Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=1[O:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=1[O:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1c(OC)cccc1OC
Reactant: O=C(Cl)c1ccccc1
Product: CCCCCC(CC(=O)Nc1cc(CNC(=O)c2ccccc2)ccc1C(C)(C)C)c1c(OC)cccc1OC

Procedure:
Following a similar procedure to that described in Example 144, but using N-(2-t-butyl-5-aminomethylphenyl)-3-(2,6-dimethoxyphenyl)octanamide (prepared as described in Preparation 72E) and benzoyl chloride, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[F:4].[N-:12]=[N+:13]=[N-:14].[Na+]>CS(C)=O>[N:12]([CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[F:4])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cccc(C(F)CBr)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC(F)c1cccc(F)c1
Temperature: 65 °C
Reaction time: 4 h
Yield: 83.2 %

Procedure:
To a solution of 11 (2.3 g, 10.5 mmol) in dry DMSO (15 mL) was added NaN3 (1.0 g, 15.7 mmol). The reaction solution was allowed to stir at 65° C. for 4 h then cooled to room temperature. The reaction mixture was partitioned between EtOAc (300 mL) and H2O (200 mL). The organic layer was washed with H2O (200 mL), brine (200 mL), and dried over Na2SO4. The solvents were removed by rotary evaporation and the crude product was purified by flash column chromatography (EtOAc/hexanes, 1:18-1:9) to yield 12 (1.6 g, 85%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 3.40-3.50 (dd, J=3.0, 13.5, 0.5H), 3.50-3.60 (dd, J=3.0, 13.5 Hz, 0.5H), 3.60-3.75 (m, 1H), 5.50-5.60 (dd, J=3.0, 8.0 Hz, 0.5H), 5.65-5.80 (dd, J=3.0, 8.0 Hz, 0.5H), 7.00-7.20 (m, 3H), 7.30-7.50 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 55.9, 56.1, 91.82, 91.84, 93.2, 93.3, 112.78, 112.84, 112.96, 113.03, 116.19, 116.20, 116.36, 116.38, 121.24, 121.27, 121.30, 121.33, 130.7, 130.8, 139.09, 139.15, 139.25, 139.31, 162.1, 164.1; GC-MS calcd for C8H7F2N3 183. found 183.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Br:9]Br>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Nc1ccnc(N)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ncc(Br)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a stirring mixture of 2,4-diaminopyrimidine (25 g, 0.23 mol, 1.0 eq) in acetic acid (375 ml) was added Br2 (36.3 g, 0.23 mol, 1.0 eq) at room temperature. The resulting mixture was stirred at room temperature (about 25° C.) for 2 hours and then filtered. The yellow solid was mixed with water (250 ml) and the pH of the resulting mixture was adjusted to 8-9 using 50% NaOH solution. Stirring was continued at room temperature for 30 min and the mixture was filtered, washed with water, and then dried under vacuum to give 38 g (87%) of 2,4-diamino-5-bromo-pyrimidine as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 6.06 (s, 2H, ex. D2O), 6.50 (br, 2H, ex. D2O), 7.76 (s, 1H); MS (+)-ES [M+H]+ m/z 191.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][C:3]=1[CH3:11].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:21])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(N)=O)ccc1Br
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(N)=S)ccc1Br
Reaction time: 4 h
Yield: 157.5 %

Procedure:
4-Bromo-3-methylbenzamide (D37, 1.0 g, 0.0047 mole) was dissolved in THF (50 ml), treated with Lawessons reagent (0.95 g, 0.0024 mole) and stirred under argon for 4 h. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel eluting with 10% EtOH/CHCl3 to afford the title compound as a yellow solid (0.87 g, 80%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:41]=[CH:42][CH:43]=2)[C:15]([NH:17][C:18]2[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][S:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:21]=[CH:20][C:19]=2[O:37][CH2:38][C:39]#[N:40])=[O:16])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].[N-:46]=[N+:47]=[N-:48].[Na+].S([O-])(O)(=O)=O.[Na+]>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:41]=[CH:42][CH:43]=2)[C:15]([NH:17][C:18]2[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][S:27]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)(=[O:28])=[O:29])[CH:21]=[CH:20][C:19]=2[O:37][CH2:38][C:39]2[NH:48][N:47]=[N:46][N:40]=2)=[O:16])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1csc(COc2cccc(C(=O)Nc3cc(CCCS(=O)(=O)c4ccc(Cl)cc4)ccc3OCC#N)c2)n1
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(COc2cccc(C(=O)Nc3cc(CCCS(=O)(=O)c4ccc(Cl)cc4)ccc3OCc3nnn[nH]3)c2)n1
Temperature: 70 °C
Reaction time: 12 h
Yield: 73.4 %

