Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:34]=[C:35]([CH2:41][CH2:42][C:43](O)=[O:44])[CH:36]=[CH:37][C:38]=3[O:39][CH3:40])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[N:53](C=O)C.[OH-].[NH4+]>C(Cl)Cl>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[C:20]([C:28]([F:30])([F:31])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:34]=[C:35]([CH2:41][CH2:42][C:43]([NH2:53])=[O:44])[CH:36]=[CH:37][C:38]=3[O:39][CH3:40])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: COc1ccc(CCC(=O)O)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(CCC(N)=O)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 0.33 h

Procedure:
To a solution of 3-{3-[6-Azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxyphenyl}propanoic acid (EXAMPLE 60) (66 mg, 0.104 mmol) in DCM (4 ml) was added oxalyl chloride (2M in DCM) (0.259 ml, 0.518 mmol) and a drop of DMF. The solution was stirred for 20 minutes, concentrated, dissolved in THF (3 ml), added ammonium hydroxide (0.144 ml, 1.035 mmol) and stirred overnight. The crude was concentrated, dissolved in MeOH, filtered and purified by RP HPLC to afford 38 mg (0.060 mmol) of 3-{3-[6-azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxyphenyl}propanamide. This was combined with N,N-dimethylformamide dimethyl acetal (1 ml, 7.50 mmol) and heated at 120° C. for 40 minutes. The reaction mixture was concentrated, added AcOH (1 ml), hydrazine hydrate (7.26 μl, 0.119 mmol) and heated at 90° C. for 1.5 hours. Added saturated aqueous sodium hydrogen carbonate to the reaction mixture and extracted 3 times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by TLC and RP HPLC and lyophilized from MeCN/water to afford the title compound. Mass spectrum (ESI) 661.3 (M+1). 1H NMR (500 MHz, CD3OD): δ 8.07 (br s, 1H); 7.97 (s, 1H); 7.89 (s, 2H); 7.25 (d, J=8.3 Hz, 1H); 7.14 (d, J=8.4 Hz, 1H); 6.94 (d, J=8.4 Hz, 1H); 6.89 (s, 1H); 6.34 (d, J=8.3 Hz, 1H); 5.76 (s, 1H); 4.57 (m, 1H); 4.24 (m, 1H); 4.05 (t, J=7.4 Hz, 4H); 3.92 (m, 1H); 3.73 (s, 3H); 3.03 (d, J=14.7 Hz, 4H); 2.45-2.37 (m, 2H); 0.60 (s, 3H).
Reaction SMILES: [K].CCO.[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6](OCC)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH3:32])[C:20]([N+:29]([O-])=O)=[C:21]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:22]=1>CCOCC>[CH3:28][N:26]([CH3:27])[CH2:25][CH2:24][O:23][C:21]1[CH:22]=[C:17]([O:16][CH3:15])[CH:18]=[C:19]2[C:20]=1[NH:29][C:6]([C:5]([O:12][CH2:13][CH3:14])=[O:11])=[CH:32]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1cc(C)c([N+](=O)[O-])c(OCCN(C)C)c1
Agent: [K]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc2cc(OC)cc(OCCN(C)C)c2[nH]1
Temperature: 100 °C
Reaction time: 115 h
Yield: 18.2 %

