Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]3[N:22]=[C:23]4[C:29]([C:30](O)=[O:31])=[CH:28][N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:24]4=[N:25][CH:26]=3)=[N:16][N:17]2[CH3:20])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[F:72][C:73]([F:84])([CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C@H:74]([NH2:76])[CH3:75]>CN(C=O)C>[F:72][C:73]([F:84])([CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C@H:74]([NH:76][C:30]([C:29]1[C:23]2[C:24](=[N:25][CH:26]=[C:21]([C:15]3[C:14]4[C:18](=[CH:19][C:11]([F:10])=[CH:12][CH:13]=4)[N:17]([CH3:20])[N:16]=3)[N:22]=2)[N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])[CH:28]=1)=[O:31])[CH3:75]
Reactant: C[C@@H](N)C(F)(F)Cc1ccccc1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(F)(F)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
In a round-bottomed flask, (R)-2,2-difluoro-1-methyl-3-phenyl-propylamine trifluoroacetate (crude from Step 3) was dissolved in DMF (1.1 ml) and N,N-diisopropylethylamine (0.25 ml, 1.43 mmol) was added. Then 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 23 mmol) was added followed by HATU (95 mg, 0.25 mmol). The yellow reaction was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was triturated with petroleum ether to afford 136 mg (94%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2,2-difluoro-1-methyl-3-phenyl-propyl)-amide as an off-white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:7][CH2:8][C:9]([OH:11])=[O:10]>C(OCC)(=O)C>[Br-:7].[C:9]([CH2:8][NH+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH2:2]1)([OH:11])=[O:10]
Reactant: O=C(O)CBr
Reactant: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(O)C[NH+]1C=CC=CC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 16.2 mL of pyridine (200 mmol) in 120 mL of ethyl acetate there are added, in portions, 27.8 g (200 mmoles) of bromoacetic acid. The batch is then stirred at ambient temperature overnight. The precipitate thereby obtained is filtered off and then washed with cold ethyl acetate. After drying, the title product is obtained in the form of a powder which is used directly in the next Step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:23](Cl)(=[O:39])[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>O1CCOCC1.O>[CH:37]1[C:38]2[CH:26]([CH2:25][O:24][C:23]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]3[C:14]([OH:16])=[O:15])=[O:39])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](C(=O)O)C1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
To a solution of (S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (500 mg, 2.171 mmol) in 1,4-dioxane (5 mL) and water (20 mL) was added potassium carbonate (1200 mg, 8.69 mmol) followed by (9H-fluoren-9-yl)methyl carbonochloridate (562 mg, 2.171 mmol) at 0° C. The mixture was stirred at RT for 18 hrs and then treated with water (10 ml). The resulting mixture was extracted with diethyl ether (2×15 ml). The aqueous phase was acidified with aq. HCl (1M) to pH 2-3, and extracted with DCM (3×20 ml). The combined organic layers were dried over MgSO4 and concentrated to give the crude product. The crude product was purified via prep HPLC (10-100% CH3CN:Water with 0.1% TFA buffer) to afford the product (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (294 mg, 30% yield) as a white solid. 1H NMR (500 MHz, methanol-d4) d 7.83 (t, J=6.6 Hz, 2H), 7.68-7.58 (m, 2H), 7.45-7.38 (m, 2H), 7.38-7.30 (m, 2H), 4.65 (br. s., 1H), 4.58 (d, J=13.7 Hz, 1H), 4.55-4.39 (m, 3H), 4.33-4.18 (m, 1H), 2.91-2.85 (m, 4H), 1.47 (s, 9H). ESI-MS(+) m/z=475 (M+Na).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:18][CH2:17][C@:13]2([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[NH:14][O:15][CH2:16][C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[NH2:14][C@@:13]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:17][O:18][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11][C@H:12]1[CH2:16][OH:15]
Reactant: Fc1ccc([C@]23CO[C@@H](COCc4ccccc4)C[C@H]2CON3)c(F)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Compound C5 (48.1 g, 133 mmol) was dissolved in acetic acid (444 mL) and treated with zinc powder (113 g, 1.73 mol). The reaction mixture, which had warmed to 40° C., was allowed to cool to room temperature and stir for 16 hours. Insoluble material was removed via filtration through a pad of diatomaceous earth, and the pad was washed with ethyl acetate (3×500 mL). The combined filtrates were neutralized with saturated aqueous sodium bicarbonate solution (2.5 L), and the aqueous layer was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (1 L), dried over sodium sulfate, filtered, and concentrated in vacuo to provide the product as a thick yellow oil, which was used in the following reaction without additional purification. Yield: 48.7 g, assumed quantitative. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 7.62-7.80 (br m, 1H), 7.28-7.39 (m, 5H), 6.94-7.06 (m, 1H), 6.83 (ddd, J=12.7, 8.5, 2.6 Hz, 1H), 4.61 (AB quartet, upfield doublet is broadened, JAB=12.2 Hz, ΔνAB=30.5 Hz, 2H), 4.22 (dd, J=11.6, 2.2 Hz, 1H), 3.83-3.92 (br m, 1H), 3.62-3.73 (br m, 1H), 3.56 (dd, J=10.2, 3.5 Hz, 1H), 3.34-3.41 (m, 1H), 2.26-2.43 (br m, 1H), 2.00-2.17 (br m, 1H), 1.65 (ddd, J=14.1, 4.5, 2.5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14](=O)[CH2:15][CH3:16])[C:6]2[CH2:7][CH:8]([CH3:10])[O:9][C:5]=2[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1C=CC=CC=1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]2=[C:11]([NH:13][CH2:14][CH2:15][CH3:16])[CH:12]=1
Reactant: CCC(=O)Nc1cc(OC)cc2c1CC(C)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: CCCNc1cc(OC)cc2c1CC(C)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.2 grams of N-(2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)propanamide, prepared in the foregoing example, in 30 cc of anhydrous benzene is gradually added into a suspension of 1.1 grams of LiAlH4 in 30 cc of anhydrous ethyl ether at 0° C. and the resulting reaction mixture is heated to the reflux temperature for 6 hours. At the end of this time the temperature is decreased to 0° C. and the aluminum complex is decomposed by addition of 3.3 cc of water. After 30 minutes of stirring at room temperature, the inorganic salts are discarded by filtration and the filtrate, dried over Na2SO4, is concentrated to dryness. The under vacuum distillation of the obtained residue affords 2.8 grams (93 percent of theoretical) of the title compound. B.p./0.2 mmHg 140°-142° C. The corresponding hydrochloride prepared by treatment of the free base with HCl melts at 110°-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)SC)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:30][CH:26]2[CH2:29][CH2:28][CH2:27]2)[NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NC1CCC1
Reactant: CSC(Nc1cc(Cl)cc(Cl)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CC#N
Product: N#CC(=C(Nc1cc(Cl)cc(Cl)c1)NC1CCC1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 49 %