Procedure:
Dimethylformamide (13 ml) was added to a mixture of 3-[(4-tert-butyl-2-thiazolyl)methoxy]-5'-[3-(4-chlorophenylsulfonyl)propyl]-2'-cyanomethoxybenzanilide (1.30 g, 2.04 mmol), ammonium chloride (0.20 g, 4.08 mmol) and sodium azide (0.25 g, 4.08 mmol), and the resulting mixture was stirred at 70° C. for 12 hours. Ice and 5% sodium hydrogensulfate aqueous solution were added to the reaction solution and the product formed was extracted with ethyl acetate. The resulting organic layer was washed with water and brine in that order, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (eluent=methanol:chloroform=5:100) and then crystallized from acetonitrile to give 3-[(4-tert-butyl-2-thiazolyl)methoxy]-5'-[3-(4-chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide (1.02 g, 74%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2O)=[CH:19][CH:18]=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].O(Br)[Br:27].[P+5].[OH-].[Na+]>CN(C=O)C.O>[Br:27][C:21]1[C:20]2[C:15](=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[S:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)(=[O:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc2c(O)c(S(=O)(=O)c3ccc(F)c(F)c3)cnc2c1
Reactant: BrOBr
Agent: [Na+]
Agent: [OH-]
Agent: [P+5]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(Br)c(S(=O)(=O)c3ccc(F)c(F)c3)cnc2c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
A mixture of 3-(3,4-difluoro-benzenesulfonyl)-7-nitro-quinolin-4-ol (1.6 g, 4.37 mmol) and phosphorus(V) oxybromide (2.5 g, 8.72 mmol) in DMF (16 ml) was stirred at 65° C. for 1 hour. The reaction mixture was diluted with water (100 ml) and the pH was adjusted to 10 with aqueous sodium hydroxide solution. After cooling the precipitate was filtered and washed with water. The obtained crude product was purified by crystallization from ethanol to obtain 1.25 g of the title compound in 67% yield.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:12]2.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH:35]=O.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH3:28])[CH2:12]2)[CH2:35][C:31]1[N:30]([CH3:29])[CH:34]=[CH:33][N:32]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCN1Cc2ccc(CNCc3ncc[nH]3)cc2C1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN1Cc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
