Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7](O)=[O:8])(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:48][CH2:49][C:50]1[C:51](=[O:76])[N:52]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([C:67]3[C:68]([C:73]([OH:75])=[O:74])=[CH:69][CH:70]=[CH:71][CH:72]=3)=[CH:63][CH:62]=2)[C:53]([CH2:56][CH2:57][CH2:58][CH3:59])=[CH:54][CH:55]=1>CN(C=O)C>[CH2:56]([C:53]1[N:52]([CH2:60][C:61]2[CH:62]=[CH:63][C:64]([C:67]3[C:68]([C:73]([OH:75])=[O:74])=[CH:69][CH:70]=[CH:71][CH:72]=3)=[CH:65][CH:66]=2)[C:51](=[O:76])[C:50]([CH2:49][NH:48][C:7](=[O:8])[CH:6]([CH2:5][SH:4])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:55][CH:54]=1)[CH2:57][CH2:58][CH3:59]
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Reactant: CCCCc1ccc(CN)c(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1ccc(CNC(=O)C(CS)CC(C)C)c(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 140 %

Procedure:
2-Acetylsulfanylmethyl-4-methyl-pentanoic acid (24 mg, 1.1 eq) and HATU (44 mg, 1.1 eq) were dissolved in DMF (2 mL). DIPEA (740 μL, 4 eq) was added, and the mixture was stirred at room temperature for 15 minutes. 4′-(3-Aminomethyl-6-butyl-2-oxo-2H-pyridin-1-ylmethyl)biphenyl-2-carboxylic acid HCl (45 mg, 0.1 mmol) was added, and the solution was stirred at room temperature for 4 hours. The reaction was quenched with water (8 mL) and concentrated HCl (3 drops), and the mixture extracted with EtOAc (10 mL). The organic layer was dried over Na2SO4, and evaporated. The residue was dissolved in MeOH (1 mL) and 1M NaOH (3 mL). The solution was stirred under nitrogen for 20 minutes, and the reaction was then quenched with acetic acid (2 mL). The MeOH was evaporated, and the aqueous component extracted with EtOAc (10 mL). The solvent was evaporated and the residue purified by reverse phase chromatography to afford the title compound (7.5 mg, 140 μmol). MS m/z: [M+H+] calcd for C31H39N2O4S, 535.7. found 535.2.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:50]1[C:55](=[O:56])[N:54]([CH3:57])[CH:53]=[C:52]2[CH2:58][N:59]([CH2:62][CH2:63][C:64]3[N:68]([CH3:69])[C:67]4[CH:70]=[CH:71][CH:72]=[CH:73][C:66]=4[N:65]=3)[C:60](=[O:61])[C:51]=12.[NH:74]1[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:57][N:54]1[C:55](=[O:56])[C:50]([N:74]2[CH2:79][CH2:78][O:77][CH2:76][CH2:75]2)=[C:51]2[C:60](=[O:61])[N:59]([CH2:62][CH2:63][C:64]3[N:68]([CH3:69])[C:67]4[CH:70]=[CH:71][CH:72]=[CH:73][C:66]=4[N:65]=3)[CH2:58][C:52]2=[CH:53]1
Reactant: C1COCCN1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1nc3ccccc3n1C)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1nc3ccccc3n1C)C2
Temperature: 120 °C
Yield: 8.8 %