Procedure:
2-(4-Chloro-phenylsulfonyl)-3-(3,5-dichlorophenylamino)-3-methylsulfanyl-2-propenenitrile (0.90 g, 2.1 mmol), cyclobutylamine (0.50 ml, 6.3 mmol) and acetonitrile (2 ml) were stirred for 40 h at 100° C. under nitrogen in a sealed flask. Work-up as described in EXAMPLE 17, 2) gave 0.47 g (49%) of the title compound. 179.5-181.5° C. (EtOAc) 1H NMR (200 MHz, CDCl3): δ=1.65 (m, 2H), 1.95 (m, 2H), 2.1 (m, 2H), 3.65 (sextet, 1H), 6.88 (d, 2H), 7.18 (t, 1H), 7.47 (d, 2H), 7.78 (d, 2H); EI SP/MS: 459 (M+4), 357 (M+2) 455 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.FC(F)(F)C(O)=O.[N+:18]([O-])([OH:20])=[O:19]>O>[OH:1][C:2]1[C:7]([N+:18]([O-:20])=[O:19])=[C:6]([OH:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(O)cc(O)n1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc(O)c([N+](=O)[O-])c(O)n1
Temperature: 23 °C
Reaction time: 5 h

Procedure:
A solution of 4,6-dihydroxy-2-methylthiopyrimidine (42 g, 0.257 mol) in trifluoroacetic acid (91 ml, 1.186 mol) was stirred at 23° C. and warmed until all solid had gone into solution. The reaction was stirred for five hours at 23° C. Next, fuming HNO3 (15 ml, 350 mmol) was added portion wise to the reaction mixture over 25 minutes at 0° C. The reaction was stirred for twenty hours at 23° C., and treated with H2O (at 23° C.) at 80% conversion (according LC-MS). The solid precipitate was captured via filteration giving 4,6-dihydroxy-2-methylthio-5-nitropyrimidine as a tan-colored solid. The crude solid was azeotroped with toluene to give 35 g of pale tan powdery solid. 1H-NMR: 300 MHz, (CD3OD, 300 MHz) 6 (ppm) 2.63 (s, 3H). LCMS-ESI−: calc'd for C5H4N3O4S: 202.0 (M−H−). Found: 202.0 (M−H−).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][CH:12]=[CH2:13])[CH:5]=1.[CH2:15](Br)[CH:16]=[CH2:17]>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][CH:16]=[CH2:15])=[C:6]([CH2:11][CH:12]=[CH2:13])[CH:5]=1
Reactant: C=CCBr
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Product: C=CCOc1ccc(C(=O)OC)cc1CC=C
Reaction time: 16 h
Yield: 93 %

Procedure:
4-Allyloxy-3-allylbenzoic acid methyl ester was prepared by reacting 3-allyl-4-hydroxybenzoic acid methyl ester (Example 49, Step 2) with allyl bromide following Method C in 93% yield. The reaction was conducted at room temperature for 16 h and the resulting product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)[C:5](O)=[O:6].[BH4-].[Li+].C(O)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([CH2:5][OH:6])[CH:3]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc(Br)cc(CO)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an ice-cold solution of 3-bromo-5-(methoxycarbonyl)benzoic acid prepared by the method in Preparation 2 (10.3 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) is added lithium borohydride (12 g, 550 mmol) portion-wise. The reaction is stirred 4 h at this temperature. Absolute ethanol (20 mL) is added dropwise, and the reaction is stirred 1.5 h. The reaction is slowly poured on ice, and 10% hydrochloric acid (aq) is added until gas evolution ceased. The aqueous layer is extracted with chloroform, and the organic layer is washed with brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to give the title compound. ESI MS m/z 229, 231 [M−H]−.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[Cl:14])=[N+:2]=[N-:3].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH2:22][C:23]#[N:24])[CH:21]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([C:22]2[N:3]=[N:2][N:1]([C:4]3[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:6][C:5]=3[Cl:14])[C:23]=2[NH2:24])[CH:21]=1
Reactant: COc1ccc(Cl)cc1CC#N
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1nnn(-c2ccc(C(F)(F)F)cc2Cl)c1N
