H), 3.89 (ddd, 1H, J=2.4, 4.8, 9.6 Hz), 4.17 (dd, 1H, J=2.4, 12.5 Hz), 4.24 (dd, 1H, J=6.6, 6.6 Hz), 4.33 (dd, 1H, J=4.8, 12.5 Hz), 4.52 (s, 1H), 4.54 (s, 1H), 5.08-5.12 (m, 1H), 5.22 (dd, 1H, J=9.5, 9.6 Hz), 5.34 (dd, 1H, J=6.6, 9.5 Hz), 5.88 (d, 1H, J=6.6 Hz), 7.36 (dd, 2H, J=7.2, 7.8 Hz), 7.45 (dd, 2H, J=7.2, 7.8 Hz), 7.57 (d, 2H, J=7.8 Hz), 7.80 (d, 2H, J=7.2 Hz). 13C NMR (150 MHz, CDCl3) δ 20.62, 20.72, 20.77, 21.05, 46.49, 57.59, 61.65, 67.47, 68.40, 72.21, 72.87, 92.21, 120.09, 120.29, 124.84, 124.96, 125.32, 127.30, 127.83, 128.15, 128.25, 129.06, 141.37, 142.80, 152.16, 169.27, 169.34, 170.46, 170.72, 180.22.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:17])=[CH:6][CH:5]=[CH:4][C:3]=1[C:18]1[C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]=2[C:21]([C:31]([NH2:33])=[O:32])=[CH:20][CH:19]=1.Cl.[OH-:35].[Na+]>C1COCC1>[OH:35][CH:21]([CH2:31][OH:32])[CH2:22][NH:23][C:26]1[CH:25]=[C:24]2[C:29]([C:30]3[C:18]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([N:8]5[CH2:16][C:15]6[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=6)[C:9]5=[O:17])[C:2]=4[CH3:1])=[CH:19][CH:20]=[C:21]([C:31]([NH2:33])=[O:32])[C:22]=3[NH:23]2)=[CH:28][CH:27]=1
Reactant: [OH-]
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4ccccc4c23)cccc1N1Cc2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(NCC(O)CO)ccc4c23)cccc1N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
A solution of 74(S)-2,2-dimethyl-1,3-dioxolan-4-yl)methylamino)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 66-15, 50 mg, 0.089 mmol) in THF (1 mL) was treated with 2 M hydrochloric acid (4.46 mL, 8.92 mmol) and the mixture was stirred at rt for 1 h. The mixture was made basic with 1 M aqueous sodium hydroxide and extracted twice with DCM. The combined organic phases, along with some insoluble precipitate, were dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from DCM to 90:9:1 DCM-methanol-28% aqueous ammonium hydroxide) to provide 7-(2,3-dihydroxypropylamino)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as an orange solid (20 mg, 39%). 1H NMR (400 MHz, methanol-d4) δ 7.90 (1 H, d, J=7.49 Hz), 7.79 (1 H, d, J=7.77 Hz), 7.67-7.74 (2 H, m), 7.58-7.62 (1 H, m), 7.49-7.55 (2 H, m), 7.42 (1 H, dd, J=6.94, 1.94 Hz), 6.99 (1H, d, J=7.77 Hz), 6.86 (1 H, d, J=8.32 Hz), 6.81 (1 H, d, J=1.94 Hz), 6.45 (1 H, dd, J=8.74, 1.80 Hz), 4.97 (2 H, s), 3.88-3.93 (1 H, m), 3.59-3.68 (2 H, m), 3.36-3.39 (1 H, m), 3.14-3.20 (1 H, m), 1.95 (3 H, s). Mass spectrum m/z 521.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11](O)[C:12](Cl)([Cl:17])[C:13]([F:16])([F:15])[F:14].[Cl-].[NH4+]>C(O)C.[Zn]>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH:11]=[C:12]([Cl:17])[C:13]([F:16])([F:15])[F:14]
Reactant: COc1cccc(OC)c1C(O)C(Cl)(Cl)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: COc1cccc(OC)c1C=C(Cl)C(F)(F)F
Reaction time: 8 h
Yield: 94 %