Procedure:
Palladium diacetate (189 mg, 0.841 mmol), Xantphos (486 mg, 0.841 mmol) and Cs2CO3 (822 mg, 2.52 mmol) were each rapidly added in sequence to a suspension of 7-chloro-5-methyl-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (300 mg, 0.841 mmol, see Example c8)) and morpholine (220 mg, 2.52 mmol) in dioxane (1 ml). The reaction was heated in a microwave at about 120° C. for about 40 min. The solvent was removed and the resulting mixture was purified by preparative HPLC (system: Waters 2767 PHW003, eluent: MeCN/ammonium acetate buffer (gradient: 10:90 to 35:65 over 15 min), column: Boston Analytics, C-18, 10 μm, 21×250 mm) to afford the title compound (30 mg, 0.074 mmol, 8.76% yield)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]([C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>C1(C)C=CC=CC=1>[C:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:34])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(=O)c1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(C(C)=O)cc4)cc3)c2cc1OC
Yield: 63.5 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (3 ml) with heat, 4-acetylphenyl isocyanate (210 mg) was added, and the admixture was refluxed with heat for 20 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 50 mg of the title compound (yield: 64%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][N:9]1[CH2:14][N:13]([CH2:15][CH:16]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][CH3:18])[CH2:12][C:11]([NH2:24])([CH3:23])[CH2:10]1)[CH2:6][CH3:7].[C:25]([OH:33])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>CO>[CH3:22][CH2:21][CH2:20][CH2:19][CH:16]([CH2:15][N:13]1[CH2:14][N:9]([CH2:8][CH:5]([CH2:4][CH2:3][CH2:2][CH3:1])[CH2:6][CH3:7])[CH2:10][C:11]([NH2:24])([CH3:23])[CH2:12]1)[CH2:17][CH3:18].[C:25]([O-:33])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1
Reactant: O=C(O)c1cccnc1
Agent: CCCCC(CC)CN1CN(CC(CC)CCCC)CC(C)(N)C1
Solvent: CO
Product: O=C([O-])c1cccnc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Hexetidine (1 mole) was dissolved in 1,000 ml methanol and heated to 50°C. To the solution nicotinic acid (1 mole) was added dropwise. After stirring for 1.5 hours at 50°C, half of the solvent was distilled off under vacuum at 40°C. The crystal slurry obtained at room temperature was filtered and recrystallized from acetic acid ethyl ester, yielding hexetidine nicotinate as white crystals.
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([C:11]1[CH:15]=[C:14]([NH2:16])[N:13]([CH2:17][CH3:18])[N:12]=1)([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+].C(N(CC)C(C)C)(C)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>ClCCl>[C:7]([C:11]1[CH:15]=[C:14]([NH:16][C:35](=[O:36])[O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:13]([CH2:17][CH3:18])[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCn1nc(C(C)(C)C)cc1N
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Yield: 76.8 %

Procedure:
To a stirred mixture of 3-tert-butyl-1-ethyl-1H-pyrazol-5-amine oxalate (350 mg, 1.36 mmol), potassium carbonate (280 mg, 2 mmol) and N,N-diisopropylethylamine (170 mg, 1.3 mmol) in dichloromethane (3 mL) at rt, was added dropwise, phenyl chloroformate (220 mg, 1.4 mmol) and the reaction mixture was stirred for a further 3 h. The reaction mixture was filtrated, the filtrate concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The organic layer was separated and washed with brine, then concentrated under reduced pressure to give a solid which was recrystallized from diethyl ether to afford phenyl 3-tert-butyl-1-ethyl-1H-pyrazol-5-ylcarbamate (300 mg, 77%) as a colorless solid. LC-MS (ESI) m/z 288 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5]([Si:9]([CH3:12])([CH3:11])Cl)([CH3:8])([CH3:7])[CH3:6].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][O:4][Si:9]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCBr
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
2-Bromoethanol (3.44 g, 27.53 mmol), t-butyldimethylchlorosilane (4.23 g, 28.07 mmol), and imidazole (3.97 g, 58.31 mmol) was dissolved in dimethylformamide (20 ml) and the solution was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and then with saturated brine, and dried over magnesium sulfate. Insoluble solids were removed by filtration, and then the filtrate was concentrated under reduced pressure to obtain t-butyldimethylsilyl 2-bromoethyl ether (6.05 g) as crude product. The crude product (1.83 g), 2-phenylimidazole (1.11 g, 7.70 mmol), and potassium carbonate (1.50 g, 10.9 mmol) was added in dimethylformamide (10 ml), and the mixture was heated at 80° C. for 10 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and then with saturated brine, and dried over sodium sulfate. Insoluble solids were removed by filtration and the filtrate was evaporated under reduced pressure. The resulting oil was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound as pale yellow oil (1.16 g, yield: 50%).
Reaction SMILES: N[C:2](=[N:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1)=[S:6])[CH3:3].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27])=[O:19].C(N(CC)CC)C>C(O)C.CO>[CH3:3][C:2]1[N:4]=[C:5]([NH:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[C:14]#[N:15])[S:6][C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:27])([F:28])[F:29]
Reactant: CC(N)=NC(=S)Nc1cccc(C#N)c1
Reactant: O=C(CBr)c1ccccc1C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(Nc2cccc(C#N)c2)sc1C(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.7 %

