Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:9]1[S:10][CH:11]=[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([N:38]=[N+:39]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C:9]1[S:10][CH:11]=[C:12]([C:14](=[N+:38]=[N-:39])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cc1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(=[N+]=[N-])c1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of ethyl 2-[2-[tert-butoxycarbonyl-[(4-methoxyphenyl)methyl]amino]thiazol-4-yl]acetate (synthesized as per preparation 44; 3.8 g, 9.35 mmol) in dry acetonitrile was added para-toluene sulfonyl azide (2.04 g, 10.3 mmol) followed by DBU (2.09 mL, 14.0 mmol) in dropwise manner. The reaction stirred for 30 min. then poured in ice cold water (20 mL) extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide crude product, which was purified by column chromatography using 5-7% ethyl acetate in hexane to afford Ethyl 2-[2-[tert-butoxycarbonyl-[(4-methoxyphenyl)methyl]amino]thiazol-4-yl]-2-diazo-acetate (3.3 g).
Reaction SMILES: [N:1]#[N:2].C([O:5][C:6](=[O:40])[CH2:7][N:8]([C:13](=[O:39])[C@H:14]([CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:38])[NH2:37])[NH:15][S:16]([C:19]1[CH:31]=[CH:30][C:22]2[S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:21]=2[CH:20]=1)(=[O:18])=[O:17])[CH2:9][CH2:10][O:11][CH3:12])C.[OH-].[Na+]>CO>[N:1]#[N:2].[CH:20]1[C:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[S:23][C:22]=2[CH:30]=[CH:31][C:19]=1[S:16]([NH:15][C@H:14]([C:13]([N:8]([CH2:9][CH2:10][O:11][CH3:12])[CH2:7][C:6]([OH:40])=[O:5])=[O:39])[CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:37])[NH2:38])(=[O:17])=[O:18]
Reactant: CCOC(=O)CN(CCOC)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2sc3ccccc3c2c1
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCN(CC(=O)O)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2sc3ccccc3c2c1
Reaction time: 10 h
Yield: 58.2 %

Procedure:
A solution of 5.5 g of N2 -(2-dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in 15 ml of methanol and 15 ml of 2N-NaOH solution was warmed to 40° C and held at that temperature for 10 hours. At the end of this period, the reaction mixture was concentrated and chromatographed on 200 ml of Daiaion ® SK 102 ion exchange resin (200-300 mesh, H30 form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (1 : 4) and eluted with ethanol-water-NH4OH (10 : 9 : 1). The main fraction was evaporated to dryness and washed with ethyl ether to give 3.05 g (62 percent) of N2 -(2-dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine as an amorphous solid. I.R. (KBr): 3,400, 1,630, 1,280 cm-1
Reaction SMILES: [CH2:1]([S:5][CH2:6][C:7]([C:10]1[N:11](S(C)(=O)=O)[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([N+:19]([O-:21])=[O:20])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)([OH:9])[CH3:8])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([S:5][CH2:6][C:7]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([N+:19]([O-:21])=[O:20])=[C:14]([C:22]([F:24])([F:25])[F:23])[CH:13]=2)([OH:9])[CH3:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSCC(C)(O)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2n1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: CCCCSCC(C)(O)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2[nH]1

Procedure:
This compound was prepared using the general de-protection procedure as describe in General Procedures Example B. The starting material used was 1-butylsulfanyl-2-(1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol (0.53 g, 1.16 mmol). The base that was used was 4N sodium hydroxide solution (1 mL, 4 mmol). The title compound was obtained as a yellow sticky oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[CH:21]/[CH:22]=[O:23])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2cccnc2c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc2cccnc2c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 7-quinolinecarboxaldehyde (prepared as described in J. Med. Chem. 1993, 36, 3308) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([OH:13])[CH:7]=1)[C:3]([OH:5])=[O:4].[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>O>[NH2:1][CH:2]([C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([OH:12])[C:11]=1[N+:14]([O-:16])=[O:15])[C:3]([OH:5])=[O:4]
Reactant: NC(C(=O)O)c1cc(O)cc(O)c1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(C(=O)O)c1cc(O)cc(O)c1[N+](=O)[O-]
Temperature: -10 °C

