Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.C(N(CC)CC)C.Cl.[CH2:21]([O:23][C:24](=[O:31])[CH:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])[CH3:22]>C(O)CCC>[CH2:21]([O:23][C:24](=[O:31])[CH:25]([NH:26][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1)[CH2:27][CH:28]([CH3:29])[CH3:30])[CH3:22]
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Reactant: CCOC(=O)C(N)CC(C)C
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC(C)C)Nc1nc(N)nc2c1CCCC2

Procedure:
A mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (117 mg, 0.64 mmol), triethylamine (259 mg, 2.56 mmol), dl-leucine ethyl ester hydrochloride (250 mg, 1.28 mmol) and n-butanol (2 ml) was reacted for 6 hours at 80-90° C. According to the post-treatment of Example 1, the object compound was obtained (104.3 mg, 72.1%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[CH:13][C:14]=2[NH2:16])[C@H:9]([N:18]([CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:8][C@@H:7]1[CH3:38])=[O:5])[CH3:2].ClCCl.N1C=CC=CC=1.[C:48](Cl)(=[O:50])[CH3:49]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[CH:13][C:14]=2[NH:16][C:48](=[O:50])[CH3:49])[C@H:9]([N:18]([CH2:23][C:24]2[CH:25]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:8][C@@H:7]1[CH3:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2c(N)cc(Cl)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2c(NC(C)=O)cc(Cl)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Yield: 102.1 %

Procedure:
To a pre-dried flask under nitrogen atmosphere was added cis-8-amino-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 109) (30 mg, 0.053 mmol), followed by anhydrous dichloromethane (2 mL), pyridine (0.5 mL), and acetyl chloride (0.015 mL, 0.21 mmol). The reaction was stirred overnight at room temperature before ethyl acetate was added, and the mixture was extracted three times with 1N HCl, followed by brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title product (33 mg, 100%) MS m/z 610 (M+ +H); 1H NMR (CDCl3) δ 7.8 (bs, 2H), 7.7 (bs, 1H), 7.65 (bs, 1H), 6. 8 (bs, 1H), 3.8 (s, 3H), 2.1 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[NH:43][C:44](=[O:48])[CH:45]([CH3:47])[CH3:46].[H-].[Na+].I[CH2:52][CH2:53][O:54][Si:55]([CH:62]([CH3:64])[CH3:63])([CH:59]([CH3:61])[CH3:60])[CH:56]([CH3:58])[CH3:57].Cl>CN(C)C=O>[Br:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[N:43]([C:44](=[O:48])[CH:45]([CH3:46])[CH3:47])[CH2:52][CH2:53][O:54][Si:55]([CH:59]([CH3:60])[CH3:61])([CH:56]([CH3:58])[CH3:57])[CH:62]([CH3:63])[CH3:64]
Reactant: CC(C)[Si](OCCI)(C(C)C)C(C)C
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(Br)c(NC(=O)C(C)C)c2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(Br)c(N(CCO[Si](C(C)C)(C(C)C)C(C)C)C(=O)C(C)C)c2)cc1
Reaction time: 0.5 h