Procedure:
A suspension of potassium (0.308 g, 7.87 mmol) in xylenes (6 mL) was heated to 100° C. and stirred rapidly as it was allowed to cool. The xylenes were removed and the potassium was washed with Et2O (×3) and covered with Et2O (10 mL). The mixture was treated with absolute EtOH (1.30 mL, 22.2 mmol) and stirred at reflux until the potassium had dissolved (3 h). The cooled mixture was treated with diethyl oxalate (1.07 mL, 7.87 mmol) then with a solution of the above nitrotoluene (2.00 g, 7.87 mmol) in dry Et2O (5 mL). After 115 h, the dark red precipitate was removed by filtration and washed with Et2O. The red solid (1.189 g) was dissolved in absolute EtOH (45 mL), acidified with AcOH (0.78 mL), and hydrogenated over Pd/C (10%, 0.44 g) at 1 atm H2 for 8 h. The mixture was filtered through Celite, concentrated, diluted with 0.2 M aqueous Na2CO3 (100 mL), and extracted with EtOAc (×4). The combined extracts were washed with water (×2), dried (Na2SO4), evaporated and purified by flash chromatography (2% Et3N/EtOAc) to give ethyl 7-[2-(dimethylamino)-ethoxy]-5-methoxyindole-2-carboxylate as a clear oil (0.44 g, 18%). 1H NMR (CDCl3) δ 10.93 (br s, 1 H, NH), 7.09 (d, J=2.1 Hz, 1 H, H-3), 6.67 (d, J=2.0 Hz, 1 H, H-4), 6.43 (d, J=2.0 Hz, 1 H, H-6), 4.38 (q, J=7.0 Hz, 2 H, OCH2CH3), 4.16 (t, J=6.5 Hz, 2 H, OCH2CH2N), 3.88 (s, 3 H, OCH3), 2.79 (t, J=7.0 Hz, 2 H, NCH2), 2.37 (s, 6 H, N(CH3)2), 1.40 (t, J=6.5 Hz, 3 H, OCH2CH3); 13C NMR δ 161.9 (CO2), 155.0, 146.0, 128.1, 127.7, 124.9 (C-2, 3a, 5, 7, 7a), 108.1 (C-3), 99.1 (C-4), 94.6 (C-6), 65.9 (OCH2CH2N), 60.6 (OCH2CH3), 58.3 (NCH2), 55.6 (OCH3), 45.1 (N(CH3)2), 14.4 (OCH2CH3). Calc for C16H22N2O4, M+306.1580. Found, 306.1577. Starting material (0.77 g, 39%) was recovered from the ethereal washes by extraction into acid, basification, and extraction with Et2O.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[CH2:31]([Mg]Br)[CH:32]=[CH2:33].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)([OH:12])[CH2:33][CH:32]=[CH2:31])=[CH:6][CH:7]=1
Reactant: O=C(CCCc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(O)(CCCc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
To a solution of ketone from Example 25, Step 1 (1.5 g, 3.61 mmol) in dry THF (15 mL) at 0° C. was added a 1M solution of allyl magnesium bromide (4.3 mL, 4.3 mmol). The reaction mixture was stirred for 45 minutes at 0° C., at which point saturated NH4Cl solution (15 mL) was added, and the product was extracted with EtOAc. The organic layer was washed with water and brine, and was then evaporated to dryness. Purification by flash chromatography (gradient of 1:20, 1:10, 1:5 EtOAc/hexane) gave a pale yellow syrup which was triturated with 1:4 ether/hexane to give the title compound as a white solid, m.p.=87°-88° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CC(=O)CC>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
A solution of 4-hydroxybenzaldehyde (15.0 g, 0.122 mole) in butanone (200 ml) was treated with anhydrous potassium carbonate (18.55 g, 0.134 mole), and the mixture stirred at room temperature for 20 mins. Ethyl 4-bromobutanoate, (24.0 g, 0.122 mole), dissolved in butanone (10 ml), was added dropwise to the stirred mixture over a period of 1 h. The reaction was stirred and refluxed for 6 h, then cooled and partitioned between water and butanone. The organic phase was separated, washed with dilute sodium hydroxide, water, brine and dried, (MgSO4). Evaporation of the solvent in vacuo gave a red oil, which was distilled at 0.05 mm/Hg to yield 19.31 g (67%) of a colourless oil, bp 152°-6° C. υmax (film) 1730, 1685, 1600, 1580, 1508 cm-1 δ (CDCl3) 1.25 (3H, t, J 7 Hz, ester CH3) 2.18 (2H, bt, J6 Hz, OCH2CH2), 2.49 (2H, bt, J6 Hz, CH2CO2), 4.09 (2H, t, J6 Hz, OCH2), 4.11 (2H, q, J7 Hz, ester CH2), 7.38 (4H, ABq, Δυ75 Hz, J9 Hz, C6H4), 9.90 (1H, s, CHO)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH2:23])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]1=[O:19].[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].O>C1COCC1>[O:19]=[C:7]1[N:6]([CH2:5][C:4]2[CH:20]=[CH:21][C:22]3[NH:23][C:24](=[O:25])[NH:1][C:2]=3[CH:3]=2)[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc2oc(=O)n(Cc3ccc(N)c(N)c3)c2c1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2oc(=O)n(Cc3ccc4[nH]c(=O)[nH]c4c3)c2c1

