Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)([C:9]1[N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:12]=[N:11][CH:10]=1)O.[OH-].[Na+]>I.CC(O)C.C(Cl)(Cl)Cl>[NH:13]1[C:9]([CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[C:37]3[C:42]=2[N:41]=[CH:40][CH:39]=[CH:38]3)=[CH:10][N:11]=[CH:12]1
Reactant: OC(c1ccccn1)(c1cccc2cccnc12)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: c1ccc(C(c2cnc[nH]2)c2cccc3cccnc23)nc1
Temperature: 160 °C

Procedure:
A mixture of pyridin-2-yl(quinolin-8-yl)(1-trityl-1H-imidazol-5-yl)methanol (Intermediate 14) (385 mg, 0.70 mmol) in 57% aqueous HI (10 mL) and iPrOH (2 mL) was added red phosphorus (219 mg, 7.0 mmol) in a resealable tube was heated at 160° C. for 16 h. The mixture was then cooled to room temperature and poured into ice-water, which was then basified with NaOH and diluted with CHCl3. The residue was isolated in a typical aqueous workup using CHCl3 and purified by MPLC with 5 to 15% MeOH:CH2Cl2 to give 8-((1H-imidazol-5-yl)(pyridin-2-yl)methyl)quinoline, (658) as a solid, 236 mg (61% in two steps). 1HNMR (CD3OD, 300 MHz) δ 8.82 (dd, J=1.8, 4.5 Hz, 1H), 8.43 (dd, J=1.8, 5.7 Hz, 1H), 8.28 (dd, J=1.8, 8.4 Hz, 1H), 7.83 (dd, J=4.0, 7.8 Hz, 1H), 7.73-7.70 (m, 2H), 7.68-7.43 (m, 3H), 7.25-7.21 (m, 2H), 7.03 (s, 1H), 6.52 (s, 1H).
Reaction SMILES: [C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].Cl[CH2:28]CCC(OC(=O)C)CCCC(C)C.ClCCCC(OC(=O)C)CCCCC>>[C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:28])[CH3:25])[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CCCCCC(O)CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O
Reactant: CC(=O)OC(CCCCl)CCCC(C)C
Agent: CCCCCC(CCCCl)OC(C)=O
Product: CC(=O)C(CCCc1ccc(C(=O)O)cc1)CCCC(O)CCCC(C)C