Procedure:
96.5 g (0.266 mole) of 1,3-dimethoxy-2-(1-hydroxy-2,2-dichloro-3,3,3-trifluoro-propyl)-benzene are dissolved in 1,000 ml of ethanol in a 1.5 l sulfonating flask with a thermometer, condenser and bubble counter, and 30 g (0.56 mole) of ammonium chloride are added. Zinc activated according to Fieser & Fieser (36.9 g=0.564 mole) is added in portions to the resulting brownish suspension, the reaction temperature rising to 42°. Stirring is continued overnight and the grey-yellow reaction mixture is then poured onto ice-water and extracted with ether and the extract is washed with water (3×) and brine, dried over magnesium sulfate and evaporated. 1,3-Dimethoxy-2-(2-chloro-3,3,3-trifluoroprop-1-enyl)-benzene (yield: 94%) is obtained as a reddish oil.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14](=[O:18])[O:15][CH2:16][CH3:17].[CH2:19]([N:26]1[CH:31]2[C:32]([F:35])([F:34])[CH2:33][CH:27]1[CH2:28][C:29](=[O:36])[CH2:30]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CN1C(=O)CCC1.C1COCC1>[CH2:19]([N:26]1[CH:31]2[C:32]([F:35])([F:34])[CH2:33][CH:27]1[CH2:28][C:29]([CH2:13][C:14]([O:15][CH2:16][CH3:17])=[O:18])([OH:36])[CH2:30]2)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(C)=O
Reactant: O=C1CC2CC(F)(F)C(C1)N2Cc1ccccc1
Agent: [Li]CCCC
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC1(O)CC2CC(F)(F)C(C1)N2Cc1ccccc1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of diisopropylamine (1.02 g, 10 mmol, 5.0 eq) in THF (10 mL) was added n-BuLi (5 mL, 2.0 M, 5.0 eq) dropwise at −50° C. After 30 min, dry EA (880 mg, 10 mmol, 5.0 eq) in NMP/THF (11 mL, 1:10) was added dropwise. After 1 h at −50° C., a solution of compound 116h (500 mg, 2 mmol, 1.0 eq) in THF (5 mL) was added slowly, and the resulting mixture was warmed from −50° C. to room temperature for 2 h. The reaction mixture was quenched with water (50 mL), extracted with EA (100 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel (EA/PE=1:3) to give ethyl 2-(8-benzyl-6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl)acetate 116i as a colorless oil. 490 mg, yield: 72%. 1H NMR (400 MHz, DMSO-d6) ppm 7.37-7.19 (m, 5H), 4.45 (s, 1H), 4.09 (q, J=7.0 Hz, 2H), 3.84-3.70 (m, 2H), 3.27 (d, J=5.0 Hz, 1H), 3.08 (d, J=11.3 Hz, 1H), 2.70 (q, J=13.6 Hz, 1H), 2.43 (s, 2H), 2.37-2.26 (m, 1H), 2.13-2.00 (m, 2H), 1.84-1.72 (m, 1H), 1.52 (d, J=14.3 Hz, 1H), 1.22 (t, J=7.0 Hz, 3H); MS: calc'd (MH+) 340, measured (MH+) 340.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].CN(C=O)C.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25].N1C=CN=C1>CCOC(C)=O>[Si:27]([O:1][CH2:2][CH:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CON(C)C(=O)C(CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
tert-butyl 3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (21a) (4.4 g, 17.5 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by DMF (35 mL) and cooled to 0° C. via an ice bath. Next, TBDMSCl (2.90 g, 19.3 mmol, 1.1 equiv.) and imidazole (2.40 g, 35.1 mmol, 2.0 equiv.) were added to the reaction flask. The solution was stirred at 0° C. for 1 h and then allowed to warm to rt, stirring an additional 2 h. The reaction solution was transferred to a 500 mL separatory funnel with EtOAc (150 mL). The mixture was washed with 1% HCl (3×40 mL), sat. NaHCO3 (1×40 mL), and sat. NaCl (2×40 mL). The organic layer was separated and dried over Na2SO4. The solution was concentrated on a rotary evaporator and dried under vacuum to give 5.9 g (93%) of 22a as an oil which crystallized to a white solid upon standing. Rf=0.54 (50% EtOAc/hexanes); mp=71-72° C.; IR (film) 3437, 3324, 2953, 2929, 2884, 2856, 1715, 1666, 1496, 1471, 1365, 1253, 1171, 1114 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.34 (br d, J=8.5 Hz, 1H, carbamate-NH), 4.73 (br s, 1H, Boc-NH—CH), 3.83 (m, 1H, CH—CH2), 3.77 (m, 1H, CH—CH2), 3.73 (s, 3H, N—OCH3), 3.19 (s, 3H, N—CH3), 1.41 (s, 9H, Boc-t-butyl-CH3), 0.84 (s, 9H, Si-t-butyl-CH3), 0.00 (s, 6H, Si—(CH3)2); 13C NMR (125 MHz, CDCl3) δ 170.9, 155.5, 79.7, 63.6, 61.6, 52.6, 32.3, 28.5, 25.9, 18.4, −5.4; LRMS (ESI-MS m/z): Mass calcd for C16H34N2O5Si [M]+, 362.54. Found 363.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].CN(C=O)C.C(N(C(C)C)CC)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([C:40]([OH:42])=[O:41])=[CH:34]2>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][C:35]([C:40]([OH:42])=[O:41])=[CH:34]4)=[O:14])=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: Nc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cc2cc(NC(=O)c3cc4cc([N+](=O)[O-])ccc4o3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the solution of 93.2 mg (0.45 mmol) 5-nitrobenzofuran-2-carboxylic acid (128) in 6 mL DMF 209.0 mg (0.45 mmol) PyBroP and 157 μL (0.9 mmol) diisopropylethylamine was added and the clear solution was stirred for 10 minutes at room temperature. The activated acid was transferred to resin 127 which was agitated for 5 hrs. The resin was drained, washed twice with DMF. The analytical sample showed no complete reaction and therefore the activation/coupling reaction was repeated once again the same way using fresh reagents. The resin was drained, washed five times with DMF to give 129 which was used immediately as described in Example 117.
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].C(N(CC)CC)C.[CH3:13][Si:14](OS(C(F)(F)F)(=O)=O)([CH3:16])[CH3:15]>C(Cl)Cl>[CH3:13][Si:14]([CH3:16])([CH3:15])[O:5][C:2]([CH:3]=[CH2:4])=[CH2:1]
Reactant: C=CC(C)=O
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=C)O[Si](C)(C)C