Procedure:
1.1 g (3.5 mmol) of methyl 3-(3,4-diaminobenzyl)-2-oxo-2,3-dihydrobenzoxazole-5-carboxylate and 626 mg (3.9 mmol) of 1,1′-carbonyldiimidazole are stirred at room temperature for 24 h in 10 ml of THF. The reaction mixture is added to 150 ml of water, and the resultant precipitate is filtered off with suction and dried in vacuo; product; 1.1 g; ESI: 340 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH:20][C:21](=[O:33])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:14]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[S-:34][C:35]#[N:36].[K+].BrBr>C(O)(=O)C>[NH2:36][C:35]1[S:34][C:11]2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH:20][C:21](=[O:33])[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=4)[CH:14]=3)[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: COC(=O)c1cc(N)ccc1Oc1ccc(F)c(NC(=O)Cc2cccc(C(F)(F)F)c2)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1c(Oc2ccc(F)c(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(N)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
To a solution of methyl 5-amino-2-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]acetyl}amino)phenoxy]benzoate (3.00 g, 6.09 mmol) in acetic acid (70 mL) was added potassium thiocyanate (2.37 g, 24.4 mmol), and the mixture was stirred at room temperature for 10 min. A solution of bromine (1.27 mg, 7.92 mmol) in acetic acid (35 mL) was added dropwise to the obtained solution over 20 min. After the completion of the dropwise addition, the mixture was stirred at room temperature for 36 hr. Insoluble material was filtered off and washed with ethyl acetate (200 mL). The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (100 mL), and the suspension was washed successively with saturated aqueous sodium hydrogen carbonate solution (2×100 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate/n-hexane (1:1) to give the title compound (2.78 g, 88%) as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][C:19]([CH3:20])=[C:6]12)=[O:4].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1CCCCC1.C(OCC)(=O)C>[CH2:3]([N:5]([CH2:11][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][C:19]([CH3:20])=[C:6]12)=[O:4])[CH2:6][CH3:19])[CH3:2]
Reactant: Cc1scc2c1N(C(=O)CCl)c1ccccc1NC2=O
Reactant: C1CCNCC1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2NC(=O)c2csc(C)c21

Procedure:
The title compound is prepared analogously to Example 2 from 4-(chloroacetyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-(diethylamino)methyl]piperidine to give colorless crystals, mp. 147°-149° C. (cyclohexane/ethyl acetate 9:1 v/v).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc(OC)cc3)n2)cc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-methoxyaniline were reacted to yield N2,N4-bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.67 (d, 1H, J=4.8 Hz), 7.43 (d, 2H, J=9.3 Hz), 7.67 (d, 2H, J=8.7 Hz), 6.87 (d, 2H, J=9.6 Hz), 6.83 (d, 2H, J=8.7 Hz), 3.83 (s, 3H), 3.81 (s, 3H); LCMS: ret. time: 22.53 min.; purity: 100%; MS (m/e): 341 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CCC(C)=O>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A reaction vessel was charged with 15 g of 4-hydroxy-4'-bromobiphenyl, 14 g of octyl bromide, 16 g of potassium carbonate and 100 ml of MEK, and the mixture was refluxed with stirring for 8 hours (the disappearance of the starting materials was confirmed by GLC). The reaction liquid was filtered to remove solids. The filtrate was concentrated and the residue was recrystallized from acetone to obtain 18 g (90%) of 4-octyloxy-4'-bromobiphenyl.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:28]4[C:23]([C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)=[C:22]([C:30]4[CH:31]=[CH:32][C:33]5[C:37]([CH:38]=4)=[N:36][N:35]([CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:34]=5)[CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C>Cl.O1CCOCC1>[CH2:39]([N:35]1[CH:34]=[C:33]2[C:37]([CH:38]=[C:30]([C:22]3[CH:21]=[C:20]([C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:15]=4)[N:28]4[C:23]=3[C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)[CH:31]=[CH:32]2)=[N:36]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ncnn2c(-c3cccc(C4CCNCC4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 4 h