Procedure:
To a mixture of 801 mg (5 mmol) 3-cyanophenylthioisocyanate in 5 ml 1N NaOH at 0° C. was added 473 mg acetamidine hydrochloride in 10 ml THF and allowed to stir at 0° C. for 16 h. The mixture was extracted with ethylacetate and the combined organic layers were dried with MgSO4 and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with ethylacetate/cyclohexane 1:2 to yield 510 mg (47%) of 1-(1-Amino-ethylidene)-3-(3-cyano-phenyl)-thiourea. (MS (m/e): 219.2 (M+H, 100%). A mixture of 50 mg (0.23 mmol) 1-(1-Amino-ethylidene)-3-(3-cyano-phenyl)-thiourea, 92 mg (0.345 mmol) 2-Bromo-1-(2-trifluoromethyl-phenyl)-ethanone and 48 ul triethylamine in 1 ml ethanol was stirred for 16 h at room temperature. The mixtures were diluted with methanol and directly subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded 10.4 mg (12%) of the title compound. (MS (m/e): 386.2 (M−H, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH3:25])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][N:21]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:22]2[CH3:25])=[CH:17][CH:16]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2ccc(Cl)cc21
Product: CC1c2cc(Cl)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Yield: 54 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Chloro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[S:30](Cl)(=[O:32])=[O:31].O>N1C=CC=CC=1>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[S:30]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=3)[CH2:3][CH:4]2[CH2:8]1)(=[O:31])=[O:32]
Reactant: CCOC(=O)c1cnc(N2CC3CNCC3C2)nc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cnc(N2CC3CN(S(=O)(=O)c4ccc5ccccc5c4)CC3C2)nc1
Reaction time: 3 h
Yield: 51 %

Procedure:
To a suspension of ethyl 2-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-ylpyrimidine-5-carboxylate (0.271 g, 1.0 mmol) in pyridine (5 ml) was added 2-naphthalene sulfonyl chloride (0.269 g, 1.18 mmol). The mixture was stirred for 3 h, then water (25 ml) was added and the product collected by filtration. The product was washed with further water and then dried overnight under vacuum to give the title compound (0.231 g, 51%). 1H NMR (300 MHz, CDCl3) δ: 1.39 (3H, t, J=6.9 Hz), 2.92-3.07 (2H, m), 3.29 (2H, dd, J=3.9, 10.2 Hz), 3.45 (2H, dd, J=3.9, 12.3 Hz), 3.59 (2H, dd, J=7.2, 10.2 Hz), 4.35 (2H, q, J=7.2 Hz), 7.58-7.75 (2H, m), 7.82 (1H, dd, J=1.8, 8.7 Hz), 7.90-8.05 (2H, m), 8.40 (1H, s), 8.77 (2H, s).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:19]1[NH:23][N:22]=[C:21]([NH:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([N:33]3[CH:37]=[N:36][C:35]([CH3:38])=[N:34]3)=[CH:27][C:26]=2[F:39])[N:20]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1.[I-].[Na+]>CC(C)=O>[F:39][C:26]1[CH:27]=[C:28]([N:33]2[CH:37]=[N:36][C:35]([CH3:38])=[N:34]2)[C:29]([O:31][CH3:32])=[CH:30][C:25]=1[NH:24][C:21]1[N:20]=[C:19]2[CH:6]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=3)[CH2:5][CH2:4][CH2:3][CH2:2][N:23]2[N:22]=1
Reactant: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(OCC(F)(F)F)cc3)n2)c(F)cc1-n1cnc(C)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2ccc(OCC(F)(F)F)cc2)c(F)cc1-n1cnc(C)n1
Yield: 25.2 %

Procedure:
A solution of 5-(5-chloro-1-(4-(2,2,2-trifluoroethoxy)phenyl)pentyl)-N-(2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (2.01 g, 3.54 mmol), sodium iodide (2.65 g, 17.7 mmol), and diisoproplylethylamine (1.55 mL, 8.85 mmol) in acetone (10 mL) was heated in a sealed vessel at 100° C. for 4 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (50% EtOAc/chloroform) to afford 474 mg (25% yield) of the titled compound as an off-white solid. LC-MS (M+H)+ 532.5. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.55 (s, 1 H), 8.11 (d, J=7.6 Hz, 1 H), 7.47 (d, J=11.6 Hz, 1 H), 7.16 (d, J=8.5 Hz, 2 H), 6.95 (d, J=8.5 Hz, 2 H), 6.86 (d, J=3.4 Hz, 1 H), 4.36 (q, J=8.2 Hz, 2 H), 4.17-4.26 (m, 3 H), 3.83 (s, 3 H), 2.47 (s, 3 H), 2.15-2.28 (m, 1 H), 1.93-2.13 (m, 3 H), 1.80-1.93 (m, 2 H).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][C:10]([F:13])([F:12])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(=O)=O.[C-:21]#[N:22].[Na+]>CS(C)=O>[C:21]([CH2:6][C@@H:7]1[CH2:11][C:10]([F:13])([F:12])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:22]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1COS(C)(=O)=O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CC#N
Temperature: 25 °C
Yield: 76 %