Procedure:
The solution of 3.50 g of tert-butyl 3-(4-bromo-3-isobutyrylaminobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 25 ml of N,N-dimethylformamide is cooled to 0° C. with stirring and admixed with sodium hydride dispersion (60%). After 30 minutes, the mixture is admixed with 1.66 g of (2-iodoethoxy)triisopropylsilane and stirred at room temperature over 16 hours. The reaction mixture is admixed with cold 1N HCl (100 ml) and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed successively with water (100 ml) and brine (100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rt=7.60.
Reaction SMILES: C(OC(=O)NC(C1SC(SC)=C(S(C2C=C(Br)C3N(CC4C=CC([N+]([O-])=O)=CC=4F)C=NC=3C=2)(=O)=O)C=1)=N)(C)(C)C.C(OC(=O)[NH:48][C:49]([C:51]1[S:52][C:53]([S:80][CH3:81])=[C:54]([S:56]([C:59]2[CH:78]=[C:77]([Br:79])[C:62]3[N:63]=[CH:64][N:65]([CH2:66][C:67]4[CH:72]=[CH:71][C:70]([N+:73]([O-:75])=[O:74])=[CH:69][C:68]=4[F:76])[C:61]=3[CH:60]=2)(=[O:58])=[O:57])[CH:55]=1)=[NH:50])(C)(C)C.[F:83][C:84]([F:89])([F:88])[C:85]([OH:87])=[O:86]>C(Cl)Cl>[F:83][C:84]([F:89])([F:88])[C:85]([OH:87])=[O:86].[Br:79][C:77]1[C:62]2[N:63]=[CH:64][N:65]([CH2:66][C:67]3[CH:72]=[CH:71][C:70]([N+:73]([O-:75])=[O:74])=[CH:69][C:68]=3[F:76])[C:61]=2[CH:60]=[C:59]([S:56]([C:54]2[CH:55]=[C:51]([C:49]([NH2:50])=[NH:48])[S:52][C:53]=2[S:80][CH3:81])(=[O:57])=[O:58])[CH:78]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(Br)c2ncn(Cc3ccc([N+](=O)[O-])cc3F)c2c1
Agent: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(Br)c2c(c1)ncn2Cc1ccc([N+](=O)[O-])cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cc(Br)c2ncn(Cc3ccc([N+](=O)[O-])cc3F)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
A solution of ({4-[7-bromo-1-(2-fluoro-4-nitro-benzyl)-1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino-methyl)-carbamic acid tert-butyl ester and ({4-[7-bromo-3-(2-fluoro-4-nitro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino-methyl)-carbamic acid tert-butyl ester ((from above step a) 0.005 g, 0.007 mmol) in CH2Cl2 (1 mL) was cooled to 0° C. and treated with 25% trifluoroacetic acid in CH2Cl2 (1.00 mL). The mixture was allowed to warm to room temperature and was stirred 3 h. Solvents were removed in vacuo. Preparatory HPLC (10–80% acetonitrile in 1% TFA/water over 30 min.) afforded the product 4-[7-bromo-3-(2-fluoro-4-nitro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.002 g, 47%) as a white solid. 1H NMR (MeOD): δ 8.714 (s, 1H), 8.308 (s, 1H), 8.231 (d, 1H, J=1.6 Hz), 8.106 (m, 2H), 8.047 (d, 1H, J=0.8 Hz), 7.556 (t, 1H, J=8.4 Hz), 5.854 (s, 2H), 2.630 (s, 3H). C20H15BrFN5O4S3: 583.95 (M+1) found 585.05.
Reaction SMILES: CO.[NH2:3][C:4]1[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[C:9](/[CH:21]=[CH:22]/[CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][C:25]3=[O:29])[CH:8]=[CH:7][C:6]=2[N:5]=1>[Pd].C(O)C>[NH2:3][C:4]1[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[C:9]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][C:25]3=[O:29])[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(/C=C/CN4CCCC4=O)cc3c21
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CC(C)Cn1cnc2c(N)nc3ccc(CCCN4CCCC4=O)cc3c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon catalyst (0.1 g), methanol (50 mL), ethanol (50 mL) and 1-{(2E)-3-[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]prop-2-enyl}pyrrolidin-2-one. The vessel was evacuated and charged with hydrogen gas (51 psi, 3.4×105 Pa). The reaction was shaken at ambient temperature overnight (approximately 18 hours). The reaction mixture was filtered to remove the catalyst and concentrated to dryness. The crude product was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-8% methanol in dichloromethane) followed by recrystallization from acetonitrile to yield 300 mg of 1-{3-[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]propyl}pyrrolidin-2-one as a white solid, mp 174-175° C.
Reaction SMILES: I.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[NH:13])SC)=[CH:5][CH:4]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[NH:13])=[CH:5][CH:4]=1
Reactant: NCCCN1CCCC1
Reactant: CSC(=N)Nc1ccc(Cl)cc1
Agent: I
Solvent: CCO
Product: N=C(NCCCN1CCCC1)Nc1ccc(Cl)cc1
Yield: 69.4 %