Procedure:
The product from step 4 was dissolved in 5 mL of 4M HCl in dioxane and the mixture was stirred for 4 h. Ethyl acetate (10 mL) was added into the resulting mixture and washed with 2M Na2CO2 (2 mL). The resulting organic solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC. (CH2Cl2/MeOH). δ 1H NMR (CD2Cl2) 1.60 (m, 1H), 1.80 (m, 2H), 2.80 (m, 3H), 4.10-4.30 (m, 3H), 5.60 (s, 2H), 5.80 (br, 2H), 7.00 (s, 1H), 7.10-7.50 (m, 9H), 7.80 (m, 2H), 7.90 (m, 2H), 7.95 (s, 1H), 8.10 (s, 1H); LC-MS [M+H]+=500.2, RT=2.39 min.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13](I)[C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(O[CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)C.C(OCC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)OCC=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1c(F)cccc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCc1c(F)cccc1CC=Cc1ccccc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Under an argon atmosphere, 300 mg of t-butyl N-(2-fluoro-6-iodobenzyl)carbamate, 0.29 mL of cinnamyl acetate, 1.28 mL of bistributyltin, and 70 mg of PdCl2(dppf)2 were dissolved in 2.5 mL of DMF, followed by stirring at 120° C. for 2 hours. After completion of the reaction, to the reaction liquid was added diethyl ether, followed by filtration through Celite, and to the filtrate was added water, followed by extraction with diethyl ether. Then, the organic layer was washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using PLC (n-hexane:ethyl acetate=3:1) to obtain 121 mg (yield 52%) of a title compound as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH3:21])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:22][C:23]1[S:27][C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH:31]=O)=[N:25][CH:24]=1>>[CH3:21][O:20][C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[CH:2]1[N:1]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([C:26]3[S:27][C:23]([CH3:22])=[CH:24][N:25]=3)[CH:29]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cnc(-c2cccc(C=O)c2)s1
Reactant: COC(=O)CCCC(N)c1c(OC)ccc2ccccc12
Product: COc1ccc2ccccc2c1C1CCCC(=O)N1Cc1cccc(-c2ncc(C)s2)c1

Procedure:
Prepared according to general procedure 1 (GP1) using methyl 5-amino-5-(2-methoxynaphthalen-1-yl)pentanoate and 3-(5-methylthiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 443.13 g/mol.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)=[O:5].C(=O)([O-])[O-].[K+].[K+].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>CC(C)=O>[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)=[O:5]
Reactant: BrCCCCBr
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCCCCBr

Procedure:
A suspension of 7.5 g of 2-hydroxy-N-(1H-indol-4-yl)benzamide and 8.28 g of potassium carbonate in 150 ml of acetone was refluxed for 75 minutes with 18 ml of 1,4-dibromobutane and the mixture was cooled. The precipitate was filtered off and rinsed with acetone and the filtrate was evaporated to dryness. The residue was purified by chromatography over silica (eluant: methylene chloride/ethyl acetate 9:1), followed by crystallization from ethyl acetate to obtain 2-(4-bromobutoxy)-N-(1H-indol-4-yl)benzamide melting at 135° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:39])[CH:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][SH:30]>>[CH3:25][O:26][C:27](=[O:39])[CH:28]([NH:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:29][S:30][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: COC(=O)C(CS)NC(=O)OC(C)(C)C
Product: COC(=O)C(CSc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1)NC(=O)OC(C)(C)C
Yield: 34.8 %