Procedure:
70 μl (0.86 mmoles) of 3-buten-2-one [compound of formula 5 wherein R1=R2=R6=H] and 2 ml of anhydrous CH2Cl2 are charged, at 0° C. under argon in a two-necked round bottom flask equipped with magnetic stirrer and dropping funnel. 170 μl (1.22 mmoles) of triethylamine (distilled on KOH) and 209 μl (1.08 mmoles) of trimethylsilyltrifluorometansulphonate (TMDOTf) (drop by drop) are added to the mixture. In this conditions 2-(trimethylsilyloxy)-1,3-butadiene [compound 6 wherein R1=R2=R6=H] is formed “in situ”. The mixture is stirred for 45 minutes and thereafter a solution of 100 mg (0.36 mmoles) of the product from Example 2 in 2 ml of anhydrous CH2Cl2 is added therein, drop by drop, together with 69 μl (0.36 mmoles) of TMSOTf. The mixture is brought to room temperature and after 30 minutes 4 ml of a saturated solution of NaHCO3 are added and the mixture is stirred vigorously for 36 h. 4 ml of water are added to the mixture and the aqueous phase is extracted with methylene chloride, the organic phase is washed with a saturated solution of NaHCO3, water, a saturated solution of NaCl and is dried on Na2SO4. After filtration the solvent is removed and 59 mg of crude product are obtained. The product is purified by flash chromatography on silica gel column (FCC) eluting with methylene chloride and triethylamine 1%. 18 mg of the wanted product are obtained (crystals). M.p.: 53-54° C. Yield 25%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([N:18]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].O.NN>C(Cl)(Cl)Cl.C(O)C>[CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OC2CCC(N3C(=O)c4ccccc4C3=O)CC2)cc1
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(OC2CCC(N)CC2)cc1
Temperature: 7.5 °C
Reaction time: 48 h
Yield: 98.5 %