Procedure:
2-Amino-2-(3,5-dihydroxyphenyl)-acetic acid (183 mg, 1 mmol) was added portionwise to stirred 5.5M nitric acid (2.5 ml, 15 mmol), which has been cooled to -10° C. in an ice/salt bath. The resulting brown solution was diluted with water (2 ml), neutralised with 2M sodium hydroxide, and purified by cationic exchange chromatography (as in Example 14) to give the title compound as a fluffy yellow solid, m.p. >280° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:10]\[CH:11]=O)=[CH:5][CH:4]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20]>ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:11]/[CH:10]=[C:9](\[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)/[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(/C(=C\C=O)c2cccnc2)cc1
Solvent: ClCCl
Product: COC(=O)/C=C/C=C(\c1ccc(OC)cc1)c1cccnc1

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-3-(3- pyridinyl)-2-propenal (5.25 g was reacted with (carbomethoxymethylene)triphenylphosphorane (7.4 g) in dichloromethane (40 mL) for 17 hours at room temperature. The crude ester was isolated in the usual way and was purified by HPLC to give 4.6 g of the ester. A portion was crystallized twice from ether-hexane to give the analytical sample of (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid methyl ester, mp 75°-76° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:20](O)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH2:40].O>CN(C=O)C>[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH:40][C:20]([C:4]1[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=2)[C:7]([CH3:8])=[C:2]([I:1])[CH:3]=1)=[O:21]
Reactant: Cc1c(I)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)CCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(I)cc(C(=O)NCCCN(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a suspension of 5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (10 g, 23.64 mmol) in DMF (20 mL) was added a solution of carbonyldiimidazole (5.14 g, 30.72 mmol) in DMF (30 mL) over a period of 40 min at 25° C. After stirring the mixture for 30 minutes, was added a solution of N,N-dimethylpropane-1,3-diamine (3.62 g, 35.45 mmol) in DMF (10 mL) over a period of 20 min at 25° C. and stirred for 40 minutes. After completion of the reaction, water (100 mL) was charged at 25° C. over a period of 1 h. The resulting suspension was stirred for 4 h and filtered. The cake was washed with water (50 mL) and dried under vacuum at 50° C. for 12 h to afford the title product as a light brown solid (10 g, 83%); 1H NMR (400 MHz, CDCl3) δ 9.36 (bs, 1 H), 8.87 (s, 1 H), 7.82 (d, J=7.53 Hz, 1 H), 7.76 (t, J=7.78Hz, 1 H), 7.49 (s, 1 H), 7.41 (d, J=8.03 Hz, 1 H), 3.43 (q, J=6.86 Hz, 2 H), 2.30-2.35 (m, 2 H), 2.29 (s, 3 H), 2.20 (s, 6 H), 1.74 (p, J=7.28 Hz, 2 H); LCMSm/z: 508 [M+].
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][P:31]([O:36]CC)(=[O:35])[O:32]CC)[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-]>C(Cl)(Cl)Cl>[C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][P:31]([OH:36])(=[O:32])[OH:35])[C:9]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOP(=O)(CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1)OCC
Agent: [I-]
Solvent: ClC(Cl)Cl
Product: O=P(O)(O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: -40 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
A mixture of 2,4,5-triphenyl-1-(7-bromoheptyl)-imidazole (0.95 g) and triethyl phosphite (1.66 g) in xylene (5 ml) was heated at reflux temperature for 20 hours. The mixture was evaporated to an oil and chromatographed on silica gel (ethyl acetate/ethanol) to give diethyl 7-(2,4,5-triphenylimidazol-1-yl)heptane-phosphonate (0.37 g, 35%) as a light brown oil. NMR μ(CDCl3) 0.9-1.7 (18H, m, 6×CH2 +2×CH3), 3.9 (2H, t, CH2N), 4.1 (4H, m, 2×CH20), 7.1-7.7 (15H, m, 3×Ph) ppm. Diethyl 7-(2,4,5-triphenylimidazol-l-yl)heptane-phosphonate (0.35 g) was dissolved in dry chloroform, cooled to -40° C and to it was added trimethylsflyl iodide (0.66 g) over 2 minutes under an atmosphere of nitrogen. The cooling bath was removed and the reaction mixture was stirred for 3 hours at room temperature then evaporated to an oil and re- evaporated from methanol and water respectively. The oil was taken up in methanol, treated with excess aqueous sodinto bicarbonate, evaporated to dryness then taken up in ethanol, filtered and the flitrate evaporated to an oil. This was taken up in water, filtered and dilute hydrochloric acid added to pH4. The precipitated oil was washed with water, taken up in methanol and precipitated with ether to give 7-(2,4,5-triphenylimidazol-1-yl)heptane-phosphonic acid (0.16 g, 51%) as a light brown oil. Found: C, 68.12; H, 6.39, N, 5.60% C28H31N2O3P+4% H2O requires: C, 68.03; H 6.76; N, 5.66%.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][CH:9]([NH2:11])[CH3:10])[CH2:4][CH3:5])[CH3:2].Cl.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23](Cl)=[O:24])=[CH:15][CH:14]=1>O>[CH3:10][CH:9]([NH:11][C:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=[CH:14][CH:15]=1)=[O:24])[CH2:8][CH2:7][CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: O=C(Cl)c1ccnc2ccccc12
Reactant: CCN(CC)CCCC(C)N
Agent: Cl
Solvent: O
Product: CCN(CC)CCCC(C)NC(=O)c1ccnc2ccccc12

