Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1CCOCC1)C.C1CCC(N=C=N[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)CC1.[NH:24]([C:84]([O:86][CH2:87]C1C=CC=CC=1)=[O:85])[C@H:25]([C:38]([NH:40][C@H:41]([C:54]([NH:56][C@H:57]([C:70]([NH:72][C@H:73]([C:81](O)=[O:82])[CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)=[O:71])[CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[CH:61][CH:60]=1)=[O:55])[CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].[NH2:94][C@H:95]([C:103]([O:105][C:106]([CH3:109])([CH3:108])[CH3:107])=[O:104])[CH2:96][CH2:97][CH2:98][NH:99][C:100](=[NH:102])[NH2:101].Cl.C1C=C2C(N(O)N=NC2=CC=1)=O>CC(N(C)C)=O>[NH:24]([C:84]([O:86][CH2:87][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:85])[C@H:25]([C:38]([NH:40][C@H:41]([C:54]([NH:56][C@H:57]([C:70]([NH:72][C@H:73]([C:81]([NH:94][C@H:95]([C:103]([O:105][C:106]([CH3:109])([CH3:108])[CH3:107])=[O:104])[CH2:96][CH2:97][CH2:98][NH:99][C:100](=[NH:101])[NH2:102])=[O:82])[CH2:74][C:75]1[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=1)=[O:71])[CH2:58][C:59]1[CH:60]=[CH:61][C:62]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[CH:63][CH:64]=1)=[O:55])[CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:48])=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCCNC(=N)N
Agent: CCN1CCOCC1
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.26 ml of N-ethylmorpholine and 440 mg of DCC are added at 0° C. to a solution of 1.95 g (2 mmoles) of Z-Lys(Boc)-Lys(Boc)-Tyr(But)-Phe-OH, 606 mg (2 mmoles) of H-Arg-OBut.HCl and 326 mg (2 mmoles) of HOObt in 5 ml of dimethylacetamide. The mixture is first stirred for 2 hours at 0° C. and is left to stand overnight at room temperature. On the following day the precipitate is filtered off and the filtrate is concentrated. Yield 2.5 g. The substance is purified by being recrystallized twice from ethyl acetate. Yield 1.7 g, melting point 134°-137°, [α]D26 =-26.4° (c=1, methanol).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)CC)C>C(#N)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc(I)ccc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(I)ccc2Cl)n1
Temperature: 150 °C
Yield: 21.6 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2-chloro-5-iodobenzoyl chloride (0.159 g, 0.528 mmol) and triethylamine (0.5 mL, 6.81 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.019 g (22% yield) of pure product: MS (ES) m/z 570 (M+1).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[N:9][CH:10]=[CH:11][C:12]=2[NH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([C:16]1[N:17]=[C:18]([C:29]([OH:31])=O)[N:19]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=1)#N.[K+].[C:33](C1N=C(C([O-])=O)N(COCC[Si](C)(C)C)C=1)#[N:34]>>[N:1]1([C:7]2[N:8]=[N:9][CH:10]=[CH:11][C:12]=2[NH:13][C:29]([C:18]2[N:19]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:20]([C:33]#[N:34])=[CH:16][N:17]=2)=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: Nc1ccnnc1N1CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Agent: [K+]
Product: C[Si](C)(C)CCOCn1c(C#N)cnc1C(=O)Nc1ccnnc1N1CCCCC1

Procedure:
3-Piperidin-1-yl-pyridazin-4-ylamine (as prepared in above step) was coupled with 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 11, step (d)), as described in Example 42, step (c) to afford 5-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (3-piperidin-1-yl-pyridazin-4-yl)-amide which was subjected to SEM deprotection as described in Example 47, step (d) to afford the title compound. 1H-NMR (DMSO-d6; 400 MHz): δ 9.79 (br s, 1H), 9.03 (d, 1H, J=4 Hz), 8.50 (s, 1H), 8.43 (d, 1H, J=4 Hz), 3.21 (m, 4H), 1.71-1.86 (m, 6H); Mass spectrum (ESI, m/z): Calcd. for C14H15N7O, 298.1 (M+H), found 298.1.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.Cl.C(N)C=C>C(O)(=O)C>[CH2:1]([N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[N:9]=[CH:8]1)[CH:2]=[CH2:3]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Agent: Cl
