Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH2:3][CH2:4]/[C:5](=[CH:19]/[C:20]([O-:22])=[O:21])/[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:7].[S:34]([O-:37])([OH:36])=[O:35].[Na+:38].O.C(O)C>C(OCC)(=O)C>[F:1][C:2]([F:33])([C:23]([F:31])([F:32])[C:24]([F:29])([F:30])[C:25]([F:28])([F:27])[F:26])[CH2:3][CH2:4][C:5]([S:34]([OH:37])(=[O:36])=[O:35])([CH2:19][C:20]([O-:22])=[O:21])[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:7].[Na+:38]
Reactant: O=S([O-])O
Reactant: CCCCCCCCCCOC(=O)/C(=C\C(=O)[O-])CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOC(=O)C(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(CC(=O)[O-])S(=O)(=O)O
Yield: 22.9 %

Procedure:
48.0 g (90 mmol) of monodecyl mono(3,3,4,4,5,5,6,6,6-nonafluorohexyl)maleate, 10.4 g (99 mmol) of sodium hydrogen sulfite and 50 mL of water/ethanol (1/1 v/v) were mixed together and heated under reflux for 5 hr. Thereafter, ethyl acetate was added, and the organic phase was washed with a saturated aqueous sodium chloride solution. The resultant organic layer was collected, and the organic solvent was distilled off in vacuum. Recrystallization from acetonitrile was performed, thereby obtaining 12.5 g (yield: 22%) of desired compound as a colorless transparent solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:27])[CH:21]([CH2:22][CH:23]=C(C)C)[O:20]3)[CH:12]2[O:28][CH3:29])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:30]=[O+][O-]>CO.ClCCl>[CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:27])[CH:21]([CH2:22][CH2:23][OH:30])[O:20]3)[CH:12]2[O:28][CH3:29])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[O+][O-]
Reactant: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CCO
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-cyclohexylcarbamoyloxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (20 mg) in a mixture of methanol (0.1 ml) and dichloromethane (5 ml) was passed through ozone at -78° C. for 3 minutes. Nitrogen was bubbled into the solution at the same temperature to remove excess ozone. The solvents were evaporated and the residue was dissolved in methanol (2 ml). To the solution was added sodium borohydride (10 mg) in one portion at 5° C. The mixture was stirred at 5° C. for 10 minutes and then concentrated in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with brine, dried, and evaporated. The crude oil was purified by column chromatography on silica gel eluted with diethyl ether to yield 6-cyclohexylcarbamoyloxy-4-[3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-1-oxaspiro[2,5]-octane (11.6 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.O.ON1C2C=CC=CC=2N=N1.[CH:29]1([N:35]=[C:36]=NC2CCCCC2)CCC[CH2:31][CH2:30]1.CNCCC>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[CH:10]=[C:6]([C:7]([N:35]([CH3:36])[CH2:29][CH2:30][CH3:31])=[O:9])[CH:5]=1
Reactant: COC(=O)c1cc(OC(F)F)cc(C(=O)O)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCNC
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCCN(C)C(=O)c1cc(OC(F)F)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
Treat a solution containing crude 5-difluoromethoxy-isophthalic acid monomethyl ester (2.5 g, 10 mmol) in THF (20 mL) at room temperature with 1-hydroxybenzotriazole hydrate (1.62 g, 12 mmol), 1,3-dicyclohexylcarbodiimide (12 mL, 1 N, 12 mmol), and n-methylpropylamine (1.23 mL, 12 mmol). Stir at room temperature overnight, filter through a filtering agent, wash with 1: 1 ethyl acetate:hexanes (50 mL). Concentrate the combined filtrates and purify (silica gel chromatography, eluting with 0:100 to 30:70 ethyl acetate:hexanes) to give the title compound as a solid (1.6 g, 53%).
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][C@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:18]([NH2:20])=[O:19])=[C:5]([F:28])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[C:5]([F:28])=[CH:4][C:3]([C:1]([NH2:2])=[O:35])=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:7]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3ccccn3)C(N)=O)c(F)cc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccccn3)C(N)=O)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-3-(pyridin-2-yl)propanamide (53 mg, 0.133 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (16 mg). MS 415.1 (M+H); UV 214.4, 278.0, 302.6 nm.
Reaction SMILES: Cl[C:2]1[CH:3]=CC(OC)=C([CH:44]=1)C[C@H]1CN2C(=O)N(CC)N=C2CN(C(N[C@@H](C2C=CC(C(OC(C)(C)C)=O)=C([N+]([O-])=O)C=2)CC)=O)C1=O.[Cl:47][C:48]1[CH:49]=[CH:50][C:51]([O:89][CH3:90])=[C:52]([CH:88]=1)[CH2:53][C@H:54]1[CH2:60][N:59]2[C:61]([OH:64])=[N:62][N:63]=[C:58]2[CH2:57][N:56]([C:65]([NH:67][C@@H:68]([C:71]2[CH:83]=[CH:82][C:74]([C:75]([O:77]C(C)(C)C)=[O:76])=[C:73]([N+:84]([O-])=O)[CH:72]=2)[CH2:69]C)=[O:66])[C:55]1=[O:87].Cl[C:92]1C=CC(OC)=C([CH:134]=1)C[C@H]1CN2C(O)=NN=C2CN(C(N[C@@H](C2C=CC(C(OC(C)(C)C)=O)=C([N+]([O-])=O)C=2)CCCC)=O)C1=O>>[NH2:84][C:73]1[CH:72]=[C:71]([C@H:68]([NH:67][C:65]([N:56]2[C:55](=[O:87])[C@@H:54]([CH2:53][C:52]3[CH:88]=[C:48]([Cl:47])[CH:49]=[CH:50][C:51]=3[O:89][CH3:90])[CH2:60][N:59]3[C:61](=[O:64])[N:62]([CH2:92][CH3:134])[N:63]=[C:58]3[CH2:57]2)=[O:66])[CH2:69][CH2:44][CH2:2][CH3:3])[CH:83]=[CH:82][C:74]=1[C:75]([OH:77])=[O:76]
Reactant: CC[C@@H](NC(=O)N1Cc2nnc(O)n2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reactant: CCCC[C@@H](NC(=O)N1Cc2nnc(O)n2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reactant: CC[C@@H](NC(=O)N1Cc2nn(CC)c(=O)n2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Product: CCCC[C@@H](NC(=O)N1Cc2nn(CC)c(=O)n2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c(N)c1