The compound (12.5 mg) obtained in Example 38-1 was dissolved in methanol (2.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (4.4 mg) and sodium cyanoborohydride (4.2 mg). The solution was adjusted to pH 4 with acetic acid and stirred at room temperature for 8 hours. The residue obtained by concentration of the solution was added with a saturated aqueous sodium hydrogen carbonate solution to neutralize the solution and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (7.7 mg) as a colorless oily substance.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([I:30])=[C:11]([C:17]([I:29])=[C:18]([NH:21][C:22](=[O:28])[CH2:23][O:24]C(=O)C)[C:19]=1[I:20])[CH2:12]CC([O-])=O)=[O:7])(=O)C.C[OH:32]>[OH-].[Na+]>[OH:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([I:30])=[C:11]([C:17]([I:29])=[C:18]([NH:21][C:22](=[O:28])[CH2:23][OH:24])[C:19]=1[I:20])[CH2:12][OH:32])=[O:7]
Reactant: CC(=O)OCC(=O)Nc1c(I)c(CCC(=O)[O-])c(I)c(NC(=O)COC(C)=O)c1I
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: O=C(CO)Nc1c(I)c(CO)c(I)c(NC(=O)CO)c1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3,5-Bis(acetoxyacetylamino)-2,4,6-triiodobenzylacetate (152 mg, 0.2 mmol) was dissolved in a mixture of methanol (6 ml) and 1 M aqueous NaOH (2 ml) and the solution was stirred for 2 h at room temperature. After neutralization with 1 M HCl, the solvents were removed by evaporation and the product was purified by preparative HPLC. Yield: 105 mg (83%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=1.[NH2:20][C@H:21]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:22][OH:23].CCN(C(C)C)C(C)C>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=[C:2]([NH:20][C@H:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:22][OH:23])[CH:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Nc1cc(C2CC2)[nH]n1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(N[C@@H](CO)c2ccc(F)cc2)cc1Nc1cc(C2CC2)[nH]n1
Temperature: 195 °C
Yield: 69.7 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyridin-4-amine (Method 90, 0.15 g, 0.54 mmol), (R)-2-amino-2-(4-fluorophenyl)ethanol (0.10 g, 0.67 mmol), and DIEA (0.12 ml, 0.67 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 195° C. for 52 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc) to give the title compound as a yellow solid (0.15 g, 72%). 1H NMR (400 MHz) 12.38 (s, 1H), 9.59 (b, 1H), 8.83 (s, 1H), 8.16 (b, 11H), 7.37 (m, 2H), 7.13 (m, 2H), 6.75 (b, 1H), 5.92 (b, 11H), 5.25 (b, 1H), 4.98 (m, 1H), 3.61 (t, J=6.4 Hz, 2H), 1.92 (m, 1H), 0.97 (m, 2H), 0.72 (m, 2H). MS: Calcd.: 398; Found: [M+H]+ 399.
Reaction SMILES: [CH:1]1([CH:4]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=2)[CH2:3][CH2:2]1.[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH:1]1([CH:4]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:5][CH2:6][CH:7]([Br:29])[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(CCCC(c2ccc(Cl)cc2)C2CC2)cc1Oc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(C(Br)CCC(c2ccc(Cl)cc2)C2CC2)cc1Oc1ccccc1
Yield: 88.6 %