Procedure:
2-[4'-(5"-nitrofuryl-2")-1,3-butadienyl]quinoline-4-carboxylic acid (α-methyl-δ-diethylaminobutyl)amide was prepared from 4.74 g (0.03 mol.) of diethylamino-4-aminopentane and 3.91 g (0.01 mol.) of 2-[4-(5"-nitrofuryl-2")-1,3-butadienyl]quinoline-4-carboxylic acid chloride hydrochloride in 50 ml of water. The process was conducted as described in Example 7.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[NH:12][C:13]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21](=[N:25][OH:26])[CH2:20][CH2:19]4)[N:15]=2)[CH2:7][CH2:6]1.[CH3:33]ON=C1C2C(=CC(C(=O)C(C3C=CN=CC=3)=O)=CC=2)CC1>>[CH3:33][O:26][N:25]=[C:21]1[C:22]2[C:18](=[CH:17][C:16]([C:14]3[N:15]=[C:11]([CH:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:9]4)[NH:12][C:13]=3[C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)=[CH:24][CH:23]=2)[CH2:19][CH2:20]1
Reactant: CON=C1CCc2cc(C(=O)C(=O)c3ccncc3)ccc21
Reactant: COCCN1CCC(c2nc(-c3ccc4c(c3)CCC4=NO)c(-c3ccncc3)[nH]2)CC1
Product: COCCN1CCC(c2nc(-c3ccc4c(c3)CCC4=NOC)c(-c3ccncc3)[nH]2)CC1
Yield: 32 %

Procedure:
The title compound (0.27 g, 32%) was prepared from the product of Step 1 and the product of Example 1 Step 4 as described in Example 1 Step 5; MS(AP+) m/e 446 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:32]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:28][CH3:32])[C:24]([F:25])([F:26])[F:27])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
To a stirred solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (67.6 mg, 0.150 mmol) in tetrahydrofuran (1.0 mL) was added sodium hydride (60% in oil, 7.2 mg, 0.18 mmol) at 0° C. After 15 min, iodomethane (46.7 μL, 0.75 mmol) was added. After being stirred for 1.5 h at room temperature, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (67.2 mg, 0.145 mmol, 96%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([N:10]1[CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1-c1nc(-c2ccccc2)c[nH]1
Product: CC(=O)n1cc(-c2ccccc2)nc1-c1ccccc1C