Procedure:
Instead of the starting material of Example 91, Step (2), that is, the compound 91a, the compound 95a was used for a similar procedure as in Example 91, Step (2) and Step (3) to obtain the title compound.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C1(C)C=CC=CC=1>[C:17]([N:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10](=[O:12])[NH:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]1=2)(=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)Cl
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Solvent: Cc1ccccc1
Product: C=CC(=O)N1c2ccccc2NC(=O)c2ccccc21

Procedure:
5.26 gm (0.025 mol) of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2.7 gm (0.03 mol) of acrylic acid chloride were refluxed in 200 ml of toluene for 3 hours. Subsequently, the reaction mixture was evaporated in vacuo to dryness, and the residue was stirred with aqueous sodium bicarbonate solution. After suction-filtering, washing with water, and drying, 5-acryloyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one was obtained with a quantitative yield. Recrystallization from ethanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[N:3]=1.[Br:24]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Br:24])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(COc2nc(N)nc(-c3ccco3)c2C#N)nc1
Solvent: CN(C)C=O
Product: Cc1ccc(COc2nc(N)nc(-c3ccc(Br)o3)c2C#N)nc1

Procedure:
From 2-amino-4-furan-2-yl-6-(5-methyl-pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile and N-bromosuccinimide in DMF. ES-MS m/e (%): 388 (M{81Br}+H+, 100), 386 (M{79Br}+H+, 98).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].N1C=CC=CC=1.Cl[C:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])=[O:21]>O1CCCC1>[F:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])=[O:21])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Reactant: CC(=O)OCC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: -40 °C
Yield: 70.4 %