Procedure:
This compound is prepared by the method described in Example 1 for 4-(4-acetyl-8-hydroxytridecyl)benzoic acid except that in Step D an equivalent quantity of 1-chloro-4-acetoxy-8-methylnonane is substituted for 1-chloro-4-acetoxynonane. The intermediates and final product thus obtained are, Step D: ethyl 4-(4-acetyl-4-tert-butoxycarbonyl-8-acetoxy-12-methyltridecyl)benzoate; Step E: ethyl 4-(4-acetyl-8-acetoxy-12-methyltridecyl)benzoate; and Step F: 4-(4-Acetyl-8-hydroxy-12-methyltridecyl)benzoic acid.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[K].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Mg+2].S([O-])([O-])(=O)=O.[NH4+:32].[NH4+:33].[OH:34][C:35]([CH2:37][CH2:38][CH2:39][CH2:40][C@H:41]1[C@@H]2[C@@H](NC(N2)=O)CS1)=[O:36].CC1[N+](CC2C(N)=NC(C)=NC=2)=CSC=1CCO.Cl.[Cl-]>[Fe].[Mn]>[NH2:32][C@H:37]([C:35]([OH:34])=[O:36])[CH2:38][CH2:39][CH2:40][CH2:41][NH2:33]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: [NH4+]
Agent: [Fe]
Agent: [Mn]
Agent: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Solvent: O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
An aqueous solution medium containing 15% of glucose, 0.1% of potassium primary phosphate (KH2PO4), 0.04% of magnesium sulfate heptahydrate, 2% of ammonium sulfate, 100 μg/l of biotin, 200 μg/l of vitamin B1 hydrochloride, 2 ppm each of iron ions and manganese ions and 1% of "AJI-EKI", pH 7.0, was separately charged in a small glass jar fermenters in an amount of 300 ml each. After sterilization, Lys-producing Brevibacterium flavum (ATCC 21127), which had been previously grown in a bouillon slant at 30° C. for 24 hours, was inoculated on the medium. Then incubation was initiated at 31° C. About 10 hours after, penicillin was supplemented in a concentration of 6 U/ml and the incubation was continued for 18 hours. At the end of the fermentation, 3.75 g/dl of L-Lysine and 2.05 g/dl of L-glutamic acid were produced and accumulated in the medium.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[BH3-]C#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11]1
Reactant: COc1ccc(N)c(-c2cc3ccccc3[nH]2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(N)c(C2Cc3ccccc3N2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
To a solution of 1.8 g 2-(2-amino-5-methoxyphenyl)-1H-indole in 60 ml acetic acid at 15° was added 1.8 g NaCNBH3 and this mixture was stirred at room temperature overnight and thereafter poured into excess 50% NaOH in ice. Extraction with CH2Cl2, drying (MgSO4), concentration and flash chromatography using 1% EtOAc/CH2Cl2 as an eluent gave 0.23 g solid, m.p. 120°-123° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]([C:13]3[C:14]([NH2:20])=[N:15][CH:16]=[C:17](Br)[N:18]=3)=[N:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21]([S:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])=[O:24])[CH3:22].CCOC(C)=O>O>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]([C:13]3[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([N:29]4[CH2:28][CH2:27][N:26]([S:23]([CH2:21][CH3:22])(=[O:24])=[O:25])[CH2:31][CH2:30]4)[N:18]=3)=[N:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: Nc1cccc(-c2nnc(-c3nc(Br)cnc3N)[nH]2)c1
Solvent: O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nnc(-c4cccc(N)c4)[nH]3)n2)CC1
Yield: 8.4 %

Procedure:
3-[5-(3-aminophenyl)-4H-1,2,4-triazol-3-yl]-5-bromo-pyrazin-2-amine (220 mg, 0.6623 mmol) was heated in neat 1-ethanesulfonyl piperazine (590.4 mg, 3.312 mmol) in the microwave at 190° C. for 2 hours. The reaction was treated with EtOAc and H2O, the two layers separated and the organics dried and concentrated to give a yellow oil which was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (23.9 mg, 8% Yield). 1H NMR (400.0 MHz, DMSO) d 8.38 (s, 2H), 8.04 (s, 1H), 7.33 (s, 2H), 7.24 (s, 1H), 7.09 (s, 1H), 6.96 (s, 1H), 6.60 (s, 1H), 3.55 (s, 4H), 3.28 (s, 4H), 3.08 (d, J=5.7 Hz, 2H) and 1.20 (s, 3H) ppm; MS (ES+) 430.0
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@:7]([C:16]([NH:18][CH:19]([CH2:34]C1C=CC=CC=1)[CH:20]([OH:33])[C:21]([F:32])([F:31])[CH:22]([NH2:30])[CH2:23]C1C=CC=CC=1)=[O:17])([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10].[CH2:41]([S:44](Cl)(=[O:46])=[O:45])[CH2:42][CH3:43].C(N(CC)CC)C>>[CH2:41]([S:44]([NH:30][CH:22]([C:21]([F:31])([F:32])[CH:20]([OH:33])[CH:19]([NH:18][C:16](=[O:17])[C@:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10])[CH3:34])[CH3:23])(=[O:46])=[O:45])[CH2:42][CH3:43]
Reactant: COC(=O)N[C@@](C(=O)NC(Cc1ccccc1)C(O)C(F)(F)C(N)Cc1ccccc1)(c1ccccn1)C(C)C
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NC(C)C(F)(F)C(O)C(C)NC(=O)[C@](NC(=O)OC)(c1ccccn1)C(C)C
Yield: 65 %