Procedure:
To a solution of 4-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-cyclohexyloxy]-benzoic acid ethyl ester (6.3 g, 16.0 mmol) in CHCl3 (50 mL) and ethanol (60 mL) was added hydrazine hydrate (16.0 g, 320.2 mmol). Stirring was continued at ambient temperature for 2 days. The reaction mixture was then cooled to 5-10° C. and the white precipitate was filtered off. The filtrate was washed with water, dried and the solvent evaporated under vacuum to afford 4.15 g (98%) of 4-(4-amino-cyclohexyloxy)-benzoic acid ethyl ester.
Reaction SMILES: [ClH:1].[CH2:2]([NH:5][CH:6]1[CH2:11][S:10][C:9]2[S:12][CH:13]=[CH:14][C:8]=2[CH2:7]1)[CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:21](I)[CH2:22][CH2:23][CH3:24].Cl>O.C1(C)C=CC=CC=1>[ClH:1].[CH2:21]([N:5]([CH2:2][CH2:3][CH3:4])[CH:6]1[CH2:11][S:10][C:9]2[S:12][CH:13]=[CH:14][C:8]=2[CH2:7]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCNC1CSc2sccc2C1
Reactant: CCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCN(CCC)C1CSc2sccc2C1

Procedure:
A mixture of 2,5 g of N-propyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-amine hydrochloride, 7.5 g of sodium carbonate, 11 ml of n-butyl iodide 25 ml of toluene and 25 ml of water is refluxed for 3 days. Removal of solvent from the organic layer affords an oil which is treated with ethanolic hydrochloric acid to afford N-butyl- N-propyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-amine hydrochloride, m.p. 161°-164°.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([O:46][CH2:47][CH2:48][O:49][CH3:50])=[N:44][CH:45]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[N:44][C:43]([O:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:42][CH:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: COCCOc1ccc(CCl)cn1
Agent: Cl
Product: COCCOc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cn1
Yield: 79 %

Procedure:
By the reaction and treatment in the same manner as in Example, 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 5-chloromethyl-2-(2-methoxyethoxy)pyridine (0.61 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(1-{[6-(2-methoxyethoxy)pyridin-3-yl]methyl}pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.77 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[N:6]=1.N1C=CC=CC=1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>CN(C)C=O.ClCCl>[C:34]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)[N:6]=1)(=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)Cl
Reactant: Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(=O)Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 2-amino-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (8.04 g) and pyridine (7.72 ml) in dry N,N-dimethylformamide (80 ml) was added slowly a solution of propionyl chloride (2.76 ml) in dichloromethane (2 ml) at a temperature below 5° C. After 30 minutes, the reaction mixture was poured into ice water (800 ml) and extracted with ethyl acetate (400 ml), and the extract was dried over magnesium sulfate. The solvent was distilled off and purified by column chromatography on silica gel to give 2-propionylamino-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (8.9 g).
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=2)[CH:6]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:8](=[O:10])[CH:9]=1)[CH3:3].[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](B(O)O)=[CH:30][N:29]=1>>[OH:1][CH:2]([C:4]1[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:28]=[N:29][CH:30]=3)[CH:22]=2)[CH:6]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:8](=[O:10])[CH:9]=1)[CH3:3]
Reactant: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C(C)O)cc2=O)cc1
Reactant: OB(O)c1cncc2ccccc12
Product: COc1ccc(COc2cn(-c3cccc(-c4cncc5ccccc45)c3)c(C(C)O)cc2=O)cc1
Temperature: 80 °C