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-2-chloro-4-trifluoromethyl-benzene (0.500 g, 1 eq) and commercial (5-chloro-2-methoxy-phenyl)-acetonitrile (0.492 g, 1.2 eq) in ethanol (4 ml) kept under nitrogen, a solution of sodium methoxide (0.183 g, 1.5 eq) in ethanol (2 ml) is added drop-wise (15 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (25 ml), washed with water (2×25 ml), dried over MgSO4 and evaporated to dryness. The yellow solid residue (0.610 g) is purified by crystallization from a mixture of dichloromethane and hexane (1:1), to afford the title compound as white solid (0.450 g, 50% yield). M.p. 152.8-153.3° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:24]([OH:26])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14](OCC1C=CC=CC=1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H].[F:29][C:30]([F:37])([F:36])C(OCC)=O.CCN(CC)CC>CO.[Pd]>[C:1]([NH:8][C@H:9]([C:24]([OH:26])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([C:30]([F:37])([F:36])[F:29])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(F)(F)F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a degassed solution of acid 4 (25 g, 68 mmol) in MeOH (250 mL) was added Pd/C (10% Pd, 350 mg, 0.33 mmol) followed by hydrogen gas (1 atm, balloon). The reaction mixture was stirred at RT for 12 h by which time TLC showed complete consumption of the starting material. The balloon of hydrogen was then removed and MeOH (100 mL), ethyl trifluoroacetate (14.6 g, 103 mmol), and Et3N (13.8 g, 136 mmol) were added. The reaction mixture was stirred an additional 9 h and the resulting black suspension was filtered through Celite. A portion of the solvent was then removed in vacuo. The remaining solution (100 mL) was treated with water (150 mL) and EtOAc (100 mL). The organic layer was removed and the aqueous layer was then carefully acidified by the addition of an aqueous solution of HCl (2M). The aqueous layer was extracted with EtOAc (5×80 mL), and the combined organic extracts were then washed with an aqueous solution of HCl (0.1 M, 4×200 mL), brine (200 mL), and dried over magnesium sulfate. Removal of the solvent in vacuo gave the desired product 6 as a viscous oil (22.4 g, 68 mmol, quantitative yield): (Sakarellos et al., J. Org. Chem. 43: 293–296 (1978), viscous oil); Rf=0.65 (65:31:4 EtOAc/hexane/AcOH); 1H NMR (300 MHz, D6-DMSO) δ 12.50 (br s, 1 H), 9.41 (t, 1 H, J=3.2 Hz), 7.11 (d, 1 H, J=4.8 Hz), 3.84–3.87 (m, 1 H), 3.15–3.19 (m, 2 H), 1.51–1.69 (m, 4 H), 1.38 (s, 9 H) ppm; 13C NMR (75 MHz, D6-DMSO) δ 174.1, 156.2 (q, J=35 Hz), 155.7, 116.0 (q, J=286 Hz), 78.1, 53.2, 38.9, 28.2, 25.2 ppm; IR (thin film) 3316, 1709 cm−1; HRMS calculated (M-Boc, C7H10F3N2O3) 227.0644. found 227.0658.
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=O)C(C)=N1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([O:40]CC)=[O:39])=[CH:36][N:35]=[CH:34]2)=[CH:29][CH:28]=1.[OH-].[Li+].C1COCC1>O.CO>[F:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[C:37]([C:38]([OH:40])=[O:39])=[CH:36][N:35]=[CH:34]2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1cncn1-c1ccc(F)cc1
Agent: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cncn1-c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-1H-imidazole-5-carboxylic acid (14b) was prepared in a similar manner as that described for the synthesis of compound 7 using ethyl 1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (14a) (143 mg, 0.61 mmol), lithium hydroxide (59 mg, 2.44 mmol), THF (0.2 mL), methanol (0.4 mL), and water (0.8 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:16][CH2:15][C:14]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:13][C:12]=3[CH:24]=2)=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>CCCCCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:16][CH2:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=3[CH:24]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CO3)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CO3)cc1
Reaction time: 16 h
Yield: 86.4 %