Procedure:
0.702 g (0.003 mole) of the compound of Example 26 and 3 ml (0.00317 mole) of acetic anhydride were heated on an oil bath at 95° C. for 2 hours, then the excess of acetic anhydride was distilled under vacuum. The obtained residue was crystallized from tert-butylmethyl ether/light petroleum. Yield 0.69 g (83%) of the title compound M.p. 102°-4° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][N:5]2[CH:13]([CH3:15])[CH3:14].[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][N:5]3[CH:13]([CH3:15])[CH3:14])[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)N1CC(=O)Nc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CC(C)N1CC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Temperature: 25 °C

Procedure:
A mixture of 6-bromo-4-isopropyl-3,4-dihydro-1H-quinoxalin-2-one (2 g, 75 mmol), 3-chlorophenylboronic acid (1.6 g, 10 mmol), potassium carbonate (4g, 30 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.35 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hrs. After cooling to room temperature the mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, then brine, dried (MgSO4) and evaporated to give crude product (1.5 g, 66%). Recrystallization from EtOAc/hexane afforded the title compound: mp 146-150° C. 1H-NMR (DMSO-d6) δ 1.16 (d, J=6.37 Hz, 6H), 3.57 (s, 2H), 4.21 (septet, J=6.59 Hz, 1H), 6.87 (d, J=7.91 Hz, 1H), 6.98 (dd, J=7.91, 1.76 Hz, 1H), 7.02 (d, J=1.76 Hz, 1H), 7.35 (m, 1H), 7.43 (t, J=7.69 Hz, 1H), 7.57 (m, 1H), 7.66 (t, J=1.76 Hz, 1H), 10.48 (s, 1H). MS (EI) m/z 300 (M)+ + 1 chlorine.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[C:7]([O:15]COC)[C:6]=1[CH3:19].Cl.O>CO>[CH3:19][C:6]1[C:7]([OH:15])=[C:8]([O:11][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:5]=1[OH:4]
Reactant: CCCOc1ccc(OCOC)c(C)c1OCOC
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCOc1ccc(O)c(C)c1O
Yield: 98.8 %

Procedure:
A solution of 5b (580 mg, 2.15 mmol) in MeOH (17.9 mL) was treated dropwise with 3 M HCl (630 μL, 17.2 mmol), then heated to reflux for one hour. Water (20 mL) was added and the solution was extracted with EtOAc (3×20 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), and concentrated to afford 6b as a red amorphous solid (387 mg, 99%). 1H NMR (CDCl3, 500 MHz) 6.51 (d, J=8.7 Hz, 1H), 6.21 (d, J=8.6 Hz, 1H), 5.74 (s, 1H), 4.36 (s, 1H), 3.87-3.85 (m, 2H), 2.09 (s, 3H), 1.75-1.71 (m, 2H), 0.96 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 147.5, 143.8, 139.0, 109.8, 108.4, 103.8, 70.2, 21.6, 9.5, 7.3; IR (film) νmax 3520, 3360, 2966, 2880, 2359, 2341, 1636, 1236, 1068, 785, 750 cm−1.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]O)=[CH:7][C:6]=1[O:13][CH3:14])[CH2:2][CH3:3].P(Br)(Br)[Br:16]>C(OCC)C>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][Br:16])=[CH:7][C:6]=1[O:13][CH3:14])[CH2:2][CH3:3]
Reactant: CCCOc1ccc(CO)cc1OC
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CCCOc1ccc(CBr)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 195.3 %