Procedure:
A stirred solution of 2.0 grams (0.005 mole of 1-cyclopropyl-1-(4-chlorophenyl)-4-(4-fluoro-3-phenoxyphenyl)butane and 0.9 gram (0.005 mole) of N-bromosuccinimide in 50 mL of carbon tetrachloride was irradiated for 2 hours with a sun lamp. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure, yielding 2.1 grams of 1-cyclopropyl-1-(4-chlorophenyl)-4-bromo-4-(4-fluoro-3-phenoxyphenyl)butane. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]([CH3:13])[CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6].[C:14]([O:18][C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:14]([O:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([N:11]([CH3:13])[CH3:12])[N:10]=2)[C:5]([OH:7])=[O:6])=[CH:23][CH:22]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CN(C)c1cc(C(=O)O)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: CN(C)c1cc(C(=O)O)cc(-c2ccc(C(=O)OC(C)(C)C)cc2)n1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 65.5 %

Procedure:
2-Chloro-6-(dimethylamino)isonicotinic acid (450 mg, 2.24 mmol), 4-(tert-butoxycarbonyl)benzene boronic acid (648 mg, 2.92 mmol), 1,4-dioxane (7.5 mL) and sodium carbonate (713 mg, 6.73 mmol) dissolved in water (3.36 mL) were placed in a flask and the mixture bubbled with nitrogen while stirring for 10 min. Palladium(II) acetate (20 mg, 0.09 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (75 mg, 0.18 mmol) were then added together and the vessel flushed with nitrogen, sealed, and heated at 90° C. for 5 h. The mixture was then cooled to room temperature, diluted with ethyl acetate (50 mL), acidified to pH 2 with 1.5 N HCl and filtered through a pad of celite. The layers were separated and the aqueous portion extracted with ethyl acetate (2×50 mL). The combined organic portions were treated with anhydrous sodium sulfate and decolorizing charcoal and stirred for 30 min before filtering. The solution was concentrated to dryness and the residue purified by trituration with a mixture of methyl tert-butyl ether (5 mL) and heptane (100 mL). The solids were collected by filtration and dried to give 2-(4-(tert-butoxycarbonyl)phenyl)-6-(dimethylamino)isonicotinic acid (502 mg, 65%) as a pale yellow powder. m/z: 343+ [M+H]; 341− [M−H]; 1H NMR (400 MHz, CDCl3) δ ppm 8.12-8.21 (m, 2H), 8.04-8.11 (m, 2H), 7.67 (s, 1H), 7.16 (s, 1H), 3.23 (s, 6H), 1.64 (s, 9H).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:20])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:58][O:59][C:60](=[O:75])[CH2:61][CH:62]([N:64]1[CH2:69][CH2:68][NH:67][CH:66]([CH2:70][CH:71]([CH3:73])[CH3:72])[C:65]1=[O:74])[CH3:63]>CN(C=O)C.O>[CH3:58][O:59][C:60](=[O:75])[CH2:61][CH:62]([N:64]1[CH2:69][CH2:68][N:67]([C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:21])=[O:20])=[CH:15][CH:14]=2)[CH:66]([CH2:70][CH:71]([CH3:72])[CH3:73])[C:65]1=[O:74])[CH3:63]
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: COC(=O)CC(C)N1CCNC(CC(C)C)C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(C)N1CCN(C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)C(CC(C)C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.1 %

Procedure:
To a stirred mixture of [4-(3-o-tolyl-ureido)-phenyl]-acetic acid (55 mg, 0.19 mmol), diisopropyl ethyl amine (0.17 ml), BOP (86 mg, 0.19 mmol) in DMF (1 ml) was added 3-(3-isobutyl-2-oxo-piperazin-1-yl)-butyric acid methyl ester (50 mg, 0.19 mmol). After stirring 16 h at room temperature the solution was diluted with water and extracted into ethyl acetate. The combined organics were washed with 5% citric acid, saturated NaHCO3, and brine; dried over MgSO4, filtered, and concentrated under reduced pressure. Column chromatography on silica gel eluting with 2% MeOH/CH2Cl2 gave 20 mg of the title compound as a yellow amorphous solid. MS [M+1]+523.3.
Reaction SMILES: [CH:1]1([N:7]([C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27][O:28][CH3:29])[CH2:23][CH2:22]2)[C:8](=[O:20])NC2SC(SCC(O)=O)=CN=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N[C@H]2CCC[C@H](COC)CC2)CCCCC1.C([O:49][C:50](=[O:61])[C:51]([S:54][C:55]1[S:59][C:58]([NH2:60])=[N:57][CH:56]=1)([CH3:53])[CH3:52])C>>[CH:1]1([N:7]([C@H:21]2[CH2:22][CH2:23][C@H:24]([CH2:27][O:28][CH3:29])[CH2:25][CH2:26]2)[C:8](=[O:20])[NH:60][C:58]2[S:59][C:55]([S:54][C:51]([CH3:52])([CH3:53])[C:50]([OH:49])=[O:61])=[CH:56][N:57]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Agent: COC[C@H]1CCC[C@H](NC2CCCCC2)CC1
Product: COC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in an similar manner to {2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclohexyl-(trans-4-methoxymethyl-cycloheptyl)-amine and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([N+:27]([O-])=O)[C:21]=1[CH3:30])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:27][C:22]1[C:21]([CH3:30])=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:25]([CH3:26])=[CH:24][CH:23]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 109.7 %