Procedure:
To tert-butyl 6—(4-methylphenyl)-2H-1-benzopyran-3-carboxylate (3.00 g) was added 4N hydrochloric acid-ethyl acetate (10 ml) at room temperature, and the mixture was stirred for 16 hours. To the reaction mixture was added hexane, and crystal was collected by filtration and washed with hexane to give 6—(4-methylphenyl)-2H-1-benzopyran-3-carboxylic acid (2.14 g) as pale yellow crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[NH:10][C:11]1[C:12]2[C:19]3[CH2:20][CH2:21][NH:22][CH2:23][C:18]=3[S:17][C:13]=2[N:14]=[CH:15][N:16]=1.Cl.[CH3:25][N:26]([CH3:33])[CH2:27]/[CH:28]=[CH:29]/[C:30](O)=[O:31]>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[NH:10][C:11]1[C:12]2[C:19]3[CH2:20][CH2:21][N:22]([C:30](=[O:31])/[CH:29]=[CH:28]/[CH2:27][N:26]([CH3:33])[CH3:25])[CH2:23][C:18]=3[S:17][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Oc1ccc(Cl)c(Nc2ncnc3sc4c(c23)CCNC4)c1
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4cc(O)ccc4Cl)c23)C1

Procedure:
The compound was synthesized in analogy to Example 122 from 4-chloro-3-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 70A (100 mg, 0.27 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (63 mg, 0.38 mmol) to yield 17 mg (13%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH3:22][N:23](C=O)C.C(O)=O>C(N)=O.C(O)(C)C>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[C:4]1[NH:3][C:2]2[N:1]=[CH:22][N:23]=[C:7]([OH:8])[C:6]=2[CH:5]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(-c2ccc3ccccc3c2)[nH]c1N
Solvent: O=CO
Solvent: NC=O
Solvent: CC(C)O
Product: Oc1ncnc2[nH]c(-c3ccc4ccccc4c3)cc12