Procedure:
A solution of the product of step b (986 mg, 3.00 mmol) and N-(3-aminopropyl)-pyrrolidine (0.948 ml, 7.50 mmol) in ethanol (10 ml) was heated at reflux for 16 h. The solvent was removed at reduced pressure and the residue suspended in aqueous ammonia (880, 25 ml). The solid was removed by filtration and the filter-cake washed sequentially with water (50 ml) and diethyl ether (50 ml) to give the title compound as a white solid (585 mg, 69%). 1H NMR (DMSO-6) 7.18-7.12 (2H, m), 6.76-6.66 (2H, m), 5.8-4.8 (3H, br s), 3.12 (2H, t, 6.9), 2.43-2.36 (6H, m), 1.69-1.56 (6H, m). Microanalysis found C 60.01 H 7.62 N 19.74. C14H21ClN4 requires C 59.88 H 7.54 N 19.95.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:6]([CH2:7][CH:2]([CH3:1])[C:3]([OH:5])=[O:4])=[O:8])=[CH:16][CH:15]=1
Reactant: Clc1ccccc1
Reactant: CC1CC(=O)OC1=O
Agent: [Al+3]
Agent: [Cl-]
Product: CC(CC(=O)c1ccc(Cl)cc1)C(=O)O
Temperature: 65 °C

Procedure:
To a solution of 114 g. of methylsuccinic anhydride in 400 ml. of chlorobenzene is added carefully 270 g. of aluminum chloride. The mixture is heated to 65° C. for 11/2 hours, is cooled, quenched with ice and concentrated hydrochloric acid and extracted with benzene. The benzene layer is extracted with aqueous sodium bicarbonate. After adjusting the pH of the bicarbonate solution to 6.3, concentrated hydrochloric acid is added slowly over a period of several hours with stirring. At pH 5.7, 78 g. of white crystals are filtered off. Recrystallization of this material from ethanol-water affords 3-(p-chlorobenzoyl)-2-methylpropionic acid as white crystals. A mixture of 35.50 g. of the preceding compound, 85 ml. of hydrazine hydrate and 400 ml. of ethyl alcohol is allowed to stir at reflux for 18 hours. The reaction mixture is concentrated to about 75% of the original volume, cooled in an ice bath and filtered to yield 26.62 g. of 6-(p-chlorophenyl)-4,5-dihydro-4-methyl-3(2H)-pyridazinone as a yellow solid. An additional 4.7 g. of product is obtained from the filtrate above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]1[C:17](=[O:18])[NH:16][C:15](=[O:19])[N:14]([CH3:20])[C:13]1=[O:21].[H][H]>[Pt].C(OCC)(=O)C>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[N:14]([CH3:20])[C:13]2=[O:21])[CH:4]=1
Reactant: Cn1c(=O)[nH]c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Cn1c(=O)[nH]c(=O)n(-c2cc(N)c(F)cc2Cl)c1=O

Procedure:
A mixture of 1-(2-chloro-4-fluoro-5-nitrophenyl)-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (28.5 g, 0.09 mol) and 5% platinum on activated carbon (1 g) in ethyl acetate is hydrogenated at 55 psi until hydrogen uptake is complete. The reaction mixture is then filtered and concentrated in vacuo to give the title product as a white solid, mp 244°-245° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3[C:19]([O:21]CC=C)=O)=[N:7][C:6]=2[CH:25]=1.NC[C@@H]1[C@H](C)CCCN1C([C:37]1[C:42]([N:43]2[N:47]=[CH:46][CH:45]=[N:44]2)=[CH:41][CH:40]=[C:39]([CH3:48])[N:38]=1)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3[C:19]([C:37]3[C:42]([N:43]4[N:44]=[CH:45][CH:46]=[N:47]4)=[CH:41][CH:40]=[C:39]([CH3:48])[N:38]=3)=[O:21])=[N:7][C:6]=2[CH:25]=1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)n1

Procedure:
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate in Example A27, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone. ESI-MS (m/z): 466 [M+1]+.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1)(C)(C)C.[H-].[Na+].CI.C(O)(C(F)(F)F)=O>CN(C=O)C>[CH3:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)=[O:16])=[CH:11][CH:10]=1
Reactant: CN1CCN(C(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CI
Solvent: CN(C)C=O
Product: CNCc1ccc(C(=O)N2CCN(C)CC2)cc1

Procedure:
A crude product of [4-(4-methyl-piperazine-1-carbonyl)-benzyl]-carbamic acid tert-butyl ester obtained in Example 1-D-293, sodium hydride and methyl iodide were treated in DMF, and further treated with TFA, to obtain (4-methylaminomethyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (4-methylaminomethyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone (126 mg) instead of 4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine used in Step D in Example 1-D-18, in the same manner as Step D in Example 1-D-18, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid methyl-[4-(4-methyl-piperazine-1-carbonyl)-benzyl]-amide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-297) as a colorless powder (6 mg, 6%).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:28])[CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[CH:9]=[CH:10][CH:11]=1)([O-])=O>CO.[Pd]>[NH2:3][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:28])[CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc(CCC(=O)Nc2cccc([N+](=O)[O-])c2)cc(OC)c1OC
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: COc1cc(CCC(=O)Nc2cccc(N)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 98.4 %