Procedure:
6-Amino-5-fluoro-1,3-dihydro-indol-2-one 3d (500 mg, 3.0 mmol) was dissolved in 10 ml of tetrahydrofuran under stirring, and added with 0.4 ml of pyridine to the solution at room temperature. After stirring to mix well, the mixture was cooled down to −40° C. in a dry ice-acetone bath. A solution of acetic acid chlorocarbonylmethyl ester (420 mg, 3.0 mmol) in 10 ml of tetrahydrofuran was added dropwise to the above reaction system. Upon completion of the addition, the dry ice-acetone bath was removed, and the reaction mixture was allowed to warm up to room temperature and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The resulting solid was washed with water for three times and dried to obtain the title compound acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-methyl ester 27a (562 mg, yield 70.4%) as a gray solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24]CC5CCNCC5)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44](C4C(C)=CN=C(Cl)N=4)S[C:42]=3[CH:41]=CC=2)=O)CC1.C(OC(N1CCC(CCCN)CC1)=O)(C)(C)C>>[CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:41][CH2:42][CH:46]5[CH2:38][CH2:36][NH:35][CH2:44][CH2:45]5)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: Cc1cnc(NCCC2CCNCC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Reactant: Cc1cnc(Cl)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Agent: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Product: Cc1cnc(NCCCC2CCNCC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of 2-[5-methyl-2-(2-piperidin-4-ylethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide, the title compound is synthesized from 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 4-(3-aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid. ES+(m/z) 450 [M+H].
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=[C:11]2[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:26][O:18][C:17]([C:15]1[CH:16]=[C:11]2[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]2=[N:13][CH:14]=1)=[O:19]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cnc2c(c1)c(-c1ccccc1)nn2Cc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2c(c1)c(-c1ccccc1)nn2Cc1ccccc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
100 mg of 1-benzyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid obtained by Example 32 was dissolved in 5 mL of N,N-dimethylformamide, added with 60 mg of potassium carbonate and 30 μl of methyl iodide, and stirred all day and night at room temperature. The residue was added with water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After distilling off the solvent, the reaction was crystallized from diisopropyl ether, to afford 100 mg of the title compound as a pale brown powder.
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH3:13][N:14]([CH3:40])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C@@H:21]1[CH2:35][C@H:34]2[C@@H:24]([CH2:25][C:26]3[C:36]4[C:29](=[CH:30][CH:31]=[CH:32][C:33]2=4)[NH:28][CH:27]=3)[N:23]([CH2:37][CH:38]=[CH2:39])[CH2:22]1)=[O:20].C(N(CC)CC)C.[CH2:48]([N:50]=[C:51]=[O:52])[CH3:49].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>ClCCl>[CH3:49][CH2:48][NH:50][C:51]([N:18]([C:19]([C@H:21]1[CH2:22][N:23]([CH2:37][CH:38]=[CH2:39])[C@H:24]2[C@@H:34]([C:33]3[C:36]4[C:26]([CH2:25]2)=[CH:27][NH:28][C:29]=4[CH:30]=[CH:31][CH:32]=3)[CH2:35]1)=[O:20])[CH2:17][CH2:16][CH2:15][N:14]([CH3:13])[CH3:40])=[O:52]
Reactant: C=CCN1C[C@H](C(=O)NCCCN(C)C)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CCN=C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCN1C[C@H](C(=O)N(CCCN(C)C)C(=O)NCC)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 18 °C
Reaction time: 14 h
Yield: 67.5 %