Procedure:
A DMSO (40 ml) solution of ((S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methyl methanesulfonate and NaCN (1.59 g, 3.24 mmol) was stirred at 45° C. for 4 hours and at 50° C. for 2 days, the progress of the reaction was monitored by LC-MS. After cooling to room temperature, the reaction was quenched by the addition of water (˜60 ml). Reaction mixture was extracted with EtOAc (˜40 ml), two layers were separated, organic layer was washed with brine (˜25 ml), the extraction and wash sequence was repeated for two more times. Organic layers were combined, dried (Na2SO4), filtered, solvent was removed in vacuo. Product was purified by silica gel chromatography (Hexane/EtOAc, gradient from 100:0 to 80:20). Compound (R)-tert-butyl 2-(cyanomethyl)-4,4-difluoropyrrolidine-1-carboxylate was obtained as a colorless oil: 2.10 g (76% yield over 2 steps).
Reaction SMILES: O[CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C.CCCCCC>[NH:23]([CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2O
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2Nc1ccccc1
Yield: 79 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 235 and aniline, the title compound was synthesized in the same manner as in Example 297. Yield: 79%. Melting point: 151-152° C. (ethyl acetate-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([CH:8]=[CH2:9])[CH:7]=1.B1C2CCCC1CCC2.[OH-:27].[Na+].OO>O1CCCC1.[Cl-].[Na+].O.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([CH2:8][CH2:9][OH:27])[CH:7]=1
Reactant: C=Cc1cc(Br)cc(NC(=O)OC(C)(C)C)c1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(Br)cc(CCO)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (3-bromo-5-vinylphenyl)carbamate (0.80 g, 2.7 mmol) in tetrahydrofuran (2.7 mL) was treated with 9-BBN in tetrahydrofuran (16.1 mL, 8.1 mol) dropwise and stirred for 2 h. The reaction mixture was cooled to 0° C. and treated with ethanol (5 mL), 3 M sodium hydroxide (3.2 mL) and 9 M hydrogen peroxide (3 mL) dropwise. The reaction mixture was heated at 50° C. for 30 min, cooled to 20° C., poured into brine (25 mL), and extracted with ethyl acetate (100 mL). A small amount of water was added to dissolve the solids that were insoluble in the brine. The organic layer was separated and washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude tan oil. This material was purified by flash column chromatography to give the desired product (0.66 g, 78%) as a colorless foam. LCMS for C9H11BrNO3 ([M-(t-Bu)+H]+H)+: m/z=259.9, 261.8.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].[Li]CCCC.[CH3:13][O:14][C:15](=[O:33])[CH2:16][CH2:17][C:18]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[O:22][CH2:21][CH2:20][O:19]1.C(Br)C=C.CN(P(N(C)C)(N(C)C)=O)C>C1COCC1.CCOC(C)=O>[CH3:13][O:14][C:15](=[O:33])[CH:16]([CH2:17][C:18]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)[O:22][CH2:21][CH2:20][O:19]1)[CH2:3][CH:1]=[CH2:2]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)CCC1(c2cccc(C(F)(F)F)c2)OCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC(CC1(c2cccc(C(F)(F)F)c2)OCCO1)C(=O)OC
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 59.4 %