Procedure:
Reaction of the resultant compound from Example 269 and 1 equivalent of propane-sulfonyl chloride and 1.1 equivalent of triethylamine provided the desired product in 65% yield. Mass spectrum: (M+H)+ =661. 1H NMR (CDCl3) δ0.80 (d, 3H), 0.88 (m, 2H), 0.95 (d, 3H), 1.10 (t, 3H), 2.0 (m, 3H), 2.40 (m, 2H), 2.85-3.15 (m, 4H), 3.30 (m, 1H), 3.50 (m, 1H), 3.95 (m, 1H), 4.90 (m, 1H), 5.25 (m, 3H), 6.12 (br d, 1H), 7.20 (m, 12H), 7.70 (m, 1H), 8.60 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1ccc2cc([N+](=O)[O-])ccc2n1

Procedure:
2-Chloro-6-nitro-quinoline (0.80 g, 4.0 mmol) and 2-methoxybenzylamine (1.5 mL, 12 mmol) were heated at 130° C. for 2 h. The reaction mixture was purified by flash chromatography on silica gel (heptane/ethyl acetate, 9:1, 4:1, 1:1). (2-Methoxy-benzyl)-(6-nitro-quinolin-2-yl)-amine was obtained as a yellow solid (0.5 g, 42%), MS: m/e=310.5 (M+H+).
Reaction SMILES: [N:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[S:3][C:2]=1[NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=O)[CH2:25][O:26][CH3:27])[CH2:19][CH2:18]1.Cl.[OH-].[Na+]>C1COCC1>[CH3:27][O:26][CH2:25][CH2:24][NH:23][CH:20]1[CH2:21][CH2:22][CH:17]([CH2:16][NH:15][C:2]2[S:3][C:4]3[CH2:10][CH2:9][O:8][C:7]4[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=4[C:5]=3[N:1]=2)[CH2:18][CH2:19]1
Reactant: COCC(=O)NC1CCC(CNc2nc3c(s2)CCOc2ccccc2-3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCNC1CCC(CNc2nc3c(s2)CCOc2ccccc2-3)CC1
Temperature: 25 °C
Reaction time: 26 h
Yield: 89.9 %

Procedure:
To a stirred solution of N1-{4-[(4,5-dihydrobenzo[2,3]oxepino[4,5-d][1,3]thiazol-2- ylamino)-methyl]cyclohexyl}-2-methoxyacetamide (free-base) (0.450 g, 1.12 mmol) in anhydrous THF (5 ml) was added 5.0 ml 1M BH3 in THF (5.0 mmol). The solution was stirred at room temperature for 26 hours. 4N HCl (12 ml) was slowly added to the stirred solution and stirred continued for 1 hour. The solution was made basic with 2N NaOH (pH˜9) and was extracted with EtOAc. Upon evaporation of the solvent, 90% (390 mg) of the desired amine was obtained as a highly viscous colorless oil. The compound was converted to its dihydrochloride salt in chloroform with 1N HCl in Et2O. Evaporation of the solvent gave 460 mg of the salt as a slightly hygroscopic white solid: m.p. 243-245° C. (dec); 1H-NMR (CDCl3) δ 1.08 (4H, t, J=10.8 Hz), 1.6 (2H, broad), 1.91 (4H, m), 2.41 (1H, broad), 2.80 (2H, t, J=4.9 Hz), 3.15 (4H, m), 3.35 (3H, s), 3.49 (2H, t, J=5.3 Hz), 4.32 (2H, t, J=5.4 Hz), 5.13 (1H, broad t), 6.98 (1H, dd, J=1.3 Hz, 7.7 Hz), 7.12 (2H, m), 8.24 (1H, dd, J=1.6 Hz, 7.9 Hz); 388 (ESMS, MH+).
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]([CH3:16])=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]=1[CH3:9])#[N:2].C1(P(Cl)([Cl:26])=O)C=CC=CC=1.[OH-].[NH4+]>>[Cl:26][C:4]1[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH3:16])[N:5]=1
Reactant: Cc1[nH]c(=O)c(C#N)c(C)c1-c1ccccc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc(Cl)c(C#N)c(C)c1-c1ccccc1
Temperature: 0 °C