Procedure:
To a solution of 4-(propyloxy)-3-methoxybenzyl alcohol (2.28 g, 11.62 mmol) in anhydrous diethyl ether (30 mL) was slowly added PBr3 (0.55 mL, 5.81 mmol) via syringe, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with diethyl ether (150 mL) and washed with saturated aqueous NaHCO3 (2×75 mL) and brine (2×75 mL). The organic layer was dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to afford 4-(propyloxy)-3-methoxybenzyl bromide (2.94 g, 98%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:25])=[C:9]([NH:11][S:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[N:10]=2)[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[F:32][C:33]([F:44])([F:43])[O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:25])=[C:9]([N:11]([CH2:39][C:38]3[CH:41]=[CH:42][C:35]([O:34][C:33]([F:32])([F:43])[F:44])=[CH:36][CH:37]=3)[S:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[N:10]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2nc3ccc(F)cn3c2C)cc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2nc3ccc(F)cn3c2C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of compound 6-E (0.300 g, 0.75 mmol) and K2CO3 (0.218 g, 1.58 mmol) in DMF (5 mL) was cooled in an ice bath and treated with a solution of 4-trifluoromethoxybenzyl bromide (0.132 mL, 0.83 mmol) in DMF (1 mL) and stirred at ambient temperature for 18 hours. The solution was partitioned between EtOAc and water, and the organic phase was separated, washed with water (3×) then brine and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was pre-absorbed on silica gel and purified by flash chromatography, using a gradient of EtOAc (10-50%) in heptanes as the eluant, to give the Compound 118, as a colorless solid (0.330 g, 82%). 1H-NMR (CDCl3): δ 8.17 (d, J=8.6 Hz, 2H), 7.85 (d, J=8.6 Hz, 8H), 7.69-7.74 (m, 1H), 7.41 (dd, J=9.9, 5.0 Hz, 1H), 7.29 (d, J=8.6 Hz, 2H), 7.03-7.14 (m, 3H), 4.74 (s, 2H), 3.97 (s, 3H), 2.26 (s, 3H); MS: m/z 538.0 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Sr+2:5].[N+:6]([O-:9])([OH:8])=[O:7]>>[N+:6]([O-:9])([O-:8])=[O:7].[Sr+2:5].[N+:6]([O-:9])([O-:8])=[O:7]
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Sr+2]
Product: O=[N+]([O-])[O-]

Procedure:
Strontium nitrate may alternatively be obtained from celestite ore via the "black ash" process, in which celestite is reduced to strontium sulfide black ash by heating with coal. The strontium sulfide is leached from the black ash with water, reacted with soda ash to form strontium carbonate, and the separated strontium carbonate treated with aqueous nitric acid to yield strontium nitrate.
Reaction SMILES: [Sn](Cl)Cl.Cl.[Cl:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=1[O:8][CH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[C:11]=1[C:12]#[N:13].[OH-].[K+]>>[NH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([CH2:9][O:8][C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[Cl:5])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(COc2ccccc2Cl)cccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Product: N#Cc1c(N)cccc1COc1ccccc1Cl
Temperature: 15 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
To a cooled (15° C.) and stirred solution of tin (II) chloride (0.78 g, 3.46 mmol) and con. hydrochloric acid (1.5 mL) was added a solution of 2-(2-chlorophenoxymethyl)-6-nitrobenzonitrile (200.0 mg, 0.69 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was poured on to crushed-ice and potassium hydroxide solution, stirred, filtered and dried to yield 140 mg of 2-amino-6-(2-chlorophenoxymethyl)benzonitrile.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([F:35])=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([F:35])=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc(F)c4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
Sodium hydroxide (35 mg) was added to a solution of ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoate (D48) (222 mg) in THF (3 mL) and water (3 mL). The reaction mixture was stirred at 90° C. for 1 hour. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoic acid (E22) (137 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.40 (6H, d), 2.62 (2H, t), 3.07 (2H, t), 5.46 (1H, m), 6.98 (1H, dd), 7.26 (1H, d), 7.91 (1H, dd), 8.72 (1H, d), 9.04 (1H, d), 11.09 (1H, s), 11.71 (1H, br s). δF (DMSO-d6, 376 MHz): −118.7. MS (ES): C21H18ClFN4O4 requires 444; found 445.1 (M+H+).