Solvent: CCOC(OCC)OCC
Solvent: C=CCN
Solvent: CC(=O)O
Product: C=CCn1cnc2c(-c3ccccc3)csc2c1=O
Yield: 57.5 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), allylamine hydrochloride (92.6 mg, 0.99 mmol), and acetic acid (0.1 ml) were used to give 66.4 mg (0.25 mmol, 57.5% yield) of the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH2:11][NH:12][C@H:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15].C1(C)C=CC=CC=1.[BH4-].[Na+]>CO>[CH2:1]([NH:9][CH2:10][CH2:11][NH:12][C@H:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:14]([CH3:16])([CH3:17])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](NCCN)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](NCCNCc1ccccc1)C(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A solution of benzaldehyde (23 g, 217 mmol) and the product of Example 111-3 (50 g, 217 mmol, 1 equivalent) in 50:50 mixture of toluene and methanol (total volume=1400 mL), stirred at 50° C. overnight, cooled to −3° C., treated with NaBH4 (16.6 g, 434 mmol, 2equivalents) slowly over 5 hours, and stirred at room temperature for 16 hours. The reaction mixture was quenched with a saturated NaHCO3 solution (1400 mL) and extracted with ethyl acetate (1.3 L). The layers were separated and the aqueous layer was extracted with ethyl acetate (850 mL). The organic layers were combined, washed with brine (900 mL), and concentrated. The residue was dissolved in heptanes (700 mL), decanted inorganic salt, distilled to oil and chased to yield 69.4 g of crude material. 1H NMR (CDCl3): δ 7.05-7.3(m, 7H), 3.75(d, 2H), 2.4-2.8(m, 5H), 1.4(s, 9H), 0.87(s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:48]/[O:49][CH2:50][CH:51]([C:53]([OH:55])=[O:54])[CH3:52])/[C:8]([NH:10][C@H:11]2[CH2:14][N:13]([C:15]([NH:17][S:18]([NH:21][C:22]3[C:27]([OH:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:23]=3[CH2:30][C:31]([O:33]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:32])(=[O:20])=[O:19])=[O:16])[C:12]2=[O:47])=[O:9])[N:6]=1.C1(OC)C=CC=CC=1.[F:64][C:65]([F:70])([F:69])[C:66]([OH:68])=[O:67]>ClCCl>[F:64][C:65]([F:70])([F:69])[C:66]([OH:68])=[O:67].[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:48]/[O:49][CH2:50][CH:51]([C:53]([OH:55])=[O:54])[CH3:52])/[C:8]([NH:10][C@H:11]2[CH2:14][N:13]([C:15]([NH:17][S:18]([NH:21][C:22]3[C:27]([OH:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:23]=3[CH2:30][C:31]([OH:33])=[O:32])(=[O:19])=[O:20])=[O:16])[C:12]2=[O:47])=[O:9])[N:6]=1
Reactant: CC(CO/N=C(\C(=O)N[C@H]1CN(C(=O)NS(=O)(=O)Nc2c(CC(=O)OC(c3ccccc3)c3ccccc3)ccc(O)c2O)C1=O)c1csc(N)n1)C(=O)O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(CO/N=C(\C(=O)N[C@H]1CN(C(=O)NS(=O)(=O)Nc2c(CC(=O)O)ccc(O)c2O)C1=O)c1csc(N)n1)C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 10.83 g (13.6 mmol) of the crude [[[[[(S)-3-[[(Z)-(2-amino-4-thiazolyl)[(2-carboxy-2-methylethoxy)imino]acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]amino]sulfonyl]amino]-3,4-dihydroxybenzeneacetic acid, diphenylmethyl ester in 45 ml of dry dichloromethane at -10° C., a cold solution of 11 ml of anisole in 110 ml of trifluoroacetic acid was added. After being stirred at 0° C. for 10 minutes, the clear solution was evaporated in vacuo at 0°-5° C. and the residue was treated with dry ether. The solid was collected by suction, washed with dry ether, dried in vacuo to give 7.28 g of impure [[[[[(S)-3-[[(Z)-(2-amino-4-thiazolyl)[(2-carboxy-2-methylethoxy)imino]acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]amino]sulfonyl]amino]-3,4-dihydroxybenzeneacetic acid, trifluoroacetate salt.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13]([Cl:15])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:9])=[O:8].[C:17]([O:20][CH2:21][C:22](Cl)=[O:23])(=[O:19])[CH3:18]>CC(N(C)C)=O>[Cl:9][C:7]([C:6]1[C:10]([I:11])=[C:2]([NH:1][C:22]([CH2:21][O:20][C:17](=[O:19])[CH3:18])=[O:23])[C:3]([I:16])=[C:4]([C:13]([Cl:15])=[O:14])[C:5]=1[I:12])=[O:8]