Procedure:
3-Cyano-4,6-dimethyl-5-phenyl-2-pyridone (7.0 grams) and phenylphosphonic dichloride (12.1 grams) were heated at 175°-180° C. for 2-3 hours. The solution was cooled, poured into ice water and made basic with ammonium hydroxide. A precipitate formed which was collected, air dried, and determined by NMR to be the desired product, yield 7.6 grams, m.p. 118°-123° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:15][C:16]1[S:17][CH:18]=[C:19]([Br:25])[C:20]=1[C:21]([O:23][CH3:24])=[O:22]>>[Br:25][C:19]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:16]([NH:15][C:12](=[O:14])[CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[S:17][CH:18]=1
Reactant: COC(=O)c1c(Br)csc1N
Reactant: O=C(O)Cc1cccc2cnccc12
Product: COC(=O)c1c(Br)csc1NC(=O)Cc1cccc2cnccc12

Procedure:
The title compound was prepared from 2-(isoquinolin-5-yl)acetic acid (427 mg, 2.18 mmol) and methyl 2-amino-4-bromothiophene-3-carboxylate (514 mg, 2.18 mmol) according to protocol A. Retention time (min)=1.634, method [1], MS(ESI) 405.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CC(C)=O>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][O:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[N:9][S:10][C:11]=2[CH:16]=1
Reactant: BrCCCCBr
Reactant: Oc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
2.0 g (6.55 mmol) 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-ol in 30 ml acetone were treated with 5.89 g (42.5 mmol, 6.5 eq) K2CO3 and 1.9 ml (16.33 mmol, 2.5 eq) 1,4-dibromobutane. The reaction mixture was stirred at 45° C. for 8 h and at RT over night, filtered and evaporated. The excess of dibromide was removed in vacuo and the crude product was purified by column chromatography on silica gel with a gradient EtOAc:hexane 1:9 to 1:4 to yield 2.0 g (71%) 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole as yellow semisolid, MS: 439 (M, 2Br).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:19]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][C:10]4[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:6][CH:7]=2)=[O:28])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(OC(C)=O)cc4)cc3)sc2c1
Yield: 94.3 %

Procedure:
Prepared as described in the Amide Coupling section above using 2-(4-aminophenyl)-6-methoxybenzothiazole (0.25 g, 0.976 mmol) and 4-acetoxybenzoyl chloride (0.22 g, 1.07 mmol) in dry pyridine (10 ml) to give the title compound (0.385 g, 94%) as a colourless solid after work-up.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:27][CH:28]=2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:31][CH2:30]3)[S:27][CH:28]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc(-c2csc(N3CCNCC3)n2)c1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2csc(N3CCN(C(=O)Nc4cccnc4)CC3)n2)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 58.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (215 mg, 0.799 mmol), 1-[4-(3-methoxyphenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.726 mmol) and diisopropylethylamine (0.253 ml, 1.45 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and ethyl acetate to give 168 mg (58.5%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:9]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[CH:4][C:3]=1[NH:30][C:31]([C@@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:38](=[O:48])[C@@H:39]([NH:43][C:44](=[O:47])[O:45][CH3:46])[CH:40]([CH3:42])[CH3:41])=O.C(O)(=O)C>CCOC(C)=O.C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([CH:10]2[N:9]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:27])[CH3:28])=[CH:22][CH:21]=3)[CH:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:31]([C@@H:33]5[CH2:37][CH2:36][CH2:35][N:34]5[C:38](=[O:48])[C@@H:39]([NH:43][C:44](=[O:47])[O:45][CH3:46])[CH:40]([CH3:42])[CH3:41])[NH:30][C:3]=4[CH:4]=3)[CH2:12][CH2:11]2)=[CH:14][CH:15]=1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cc(C2CCC(c3ccc(Br)cc3)N2c2ccc(C(C)(C)C)cc2)ccc1N)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(C3CCC(c4ccc(Br)cc4)N3c3ccc(C(C)(C)C)cc3)cc2[nH]1)C(C)C
Temperature: 75 °C