Procedure:
(The following reaction is done in an N2 atmosphere.) Dissolve N-(3-Nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-propionamide (89) (100 mg, 0.28 mmol) in MeOH (4.5 mL) and add Pd on carbon (10% (w/w) Pd content, 29.5 mg, 0.028 mmol) followed by NH4CO2H (175 mg, 2.77 mmol) at rt. Degas the reaction mixture carefully (flush with N2) and stir it for 75 min at rt. Filtrate reaction mixture through a short pad of celite and remove solvent. Treat residue with EtOAc, filtrate again through a short pad of celite and remove solvent to obtain N-(3-Amino-phenyl)-3-(3,4,5-trimethoxy-phenyl)-propionamide (90) (91 mg, 99%) as a white solid. No further purification. 1H NMR (400 MHz, CD3OD): 2.65 (t, 2H, J=7.5 Hz); 2.98 (t, 2H, J=7.5 Hz); 3.75 (s, 3H); 3.82 (s, 6H); 6.50 (dd, 1H, J1=8.0 Hz, J2=2.0 Hz); 6.58 (s, 2H); 6.80 (dd, 1H, J=8.0 Hz, J2=2.0 Hz); 7.02-7.07 (m, 1H); 7.04 (t, 1H, J=8.0 Hz).
Reaction SMILES: [CH2:1]([C:8]1[CH:15]=[C:12]([CH:13]=O)[C:11]([OH:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:24](C(OCC)=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CC(=O)CC>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][C:12]=2[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Cc2ccccc2)ccc1O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)c1cc2cc(Cc3ccccc3)ccc2o1

Procedure:
6.9 g of 1A was dissolved in 130 ml of 2-butanone. The solution was heated to reflux and 8.1 g of potassium carbonate was added. Then 7.8 g of diethyl bromomalonate was added, drop-by-drop over a 10-minute period. The mixture was stirred at reflux for 58 hours, then was cooled and filtered. The filtrate was concentrated under reduced pressure to leave an oil, which was poured into water. The mixture was extracted with ether. The extract was washed with 5% sodium hydroxide solution, then with water, dried (MgSO4), and concentrated under reduced pressure. The residue was recrystallized from methanol and dried over P2O5 to give 1, mp: 78°-79° C.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.S(Cl)(Cl)=O.[NH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2>O.O1CCCC1>[NH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[C:36]3[C:41]=2[N:40]=[CH:39][CH:38]=[CH:37]3)=[O:12])=[CH:13][CH:14]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: Nc1cccc2cccnc12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: N=C(N)Nc1ccc(C(=O)Nc2cccc3cccnc23)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 200 mg. (.92 m. mol) 4-guanidinobenzoic acid hydrochloride and 190 mg. (.93 m. mol) of bis-trimethylsilylacetamide in 20 ml. of dry tetrahydrofuran was heated at reflux until a solution was achieved, and then cooled to room temperature. Thionyl chloride (380 mg., 1.86 m. mol) was added and the reaction mixture allowed to stir for 5 min. 8-Aminoquinoline (670 mg., 4.64 m. mol) was added in 5 ml. of tetrahydrofuran and the mixture allowed to stir for 30 min. Water (.2 ml) was added to the reaction mixture and the solids filtered and dissolved in 60 ml. of methanol and 120 ml. of chloroform. Addition of diethyl ether precipitated the desired product, 153 mg., m.p. 271°-273° C.
Reaction SMILES: [OH:1][C:2]1[C:10]2[S:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20].O>CN(C=O)C>[CH2:20]([O:1][C:2]1[C:10]2[S:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: Cc1nc2cccc(O)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cccc2nc(C)sc12
Temperature: 50 °C
Yield: 71.4 %