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: CC(=O)OCC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5-Amino-2,4,6-triiodo-isophthaloyl dichloride was dissolved in dimethyl acetamide (DAMC) and a solution of acetoxyacetylchloride (2 eq) in DMAc was slowly added with efficient stirring. The reaction mixture was stirred overnight and the following day, the mixture was slowly poured into stirred ice water. The precipitate was filtered off and dried to give the desired material. The structure was confirmed by 1H NMR (CDCl3, 300 MHz): 10.43 (brs, 1H); 4.71 (s, 2H); 2.11 (s, 3H)
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1.[O:10]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[O-].[K+].O1[CH2:31][CH2:30][NH:29]C1=O>>[O:10]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:31][CH2:30][NH2:29])=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: O=C1NCCO1
Agent: C[O-]
Agent: [K+]
Solvent: Cc1cc(C)cc(C)c1
Product: NCCOc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.7 %

Procedure:
Mesitylene (24 mL) was added into a round bottom flask containing 4-phenoxyphenol (5.00 g, 26.85 mmol). Potassium methoxide (25% in methanol) (0.79 mL, 2.685 mmol) was added and stirred for 15 minutes. 2-oxazolidinone (2.34 g, 26.85 mmol) was then added, and the reaction mixture was heated to reflux temperature and stirred for 16 h. After cooling the reaction mixture to room temperature, the reaction mixture was filtered over Celite® and the solvent evaporated under reduced pressure. The crude reaction product was isolated by flash column chromatography to yield 2.75 g (45%) of the amine. 1H NMR (MeOD, 400 MHz) δ 8.21-8.11 (m, 2H), 8.35-7.91 (m, 1H), 7.83-7.67 (m, 6H), 7.02-6.96 (m, 2H), 4.71 (dd, 2H, J=5.9, 5.9 Hz), 3.68 (dd, 2H, J=5.8, 5.8 Hz).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][S:9][C:8]=2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[C:20]12[C:28](=[O:29])[O:27][C:25](=[O:26])[C:21]=1[CH2:22][CH2:23][CH2:24]2>C1COCC1>[C:1]1([C:7]2[CH:11]=[CH:10][S:9][C:8]=2[NH:12][C:28]([C:20]2[CH2:24][CH2:23][CH2:22][C:21]=2[C:25]([OH:27])=[O:26])=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OC(=O)C2=C1CCC2
Reactant: Nc1sccc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)C1=C(C(=O)Nc2sccc2-c2ccccc2)CCC1
Temperature: 25 °C
Yield: 36 %

Procedure:
3-Phenyl-thiophen-2-ylamine (73 mg, 417 μmol, Int1.1), NEt3 (84.3 mg, 116 μL, 833 μmol) and 1-cyclopentene-1,2-dicarboxylic anhydride (144 mg, 1.04 mmol) were dissolved in dry THF (3 mL). The green-yellow suspension was stirred at RT over the week-end and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC (MeOH/H2O with 0.1% formic acid) to give the title compound as a yellow oil (47 mg, 32%, purity estimated at 90%). MS (ESI): m/z=312.2 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][O:5][C:4]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:3]1=2.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23](Cl)=[O:24].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:4]3[O:5][CH2:6][C:2]([CH3:19])([CH3:1])[C:3]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:24]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1cc2c(cc1-c1cnc(N)cn1)C(C)(C)CO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3c(F)cccc3F)cn1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a solution of 5-(3,3,6-trimethyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2-ylamine (177) (19 mg, 0.075 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (19 μl, 2 eq) followed by addition of DIEA (65 μl). The resulting solution was stirred at r.t. for 1 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (400 μl) at 60° C. for 1 h before worked up with EA/brine. Prep HPLC purification furnished (2,6-difluorophenyl)-N-[5-(3,3,6-trimethyl(2,3-dihydrobenzo[b]furan-5-yl))pyrazin-2-yl]carboxamide (178) (10.5 mg, yield: 35.4%, purity>95%) as off-white solid.