Procedure:
To a suspension of 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-nitrobenzene (42 g) and ammonium chloride (4.2 g) in ethanol (378 ml)-water (42 ml) was added iron (7.0 g), and the mixture was refluxed for 6 hours, during which iron (7.0 g) was added thereto twice. Insoluble materials were filtered off, and the filtrate was concentrated. To the residue was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to give 3-amino-1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethylbenzene (42.8 g) as pale yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH:4]([CH2:9][C:10]#[C:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2)[C:5]([O:7]C)=[O:6].O[Li].O>C1COCC1.O>[CH3:29][O:28][C:27]1[CH:26]=[CH:25][NH:24][C:23]=1/[CH:22]=[C:14]1\[C:15](=[O:21])[NH:16][C:17]2[C:13]\1=[C:12]([C:11]#[C:10][CH2:9][CH:4]([C:3]([OH:30])=[O:2])[C:5]([OH:7])=[O:6])[CH:20]=[CH:19][CH:18]=2
Reactant: COC(=O)C(CC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2)C(=O)OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCC(C(=O)O)C(=O)O)c21

Procedure:
Using Method F above, (Z)-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]propanedioic acid dimethyl ester (68 mg, 0.16 mmol) (from Example 26 above) was hydrolyzed with LiOH.H2O (140 mg, 3.32 mmol) in THF (1 mL) and water (1 mL) at room temperature for 20 h to yield (Z)-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]propanedioic acid. (Yield 49 mg, 82%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:16](Br)[CH:17]=[CH2:18]>CCO>[CH2:18]([S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1)[CH:17]=[CH2:16]
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: C=CCBr
Solvent: CCO
Product: C=CCSc1nnc(-c2ccc3[nH]cnc3c2)o1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and allylbromide (0.093 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [ClH:1].[N:2]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[C:19]([NH:26][C@@H:27]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]=[N:21][C:22]=3[C:23]([NH2:25])=[O:24])=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:33][N:34]([CH3:41])[CH2:35]/[CH:36]=[CH:37]/[C:38](O)=[O:39].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[CH3:33][N:34]([CH3:41])[CH2:35]/[CH:36]=[CH:37]/[C:38]([N:29]1[CH2:30][CH2:31][CH2:32][C@@H:27]([NH:26][C:19]2[N:20]=[N:21][C:22]([C:23]([NH2:25])=[O:24])=[C:17]([NH:16][C:13]3[CH:14]=[CH:15][C:10]([C:8]([N:2]4[CH2:3][CH2:4][O:5][CH2:6][CH2:7]4)=[O:9])=[CH:11][CH:12]=3)[N:18]=2)[CH2:28]1)=[O:39].[ClH:1]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: NC(=O)c1nnc(N[C@@H]2CCCNC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)C/C=C/C(=O)N1CCC[C@@H](Nc2nnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(piperidin-3-ylamino)-1,2,4-triazine-6-carboxamide HCl salt (47 mg, 0.10 mmol) in NMP (4 mL) was added (E)-4-(dimethylamino)but-2-enoic acid (50 mg, 0.30 mmol), DIEA (180 μL, 1.0 mmol) and then PyBOP (104 mg, 0.20 mmol). The mixture was stirred at RT for 2 h, quenched with TFA (0.2 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC to isolate the title compound (80) as an HCl salt (32 mg). MS found for C26H35N9O4 as (M+H)+ 538.2, (M−H)− 536.3. UV: λ=246 nm.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:13].[CH2:14](N(CC)CC)[CH3:15]>CCO.CCOC(C)=O.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]>[CH:14]([C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:13])=[CH2:15]
Reactant: Cc1cc2c(c(C)c1Br)COC2=O
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: C=Cc1c(C)cc2c(c1C)COC2=O
Temperature: 140 °C

Procedure:
5-Bromo-4,6-dimethyl-2-benzofuran-1(3H)-one (375 mg, 1.56 mmol), potassium vinyl trifluoroborate (417 mg, 3.11 mmol), Pd(dppf)Cl2 (127 mg, 0.156 mmol), and triethylamine (409 μL, 3.11 mmol) were combined together in EtOH (10 mL) and heated at 140° C. for 30 min. Analysis by LC as well as TLC (hexanes/EtOAc=1/0.3) indicated that reaction had gone to completion. The reaction mixture was then diluted with EtOAc, washed with NaCl, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was then re-dissolved in dichloromethane, absorbed to silica gel, concentrated, and loaded onto a silica MPLC column for separation to afford of 5-ethenyl-4,6-dimethyl-2-benzofuran-1(3H)-one.