Procedure:
To 7-hydroxy-2-methylbenzothiazole (500 mg, 3.0 mmol) in DMF (3 mL) was added K2CO3 (459 mg, 3.32 mmol) followed by allyl bromide (287 uL, 3.32 mmol). The reaction was heated at about 50° C. for about 4 hours and then poured into water. The aqueous mixture was extracted with EtOAc, the combined organic layers were dried over Na2SO4, and the solvent then removed by rotary evaporation. The resulting oil crystallized on standing to give 7-allyloxy-2-methyl-benzothiazole as yellow crystals (440 mg, 71%); LSIMS m/z 206, m.p. 38-39° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([CH2:43][O:44][C:45]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])=[O:46])[O:23][C:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:25])=[O:19]>CCCCCC>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([O:23][C:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:25])[CH2:43][O:44][C:45]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])=[O:46])=[O:19]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)CCCCCCC/C=C\CCCCCCCC
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCCCC
Yield: 23 %

Procedure:
In a second hexane fractionation, above olein-fraction was fractionated, (3,22:1 hexane to oil ratio at -10° C.); a stearin fraction was obtained. This stearin fraction contained 60 wt % of diglycerides of which 56,7 wt % were of the SU-type. The overall yield from fractionations was 29%. A third fractionation was performed on the stearin fraction obtained (5:1 hexane to oil at 24,5° C.). The olein-fraction was collected, it contained 62 wt % of diglycerides of which 72,5 wt % were SU-diglycerides. The overall yield was 23%.
Reaction SMILES: ONC(=N)C1C2C(C=CC=1)=NN(CCCC(OCC)=O)C=2.[OH:22][NH:23][C:24](=[NH:42])[C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[N:28][N:29]2[CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].[Cl:43][C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][C:52]=1[O:53][CH:54]([CH3:56])[CH3:55])[C:47](O)=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C.O>[Cl:43][C:44]1[CH:45]=[C:46]([C:47]2[O:22][N:23]=[C:24]([C:25]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:26]=3[CH:27]=[N:28][N:29]4[CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:42]=2)[CH:50]=[CH:51][C:52]=1[O:53][CH:54]([CH3:55])[CH3:56]
Reactant: CCOC(=O)CCCn1ncc2c(C(=N)NO)cccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCOC(=O)CCCn1cc2c(C(=N)NO)cccc2n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)CCCn1ncc2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 4-{4-[(hydroxyamino)(imino)methyl]-2H-indazol-2-yl}butanoate & ethyl 4-{4-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}butanoate (D56) (0.27 g, 0.930 mmol) (a 3:2 mix of 1 and 2-isomers), 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D3) (0.200 g, 0.930 mmol), EDC (0.196 g, 1.023 mmol) and HOBT (0.157 g, 1.023 mmol) in N,N-dimethylformamide (5 ml) was stirred at 80° C. for 16 hrs then at 120° C. for 2 hours. The reaction was cooled, diluted with ethyl acetate (40 ml) and water (40 ml) and the organic washed with 3×15 ml of water, dried (magnesium sulphate) and evaporated. The crude material was purified by flash chromatography eluting with 3:7 ethyl acetate/hexane to give two products which were triturated with 1:1 ether/hexane to give 66 mgs of upper spot and 36 mgs of lower. The upper spot was the desired 1-substituted indazole. δH (CDCl3, 400 MHz): 1.24 (3H, t), 1.46 (6H, d), 2.31 (4H, m), 4.12 (2H, q), 4.55 (2H, t), 4.73 (1H, m), 7.08 (1H, d), 7.52 (1H, dd), 7.62 (1H, d), 8.07 (1H, dd), 8.11 (1H, dd), 8.29 (1H, d), 8.70 (1H, d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCCC1.C(O)C>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnc(-c2cccc(F)c2)nc1
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of methyl 2-(3-fluorophenyl)pyrimidine-5-carboxylate (45 g, 0.19 ml) in a 1:1 mixture of tetrahydrofuran and ethanol (120 mL) was added Li(OH).H2O (12.2 g, 0.29 mol) dissolved in water (120 mL) and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated under reduced pressure, dissolved in water (500 mL), acidified with 1N aqueous HCl and filtered. The residue was washed with water (100 mL×3) and dried to give 37 g (yield 89.5%) of 2-(3-fluorophenyl)pyrimidine-5-carboxylic acid. 1H NMR (DMSO-d6) 7.49 (m, 1H) 7.67 (m, 1H) 8.18 (m, 1H) 8.34 (m, 1H) 9.34 (s, 2H). LRMS (ES+) M+H 219.