Procedure:
The product from Example 191H (0.5 g, 0.696 mmole) was treated with acetic acid (5 mL, 87 mmole) and heated in an oil bath at 75° C. for 70 min. The reaction mixture was cooled to room temperature and concentrated in vacuo leaving an oily residue. The residue was dissolved in EtOAc (100 mL) washed with 10%0/NaHCO3 (20 mL) and 10% NaCl (20 mL), dried over anhydrous Na2SO4(s), filtered and solvent removed in vacuo leaving a brown foamy solid. The residue was dissolved in 10 mL CH2Cl2 and applied to a 12 g silica gel column. The column was eluted with a gradient of CH2Cl2/MeOH, 99/1 to 95/5 over 15 minutes and the product was isolated as a tan solid as a mixture of isomers (0.31 g). ESI(m/z)+: 702.3.
Reaction SMILES: CC1C2C(=CC(N(CC)CC)=CC=2)[O:5]C(=O)C=1.[BH4-].[Na+].[CH2:20]([N:22]([CH2:36][CH3:37])[C:23]1[CH:32]=[C:31]2[C:26]([C:27]([CH2:34][OH:35])=[CH:28][C:29](=[O:33])[O:30]2)=[CH:25][CH:24]=1)[CH3:21].[P:38](N)([O-:40])[O-:39].N1C=NN=N1>>[CH2:36]([N:22]([CH2:20][CH3:21])[C:23]1[CH:32]=[C:31]2[C:26]([C:27]([CH2:34][OH:35])=[CH:28][C:29](=[O:33])[O:30]2)=[CH:25][CH:24]=1)[CH3:37].[P:38]([O-:40])([O-:5])[O-:39]
Reactant: CCN(CC)c1ccc2c(C)cc(=O)oc2c1
Reactant: NP([O-])[O-]
Agent: CCN(CC)c1ccc2c(CO)cc(=O)oc2c1
Agent: [BH4-]
Agent: [Na+]
Product: [O-]P([O-])[O-]