Reaction SMILES: [H-].[Na+].CO.[Br:5][CH:6]([C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH:19]([F:21])[F:20])[N:12]=[C:11]([C:22]([F:25])([F:24])[F:23])[C:10]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7]Br.Cl>C1COCC1>[Br:5][C:6]([C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH:19]([F:21])[F:20])[N:12]=[C:11]([C:22]([F:23])([F:24])[F:25])[C:10]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH2:7]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1C(Br)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(Br)c1c(C(=O)OC)c(C(F)F)nc(C(F)(F)F)c1C(=O)OCC
Temperature: 5 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
To a stirred mixture of 0.49 g (0.012 mole) of 60% sodium hydride in oil dispersion and 4 ml of anhydrous THF is added 10 ml of methanol under nitrogen. The reaction mixture is cooled with an ice bath to 5° C. then treated slowly with a solution of 3.0 g (0.0058 mole) of product of Example 128 in 2 ml of anhydrous THF, while the reaction mixture is maintained below 15° C. The mixture is stirred at 0° C. for 2 hours and poured into 180 ml of 1% hydrochloric acid then extracted three times with 50 ml of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and concentrated. The residue is purified by a radially-accelerated preparatory TLC using 10% ethyl acetate/cyclohexane as eluent to give 0.85 g (33%) of the desired product as a light yellow oil, nD25 1.4734. Anal. Calc'd. for C14H11BrF5NO4 : C, 38.91; H, 2.57; N, 3.29; Found: C, 39.00; H, 2.64; N, 3.37.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>ClCCl>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19]([N:2]2[C:1]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:5][CH2:4][CH2:3]2)=[O:20])=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Reaction time: 3 h
Yield: 65.9 %

Procedure:
To a solution of tetrahydroisoquinoline (3.99 g, 30 mmol) in triethyl amine(6 g, 60 mmol) and dichloromethane(150 mL) cooled in ice bath was added p-nitrophenyl chloroformate (6.06 g, 30 mmol) drop wise over a period of 1 h. The reaction mixture was srirred at room temperature for 3 h and then washed with water (3×100 mL), dried over sodium sulfate and concentrated to afford an oil which was triturated with ether:hexane to afford the titled compound as yellow solid (5.9 g, 65%).
Reaction SMILES: [Si:1]([OH:5])([OH:4])([OH:3])[OH:2].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:13](O)[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1>>[Si:1]([OH:5])([OH:4])([OH:3])[OH:2].[CH2:13]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[OH:12])[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccco1
Reactant: Oc1ccccc1
Agent: O[Si](O)(O)O
Product: Oc1ccccc1Cc1ccco1

Procedure:
1 part by weight of the phenol silicate compound as produced in Example 1 is mixed with 0.5 to 3 parts by weight of furfuryl alcohol then heated to 70° to 120° C. for 30 to 120 minutes thereby producing a brown, liquid poly (furfuryl phenol silicate) resinous product. The resinous product is cured by adding an acid compound such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid and sodium hydrogen sulfate, thereby producing a brown solid, tough resinous product.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30]([C:34]([O:36]CC)=[O:35])=[N:29][CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:39]([CH3:41])[CH3:40])[O:13][N:12]=1.Cl.O>O1CCCC1.CO>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30]([C:34]([OH:36])=[O:35])=[N:29][CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:39]([CH3:41])[CH3:40])[O:13][N:12]=1
Reactant: CCOC(=O)c1nccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)nccc3c2)cc1
Temperature: 90 °C
Yield: 47.7 %

Procedure:
A 1 N solution of sodium hydroxide (156.4 μL, 156.4 μmol) was added to ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-isoquinolinecarboxylate (43.9 mg, 78.2 μmol) in tetrahydrofuran and methanol (1:1, 1.6 mL) and the mixture was heated in the microwave at 90° C. for 10 minutes. After cooling, the mixture was neutralized with 1 N hydrochloric acid (156.4 μL), water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated to give 19.9 mg (48%) of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-isoquinolinecarboxylic acid as a solid. 1H NMR (400 MHz, d6-DMSO): δ 13.64 (br s, 1H), 8.63 (d, J=9 Hz, 1H), 8.55 (d, J=6 Hz, 1H), 8.29 (s, 1H), 8.06 (m, 2H), 7.75 (d, J=9 Hz, 2H), 7.65-7.61 (m, 2H), 7.55 (dd, J=9, 7 Hz, 1H), 6.95 (d, J=9 Hz, 2H), 4.90 (s, 2H), 3.48 (septet, J=7 Hz, 1H), 1.34 (d, J=7 Hz, 6H). ESI-LCMS m/z 533 (M+H)+.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[OH-].[Na+]>[C:1]1([S:7]([NH:11][CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]([OH:22])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(Cc1ccccc1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 151 mmol (26.6 g) of benzenesulphonyl chloride and 50 ml of 4M aqueous sodium hydroxide is added to a solution of 37.8 mmol (6.25 g) of phenylalanine in 50 ml of 4M aqueous sodium hydroxide. The reaction mixture is stirred at room temperature for 24 hours. The solution is then rendered acidic to pH=2 with dilute hydrochloric acid and extracted with ether. The organic phase is dried over magnesium sulphate and concentrated. The resulting residue is recrystallised from ethanol to yield the expected compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:13]([CH:14]=[O:15])=[C:12]([Cl:16])[N:11]=[CH:10][N:9]=1.[OH:17][C:18]1[C:19]([CH3:24])=[N:20][CH:21]=[CH:22][CH:23]=1.O>CN(C)C=O>[OH:17][C:18]1[C:19]([CH3:24])=[N:20][CH:21]=[CH:22][CH:23]=1.[Cl:16][C:12]1[C:13]([CH:14]=[O:15])=[C:8]([O:17][C:18]2[C:19]([CH3:24])=[N:20][CH:21]=[CH:22][CH:23]=2)[N:9]=[CH:10][N:11]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: Cc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1Oc1ncnc(Cl)c1C=O
Temperature: 25 °C

Procedure:
Potassium carbonate (10.22 g, 74 mmol) was added to a mixture of 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 5.0 g, 28.3 mmol) and 3-hydroxy-2-methylpyridine (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 3.66 g, 33.5 mmol) in anhydrous dimethylformamide (100 mL). The mixture was stirred at room temperature. The mixture was cooled to 0° C. and water (100 mL) was slowly added. The temperature rose to 18° C. during the addition. The mixture was recooled to 0° C. and stored in the freezer overnight. The precipitate was filtered off. LC-MS indicated that this was the result of the addition of two 3-hydroxy-2-methylpyridine moieties to the pyrimidine. The mother liquor was extracted with ethyl acetate and the extract was concentrated and purified using a Supelco 100 g column, eluting with 0-5% methanol/dichloromethane. Fractions containing the desired product were pooled, concentrated, and held under vacuum to give 4-chloro-6-(2-methyl-pyridin-3-yloxy)-pyrimidine-5-carbaldehyde (521 mg, 7%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 2.32 (s, 3H), 7.36 (dd, 1H, J=4.8, 8.2 Hz), 7.66 (dd, 1H, J=1.2, 8.2 Hz), 7.8.41 (dd, 1H, J=1.5, 4.8 Hz), 8.72 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[CH3:13][N:14]([CH3:18])[CH2:15][C:16]#[CH:17].C(N(C(C)C)CC)(C)C>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.[Cu](I)I.C(#N)C>[CH3:13][N:14]([CH3:18])[CH2:15][C:16]#[C:17][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4]
Reactant: C#CCN(C)C
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C)CC#Cc1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A resealable tube was charged with 2-bromo-5-(trifluoromethyl)aniline (1.00 g, 4.16 mmol), 1-dimethylamino-2-propyne (0.520 g, 6.20 mmol), PdCl2(PPh3)2 (0.15 g, 0.21 mmol), copper iodide (0.80 mg, 0.42 mmol), diisopropylethylamine (1.0 mL) and acetonitrile (3.0 mL). The system was purged with argon, the tube sealed and the mixture stirred at room temperature for 20 h. The reaction mixture was filtered through celite and concentrated. The residue was purified via column chromatography on silica gel (gradient elution with 0-10% methanol-dichloromethane) to afford 2-(3-dimethylamino-1-propynyl)-5-(trifluoromethyl)aniline as a brown oil. MS m/z=243 [M+H]+. Calc'd for C12H13F3N2: 242.