Procedure:
Trimethylsilyl trifluromethanesulfonate (7.6 g, 34.2 mmol, 1.1 eq) was added dropwise during 2 hours to a stirred mixture of N-[3-(dimethylamino)propyl]-6-allylergoline-8β-carboxamide (11.9 g, 31.5 mmol, 1 eq), triethylamine (3.8 g, 37.6 mmol, 1.2 eq) and dichloromethane (280 g) at −2° C. The mixture was stirred for 14 hours at 18° C. Ethyl isocyanate (11.1 g, 156.2 mmol, 5 eq) was added in one portion to the stirred mixture at 18° C. The obtained mixture was stirred for 48 hours at the same temperature. Tetrabutylammonium fluoride, 1.0 M solution in THF (30.4 g, 34.2 mmol, 1.1 eq) was added dropwise during 2 hours to the stirred mixture at −2° C. The reaction mixture was stirred for 2 hours at the same temperature and evaporated under reduced pressure. A solution of the residue in tert-butyl methyl ether was washed with aqueous solution of sodium bicarbonate and aqueous solution of sodium chloride, dried over sodium sulfate and passed through short silica gel column. The column was washed with acetone and the acetone solution was evaporated under reduced pressure to give 9.6 g (68.2%) of cabergoline as amorphous solid with 98% purity by HPLC. A hot solution of the amorphous cabergoline in tert-butyl methyl ether was kept at 0–5° C. for 60 hours. The precipitated solid was filtered off, washed on the filter with cold tert-butyl methyl ether and dried under reduced pressure at 15–25° C. to give 8.5 g (50%) solvate form A of cabergoline as white crystals with mp 66–70° C. and 99.8% purity by HPLC.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:22]([O-])([O-])=O.[K+].[K+].COC(=O)C1C=CC(O)=CC=1.BrCCCCCCCCCC=C>>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:22]
Reactant: CCCCCCCCCCOc1ccc(C(=O)OC)cc1
Reactant: O=C([O-])[O-]
Agent: C=CCCCCCCCCCBr
Agent: COC(=O)c1ccc(O)cc1
Agent: [K+]
Product: C=CCCCCCCCCCOc1ccc(C(=O)OC)cc1

Procedure:
Synthesized as described above for compound 1. Quantities: K2CO3 (9.08 g, 66 mmol), methyl-4-hydroxy-benzoate (5.00 g, 33 mmol), 11-bromo-1-undecene (7.6 mL, 34 mmol). Yield 10.1 g (quant). 1NMR: δH (CDCl3; 300 MHz): 1.24-1.52 (12 H, m, CH2), 1.80 (2 H, m, O—CH2—CH2), 2.04 (2 H, m, CH2═CH—CH2), 3.87 (3 H, s, OCH3), 4.00 (2 H, t, 3J=6.5 Hz, O—CH2), 4.95 (2 H, m, CH2═CH), 5.82 (1 H, m, CH2═CH), 6.90 (2 H, d, 3J=9.0 Hz, Ar—H), 7.97 (2 H, d, 3J=9.0 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 26.4, 29.3, 29.5, 29.7, 29.8, 29.9, 34.2, 52.2, 68.6, 114.45, 114.5, 122.7, 131.9, 139.6, 163.4, 167.3.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:14]1([O:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[O:20]([C:21]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)CCO
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)CCOC(=O)Oc1ccccc1

Procedure:
To a 500 ml three-necked round-bottomed flask equipped with an internal thermometer, reflux condenser, mechanical stirrer, addition funnel, and argon inlet are added N,N-dimethylethanolamine (25.00 g, 0.281 mol), toluene (200 ml), and triethylamine (31.21 g, 0.309 mol). The mixture is treated with a solution of phenylchloroformate (43.91 g, 0.281 mol) dissolved in 50 ml or toluene over 15 min. After addition is complete, the mixture is heated to reflux lot 3 h. The cooled mixture is washed with saturated sodium bicarbonate solution (2×100 ml) and water (100 ml). The organic phase is dried over MgSO4, filtered, and concentrated first by rotary evaporation at 50° C. (water aspirator vacuum) and then at 60° C. (0.05 mmHg) in a Kugelrohr oven to give 8 as a light yellow oil, 49.93 g (85%) that crystallizes on standing.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[F:21])[N:17]=[CH:16][CH:15]=[CH:14]3)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:22]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:3]=[C:4]2[N:9]([CH2:10][C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]=[CH:16][CH:15]=[CH:14]4)[N:22]=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)nc1NCc1cc2cccnc2cc1F
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Fc1cc2ncccc2cc1Cn1nnc2ncc(Br)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 5-bromo-N*3*-(7-fluoro-quinolin-6-ylmethyl)-pyrazine-2,3-diamine (90 mg, 0.26 mmol) in acetic acid (4 mL), was added a solution of sodium nitrite (11.4 mg, 0.26 mmol) in water (1 mL) at once. After stirring at room temperature for 3 hour, the solvent was removed in vacuo and the residue was diluted with NaHCO3(aq.), extracted with DCM. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography with (DCM:MeOH=50:1) to give the title compound as a yellow solid (57.0 mg, 61%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.03 (s, 1H), 8.94 (d, 1H), 8.40 (d, 1H), 8.08 (d, 1H), 7.84 (d, 1H), 7.55 (dd, 1H), 7.53 (dd, 1H), 6.21 (s, 2H). LCMS (method A): [MH]+=359/361, tR=2.23 min.
Reaction SMILES: [CH:1]1([C:7](=O)[CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][C:32](=[O:34])[O:31][N:30]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:35][CH2:36][CH3:37])[N:11]3[N:38]=[C:39]([CH3:41])[N:40]=[C:10]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:44][O:45][CH3:46].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH:1]1(/[C:7](=[N:44]/[O:45][CH3:46])/[CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][C:32](=[O:34])[O:31][N:30]=4)=[CH:21][CH:22]=3)=[C:12]([CH2:35][CH2:36][CH3:37])[N:11]3[N:38]=[C:39]([CH3:41])[N:40]=[C:10]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)C2CCCCC2)c2nc(C)nn12
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(=N\OC)C2CCCCC2)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 25.5 %