Procedure:
2-tert-Butoxycarbonylamino-3-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]thiazol-5-ylsulfanyl}-propionic acid methyl ester (196 mg, 35%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-tert-butoxycarbonylamino-3-mercapto-propionic acid methyl ester (470 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][CH2:6][CH3:7])[CH:3]=[O:4].[CH2:8]1[CH:12]2[CH:13]3C=CC([CH:11]2C=[CH:9]1)C3>>[CH2:5]([C:2]1([CH:3]=[O:4])[CH2:11][CH:12]2[CH2:13][CH:1]1[CH:9]=[CH:8]2)[CH2:6][CH3:7]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=C(C=O)CCC
Product: CCCC1(C=O)CC2C=CC1C2
Temperature: 170 °C
Yield: 44.9 %

Procedure:
2-Methylene pentanal (302 g) and dicyclopentadiene (244 g) were loaded into a 2-L autoclave. The autoclave was sealed and heated to 170° C. The reaction was monitored by Gas Chromatography (“GC”) analysis, which showed the completion after 3 hours. The reaction was cooled to room temperature. The crude product was purified by distillation to yield 2-propylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde (136 g).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][OH:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:9][CH2:8][C:4]1[S:3][CH:7]=[CH:6][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1cccs1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCc2cccs2)cc1
Temperature: -40 °C
Reaction time: 0.42 h
Yield: 70.7 %

Procedure:
Sodium hydride (0.41 g, 20 mmol) was added to a solution of 2-thiophene methanol (2.0 g, 18 mmol) in THF (20 ml) at −40° C. The reaction was stirred at −40° C. for 25 min., then neat benzylbromide (3.6 g, 20 mmol) was added by syringe. The solution was stirred at −40° C. for 0.5 hr, then at room temperature for 1 hr. The THF was evaporated off and the remaining residue was taken up in ether (˜50 ml). The organic solution was washed with water (1×10 ml), brine (1×10 ml) and dried over MgSO4. Evaporation of solvents left an oil which was purified by column chromatography using 1% ether-hexanes to give 2.6 g of the thiophene as a pale yellow oil (78% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:19])=[N:4][C:5](Cl)=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:21][NH2:22]>>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:22][NH:21][C:13](=[O:14])[C:6]=2[CH:5]=[N:4][C:3]=1[CH3:19]
Reactant: NN
Reactant: CCOC(=O)c1c(Cl)nc(C)c(N)c1C(=O)OCC
Solvent: O
Product: Cc1ncc2c(=O)[nH][nH]c(=O)c2c1N
Temperature: 100 °C

Procedure:
To 57 mg of 3-amino-6-chloro-4,5-diethoxycarbonyl-2-methylpyridine was added 0.5 ml of hydrazine monohydrate, and the mixture was heated in a stream of nitrogen at 100° C. for 30 minutes. The solvent is distilled off, and the resultant crystals were collected by filtration with ethanol. After water was added to the crystals, the mixture was neutralized with 1N hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[S:33][N:32]=[N:31][C:30]=1[CH3:34])=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[S:33][N:32]=[N:31][C:30]=1[CH3:34])=[O:28]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: Cc1nnsc1C(=O)CBr
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2snnc2C)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 5-bromoacetyl-4-methyl-1,2,3-thiadiazole (Preparation is described in Example 228).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:4].[C:11]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1sccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1sccc1OC
Temperature: 55 °C
Yield: 108.4 %

Procedure:
To a mixture of 3-hydroxy-thiophene-2-carboxylic acid methyl ester (5 g, 31.6 mmol) and K2CO3 (22.2 g, 161 mmol) in acetone (50 mL) is added CH3I (10.8 mL, 173 mmol,) dropwise at 0° C. The reaction mixture is heated at 55° C. for 4 hours, cooled to room temperature, filtered through diatomaceous earth, and the filtrate is concentrated under vacuum. The residue is diluted with water (100 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layer is washed with brine solution (50 mL), dried over Na2SO4, and evaporated under vacuum to give title compound as a brown solid (5.9 g). ESI/MS m/z 173.1 (M+H)+.