Procedure:
7-(Diethylamino)-4-hydroxymethylcoumarin (9) was prepared by oxidation of 4-methyl-7-(diethylamino)coumarin with SeO2, and subsequent reduction with NaBH4. Reaction of alcohol 9 with phosphoramidite 8 in the presence of 1H-tetrazole provided a phosphite intermediate, which was oxidized in the same pot with anhydrous TBHP to afford phosphate 10 (Scheme 2). Removal of the protecting groups required some exploration. An initial attempt to deprotect both the Boc and MOM groups with TFA resulted in the loss of the Boc group in 1 h; however, only 50% of the MOM group was removed even after stirring for 3 days at rt. Reaction with Me3SiBr in CH2Cl 2, rather than removing the methyl ester of the phosphate, resulted instead in the loss of the coumarin moiety from the lipid. When 10 was heated in 6 M HCl/THF (2:1) at 60° C. for 6 h, all three groups, Boc, MOM, and the phosphate methyl ester, were removed to provide DECM-S1P (1), which on neutralization and N-acylation using p-nitrophenyl palmitate in DMF/CH2Cl2 gave C1P analogue 1a in good yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[C:14][C:15]2[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][N:16]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(OCC)=O.C(OCC)(=O)C>C1COCC1>[OH:22][CH2:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:14]#[C:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:20]=1
Reactant: COc1cc(C#Cc2cc(C(=O)O)ccn2)cc(OC)c1OC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(C#Cc2cc(CO)ccn2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
2-(3,4,5-Trimethoxyphenylethynyl)pyridine-4-carboxylic acid (90 mg) was dissolved in THF (6 mL), and to the solution triethylamine (35 mg) was added at 0° C. under an argon atmosphere. Ethyl chloroformate (34 mg) was then added to the mixture, and the mixture was stirred for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate. After concentrating the reaction mixture, the residue was dissolved in THF (2 mL), and to the solution an aqueous solution (1 mL) of sodium borohydride (16 mg) was added at 0° C., and the resultant mixture was stirred for 1 hour. The reaction mixture was extracted with ethyl acetate, and the resultant organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure, the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1 to ethyl acetate) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:20]([NH:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)([CH3:23])([CH3:22])[CH3:21]>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:25](=[O:31])[NH:24][C:20]([CH3:22])([CH3:21])[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.21 g, 0.80 mmol) and (S)-proline tert-butyl amide (0.15 g, 0.88 mmol) gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1C=C2C(NC(NC2=CC=1)=O)=O.O=P(Cl)(Cl)Cl.Cl.[NH2:31][S:32]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39]N)=[CH:37][CH:36]=1)(=[O:34])=[O:33].C(N(C(C)C)CC)(C)C>C(O)C>[Cl:1][C:2]1[N:11]=[C:10]([CH2:39][C:38]2[CH:37]=[CH:36][C:35]([S:32]([NH2:31])(=[O:34])=[O:33])=[CH:42][CH:41]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: Cl
Agent: O=c1[nH]c(=O)c2ccccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: NS(=O)(=O)c1ccc(Cc2nc(Cl)nc3ccccc23)cc1
Yield: 88 %

Procedure:
A mixture of 2,4-dichloroquinazoline [prepared from benzoyleneurea and POCl3 by the method of Butler et al., J. Chem. Soc. 1959, 1512.] (100 mg, 0.502 mmol, 1 eq), 4-aminosulfonylbenzylamine hydrochloride (117.5 mg, 0.527 mmol, 1.05 eq) and diisopropylethylamine (0.26 mL, 1.506 mmol, 3 eq) in absolute ethanol (1.6 mL) was stirred at ambient temperature for 4 h. The precipitated solid was collected by filtration, washed with water and cold ethanol, and dried to afford 154 mg (88%) of 2-chloro-4-(4-aminosulfonylbenzyl)quinazoline as a white solid. LC/MS: 349 [M+H]+; HPLC: 96% at 1.86 min (Primesphere 5 μm C18 column 4.6×30 mm, 10–90% aqueous methanol over 2 min containing 0.2% phosphoric acid, 5 mL/min, monitoring at 254 nm); 1H NMR (400 MHz, DMSO-d6): δ 9.37 (t, J=5.8 Hz, 1 H), 8.32 (d, J=8.2 Hz, 1 H), 7.85–7.53 (m, 7 H), 7.32 (s, 2 H), 4.81 (d, J=5.7 Hz, 2 H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([Cl:21])[NH:10][C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][Cl:33]>CN(C)C=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([Cl:21])[N:10]([CH2:30][CH2:31][CH2:32][Cl:33])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: O=c1[nH]c(Cl)c(-c2ccccc2)c(=O)n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2)c(Cl)n(CCCCl)c(=O)n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a suspension of 78.19 g (250 mmol) of 3-benzyl-6-chloro-5-phenylpyrimidine-2,4(1H,3H)-dione and 55.3 g (400 mmol) of potassium carbonate in 450 ml of N,N-dimethylformamide, 49.4 ml (500 mmol) of 1-bromo-3-chloropropane was added at room temperature. This mixture was stirred at 80° C. for 5 hours. After cooling, the reaction mixture was concentrated to dryness; the resulting residue was dissolved in chloroform-water. After the organic layer was washed with water and dried, the solvent was distilled off to yield an oily substance, which was then purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1→2/1) to yield 71.89 g (73.9%, yellow oily substance) of the desired product.