Procedure:
A mixture of 4-(2-cyclohexyl-2-oxoethyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.25 g), (aminooxy)methane hydrochloride (0.74 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.067 g, 26%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:13][NH:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].CCN(C(C)C)C(C)C>C(#N)C>[Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:13][N:12]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1cccc(F)c1
Reactant: COC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CN1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2cccc(F)c2)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 1.0 g (3.23 mmol) of (3-(R)-t-Butyldimethylsilyloxymethyl-4-(S)-(3-fluorophenyl)pyrrolidine in 8 mL of acetonitrile was treated with 0.47 mL (4.95 mmol) of methyl bromoacetate and 0.86 g (4.95 mmol) of DIEA and the reaction was heated in 80° C. bath. After 2 hr, the solution was cooled, and partitioned between water-EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was purified on a flash column using a gradient of 10-20% EtOAc in hexanes to isolate 0.45 g of the title compound. 1H NMR (CDCl3) 0.027 (2s, 6H), 0.87 (s, 9H), 2.4 (m, 1H), 2.7-3.1 (m, 5H), 3.33 and 3.47 (ABq, 2H), 3.63 (m, 2H), 3.76 (s, 3H), 6.8-7.3 (m 4H).
Reaction SMILES: C(O[CH:4](OCC)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O)C.Cl.[NH2:18][NH:19][C:20]([NH2:22])=[O:21]>C(O)C>[F:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[CH:4]=[N:22][C:20](=[O:21])[NH:19][N:18]=2)=[CH:12][CH:11]=1
Reactant: CCOC(OCC)C(=O)c1ccc(F)cc1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CCO
Product: O=c1ncc(-c2ccc(F)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,2-diethoxy-1-(4-fluorophenyl)ethanone (5.2 g, 23 mmol), semicarbazide hydrochloride (2.6 g, 24 mmol) in ethanol (50 mL) was stirred overnight at ambient temperature and then heated to 80° C. for 5 hours. The reaction mixture was concentrated and the resulting residue was dissolved in acetic acid (50 mL) which was heated to 130° C. for 6 h. After cooling, the mixture was concentrated under reduced pressure. The residue was triturated with ethyl ether, filtered, and washed with diethyl ether and then hexanes. The crystalline material was collected and dried under high vacuum to give the desired product. (4.2 g, 96%) LCMS: (M+H)=192.1.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:11][C:10](=[O:12])[CH2:9][CH2:8][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH3:19]
Reactant: CCO
Reactant: CC(CCC(=O)O)CCC(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCC(C)CCC(=O)O

Procedure:
145 g of crude 4-methylpimelic acid, 68 ml of absolute ethanol and 12 ml of concentrated sulfuric acid were refluxed for 5 hours. The mixture was poured onto ice and extracted several times. The combined ether solutions were extracted with saturated NaHCO3 until the development of CO2 was finished. The aqueous extracts were covered with a layer of ether and adjusted while stirring to pH 2 to 3 with diluted sulfuric acid. The ether layer was separated and the aqueous phase was saturated with (NH4)2SO4 and extracted three times with ether.