Procedure:
420 mg (1.5 mmol) of 2-amino-3-ethoxycarbonyl-5-(naphth-2-yl)-1H-pyrrole are stirred in 3 ml of formamide, 1.5 ml of DMF and 0.75 ml of formic acid at 150° C. for 22 hours. The reaction mixture is diluted with approximately 1 ml of isopropanol and filtered. Washing with ethanol, isopropanol and hexane yields the title compound; m.p.>300° C.; 1H-NMR (200 MHz, DMSO-d6): 12.2 (sb), 8.39 (s, 1H), 8.0 (m, 2H), 7.9 (m, 3H), 7.53 (m, 2H), 7.11 (s, 1H).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[S:20][C:21](Cl)=[C:22]([Cl:25])[C:23]=2[Cl:24])[N:16]([CH3:27])[N:15]=1.[Br:28]Br>C1COCC1.O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[S:20][C:21]([Br:28])=[C:22]([Cl:25])[C:23]=2[Cl:24])[N:16]([CH3:27])[N:15]=1
Reactant: Cn1nc(-c2c(Cl)cccc2Cl)nc1-c1sc(Cl)c(Cl)c1Cl
Reactant: BrBr
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(-c2c(Cl)cccc2Cl)nc1-c1sc(Br)c(Cl)c1Cl
Reaction time: 1 h
Yield: 17.2 %

Procedure:
n-Butyllithium (2.5 mmol) was slowly added to a solution of 3-(2,6-dichlorophenyl)-5-(3,4,5-trichlorothien-2-yl)-1-methyl[1,2,4]triazole (325 mg, 1.0 mmol) in THF at -78° C., and the mixture was stirred one hour. Bromine (3.0 mmol) was added and the reaction stirred two hours, then diluted with water, extracted with ether, washed with brine, and dried over magnesium sulfate. The product was concentrated to 620 mg of dark oil. This was chromatographed (SiO2, 10% EtOAc-Hex) to give 79 mg of the title product as a pink solid. MP 197-199° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[Br:26][C:27]1[CH:28]=[C:29](I)[CH:30]=[C:31]([Br:33])[CH:32]=1.C(O)(C(F)(F)F)=O>C1COCC1.CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:29]2[CH:28]=[C:27]([Br:26])[CH:32]=[C:31]([Br:33])[CH:30]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: C#CCCCCCc1cccc(OCCCC(=O)O)c1CCC(=O)O
Reactant: Brc1cc(Br)cc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)CCCOc1cccc(CCCCCC#Cc2cc(Br)cc(Br)c2)c1CCC(=O)O
Temperature: 60 °C
Yield: 57.4 %

Procedure:
To a solution of 4-[2-(2-Carboxy-ethyl)-3-hept-6-ynyl-phenoxy]-butyric acid (250 mg, 0.72 mmol), 3,5-dibromoiodobenzene (preparation in J. Org. Chem. 2003, 68, 8750) (261 mg, 0.72 mmol), CuI (7 mg, 0.036 mmol) in THF (5 mL) and Et3N (5 mL) was added bis-(triphenylphosphine)palladium(II) dichloride (25 mg, 0.036 mmol). The reaction mixture was heated at 60° C. for 3 h. Then the reaction mixture was cooled down, a few drop of TFA was added and the resulting mixture was evaporated under vacuo. The crude material was purified by column chromatography using a gradient from EtOAc to 20% MeOH-EtOAc as eluant to give the title compound (240 mg, 60%) as a oil. HR-MS-EI(+): calculated for C26H28O5Br2(M+Na) 601.0195, found 601.0193.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][NH:11]C(OC(C)(C)C)=O)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20].C(OCC)C>C(Cl)Cl>[NH2:1][C@H:2]([C:8]([NH:10][NH2:11])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7].[F:22][C:21]([C:19]([OH:25])=[O:20])([F:24])[F:23]
Reactant: CC(C)(C)OC(=O)NNC(=O)[C@@H](N)CCC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: NNC(=O)[C@@H](N)CCC(=O)O

Procedure:
A solution of EMC-Glu-NH—NH-BOC (32.4 g) and TFA (165 mL) in DCM (165 mL) was stirred at RT for 80 min after which diethyl ether (4 L) was added. The precipitated product was collected by suction filtration, washed with ether and dried yielding EMC-Glu-NH—NH2 TFA (20 g).