Procedure:
To a 100 mL round-bottom flask were added 4.20 g (9.76 mmol) of 2-(1-hydroxyethyl)-1-[3-bromophenyl]-5-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one, 3.38 g (19.52 mmol) isoquinolin-4-ylboronic acid, 0.75 g (0.97 mmol) 1,-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex. The flask was equipped with a condenser, evacuated, and purged with nitrogen. Evacuation was repeated three times and 50 mL THF and 40 mL 1 M aq cesium carbonate were added. The reaction mixture was heated at 80° C. for 3 h, Upon cooling, the organic layer was separated, washed with 15 mL water, dried over Na2S04 filtered, stirred over Quadrapure TU resin (Aldrich), concentrated in vacuo, and used without further purification, LCMS (M+H)+ 479.5.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Br[CH2:17][C:18]([NH2:20])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:17][C:18]([NH2:20])=[O:19]
Reactant: NC(=O)CBr
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: N#Cc1ccc2c(cc(C(F)F)n2CC(N)=O)c1Cl

Procedure:
Synthesized as described in Example 4 using 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile, bromoacetamide (2 eq) and Cs2CO3 (2 eq): MS (ES) m/z 284 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:5]([CH3:20])=[C:6]([CH:18]=[CH2:19])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C[N+]1([O-])CCOCC1.C(#N)C.[OH2:41].[OH2:42].CC(C)=O>[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:5]([CH3:20])=[C:6]([CH:18]([OH:42])[CH2:19][OH:41])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O
Reactant: C=Cc1c(OCc2ccc(F)cc2F)c(Br)c(=O)n(-c2c(F)cccc2F)c1C
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)=O
Solvent: CC#N
Product: Cc1c(C(O)CO)c(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Reaction time: 1 h

Procedure:
To a room temperature solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methyl-5-vinylpyridin-2(1H)-one (0.970 g, 2.07 mmol) in water/acetone 1:3 (8.7 mL) was added, sequentially, osmium tetroxide (0.110 g, 0.433 mmol) and N-methyl morpholine oxide (1.32 g, 11.2 mmol). The resulting solution was stirred for one hour until complete consumption of starting material by LCMS analysis, and the reaction was concentrated in vacuo. The resulting dark residue was subjected to SiO2 chromatography with ethyl acetate/hexanes (3:7) to furnish a solid. 1H NMR (400 MHz, CDCl3) δ 7.59 (app q, J=8.2 Hz, 1H), 7.45 (ddd, J=14.7, 8.5, 6.8 Hz, 1H), 7.08 (app t, J=8.5 Hz, 2H), 6.94 (app t, J=8.2 Hz, 1H), 6.88 (app t, J=8.5 Hz, 1H), 5.31 (AB-q, J=10.6 Hz, Δ=38.3 Hz, 2H), 5.07 (dd, J=9.1, 3.8 Hz, 1H), 3.83 (t, J=10.8 Hz, 1H), 3.60 (dd, J=11.4, 3.9 Hz, 1H), 2.94 (br s, 1H), 2.16 (s, 3H); LC/MS C-18 column, tr=2.26 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 502 (M+H). ES-HRMS m/z 502.0276 (M+H calcd for C21H17BrF4NO4 requires 502.0272).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1)(=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)Cl
Reactant: CC(NC(=O)c1cccc(N)n1)c1ccc(OCC(F)(F)F)nc1
Product: CCC(=O)Nc1cccc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)n1
Yield: 18 %

Procedure:
The title compound is prepared in 18% yield (5.1 mg) from 6-amino-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)picolinamide (25 mg, 0.073 mmol, Step-1, single enantiomer) and propionyl chloride (24 mg, 0.26 mmol) by the similar manner in Step-2 of Example-8.
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH3:17])=[CH:6][CH:5]=1.C(=O)([O-])[O-:19].[Ca+2]>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH:17]=[O:19])=[CH:8][CH:9]=1
Reactant: Cc1ccc(F)cc1-c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: BrBr
Agent: [Ca+2]
Solvent: O
Product: O=Cc1ccc(F)cc1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
Bromine (67 g) is added slowly to a stirred solution of 4-chloro-5'-fluoro-2'-methylbiphenyl (of 46.9 g) while being illuminated. The temperature is kept between 105-110° C. for 1 hour. Water (120 ml) and calcium carbonate (90 g) are then added to this product with stirring at reflux for 20 hours. The organics are extracted with chloroform (400 ml.), and the organic phase is washed with water, separated and dried (MgSO4). The chloroform is evaporated. The residue is recrystallized from hexane.