Procedure:
Diisopropylamine (1.74 mL, 12.5 mmol) was dissolved in THF (6.2 mL) under a nitrogen atmosphere and cooled to −78° C. A solution of n-BuLi (2.5 M in hexanes, 5.3 mL) was added dropwise, keeping the temperature below −67° C. The reaction was warmed to −15° C. for 15 min, then cooled back down to −78° C. A solution of 3-[2-(3-trifluoromethylphenyl)-[1,3]dioxolan-2-yl]propionic acid methyl ester (2.71 g, 8.90 mmol) in THF (1.5 mL) was added and the mixture was stirred for 40 min. Allyl bromide (0.92 mL, 11 mmol) and HMPA (0.46 mL, 2.7 mmol) were added simultan-eously and the reaction was stirred at room temperature overnight. The mixture was diluted with EtOAc (400 mL), washed with saturated NH4Cl (3×150 mL), water (2×150 mL), and brine (200 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by CombiFlash chromatography (silica, 0–40% ether/heptane) to give 2-[2-(3-trifluoromethylphenyl)-[1,3]dioxolan-2-ylmethyl]pent-4-enoic acid methyl ester (1.82 g, 59%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.73 (s, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 5.80–5.61 (m, 1H), 5.10–4.97 (m, 2H), 4.10–3.90 (m, 2H), 3.80–3.60 (m, 5H), 2.83–2.68 (m, 1H), 2.50–2.13 (m, 3H), 1.97 (dd, J=14.7, 2.7 Hz, 1H); 19F NMR (282 MHz, CDCl3) δ −62.9; ESI MS m/z 345 [C17H19F3O4+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:20]O>>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:20])=[O:5]
Reactant: CO
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(S(C)(=O)=O)cc1Cl
Reaction time: 18 h

Procedure:
To a mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (5 g, 21.3 mmol) in anhydrous methanol (100 mL) was added concentrated sulfuric acid (0.5 mL). The resulting solution was stirred for 18 h at reflux. Upon cooling, the mixture was concentrated under reduced pressure, dissolved in CH2Cl2 and washed with NaHCO3 solution and brine. The organic phase was dried over sodium sulfate and concentrated to afford methyl 2-chloro-4-(methylsulfonyl)benzoate as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1B(O)O.Br[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][C:43]3[C:48]([Cl:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=3[Cl:51])=[CH:35][CH:34]=2)[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:18]([CH3:52])[CH:17]=1>>[Cl:49][C:48]1[CH:47]=[C:46]([CH3:50])[CH:45]=[C:44]([Cl:51])[C:43]=1[O:42][CH2:41][CH2:40][O:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][CH:22]([C:19]2[CH:20]=[CH:21][C:16]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:17][C:18]=2[CH3:52])[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:34][CH:35]=1
Reactant: COCCCc1ccccc1B(O)O
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(Br)cc3C)cc2)c(Cl)c1
Product: COCCCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 1, step 1 using [2-(3-methoxypropyl)phenyl]boronic acid from step 1 and tert-butyl (2-(4-bromo-2-methylphenyl)-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propyl)carbamate from EXAMPLE 2, step 2 as starting materials.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[C:15]3[Cl:20])C=CC=CC=1.Cl.[CH2:23]([CH:30]1[C:39]2[C:34](=[CH:35][C:36]([F:40])=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH:31]1[NH2:41])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH2:23]([CH:30]1[C:39]2[C:34](=[CH:35][C:36]([F:40])=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH:31]1[NH:41][C:8]([NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]=[C:15]2[Cl:20])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC1CCc2cc(F)ccc2C1Cc1ccccc1
Reactant: O=C(Nc1cccc2c(Cl)nccc12)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(Nc1cccc2c(Cl)nccc12)NC1CCc2cc(F)ccc2C1Cc1ccccc1
Yield: 27.8 %

Procedure:
(1-Chloro-isoquinolin-5-yl)-carbamic acid phenyl ester (150 mgs, 0.5 mmol), 1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydrochloride (146 mgs, 0.5 mmol), and sodium bicarbonate (42 mgs, 0.5 mmol) were combined and stirred for one hour in DMSO (4ml) at ambient temperature. The product was purified by directly injecting the crude reaction onto a reverse phase prep-HPLC (10-90% water:acetonitrile gradient). The appropriate fractions were lyophilized to yield 1-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(1-chloro-isoquinolin-5-yl)-urea (64 mgs, 28%) MS (MH+) 459; 1H NMR (CD3OD) δ 1.93-2.06 (m, 1H), 2.09-2.13 (m, 1H), 2.91-3.07 (m, 4H), 3.40-3.42 (m, 1H), 4.07-4.10 (s, 1H), 6.69-6.78 (m, 1H), 6.80-6.89 (m, 2H), 7.12-7.26 (m, 5H), 7.72 (t, 1H, J=8.2 Hz), 7.83 (d, 1H, J=6.1 Hz), 8.19 (d, 1H, J=8.6 Hz), 8.17-8.24 (m, 2H). HPLC Rt=4.04 min (50-90% water:acetonitrile gradient, 100% pure).