Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[CH:6]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH:13]=O)([CH3:8])[CH3:7]>C(Cl)Cl.CCCCCC.[Zn]>[Br:2][C:1]([Br:5])=[CH:13][C:12]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:10]([O:9][CH:6]([CH3:8])[CH3:7])[CH:11]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(C=O)cc1OC(C)C
Agent: [Zn]
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc(C=C(Br)Br)cc1OC(C)C
Temperature: 0 °C
Reaction time: 22 h
Yield: 99.8 %

Procedure:
Carbon tetrabromide (51.3 g, 154.7 mmol) was added portion-wise to a magnetically stirred mixture of zinc dust (10.1 g, 154.5 mmol) and PP3 (40.5 g, 154.4 mmol) in CH2Cl2 (350 mL) maintained at 0° C. on an ice-salt bath. The resulting suspension was allowed to warm to room temperature and then stirred for a further 22 h. After this time the reaction mixture was re-cooled to 0° C. and isovanillin isopropyl ether (15.0 g, 77.3 mmol) was added dropwise over 2 min. The resulting mixture was allowed to stir at room temperature for 1 h then diluted with hexane (200 mL) and filtered through a No. 3 porosity sintered-glass funnel. The filtrate was concentrated on to silica gel (400-200 mesh, 30 g) and the resulting solid added to the top of a flash chromatography column (20 cm long×10 cm wide) which was subjected to gradient elution with 2:1, 1:1 then 1:2 hexane/CH2Cl2. Concentration of the appropriate fractions (Rf 0.5 in 1:1 hexane/CH2Cl2) afforded the title compound (27.0 g, 99%) as white crystalline masses, m.p. 67-69° C. νmax (KBr) 3009, 2975, 2929, 1597, 1572, 1508, 1463, 1441, 1429,1373, 1301, 1276, 1260, 1233, 1144, 1110 and 999 cm1. 1H n.m.r. δ7.38 (s, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.08 (dd, J=8.4 and 2.1 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.53 (septet, J=6.0 Hz, 1H), 3.86 (s, 3H), 1.38 (d, J=6.0 Hz, 6H). 13C n.m.r. δ150.5 (C), 146.7(C), 136.4 (CH), 127.7(C), 122.1 (CH), 115.3 (CH), 111.3 (CH), 87.0(C), 71.4 (CH), 55.8 (CH3), 22.0 (2×CH3). Mass spectrum m/z 352 (20) 350 (40) 348 (22)(M+•), 310 (50) 308 (100) 306 (50) [(M−C3H6)+•], 295 (30), 293 (61) 291 (33) [(M−C3H6−CH3+•)+]. Anal. Calcd for C12H14Br2O2 C, 41.2; H, 4.0; Br, 45.7. Found: C, 41.1; H, 3.7: Br, 45.3%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.O1CCCC1.C[CH2:24][O:25][C:26]([C@@H:28](O)[CH3:29])=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C>[CH:15]1([C:13]([NH:12][C:7]2[N:8]=[CH:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([O:1][C@H:28]([CH3:29])[C:26]([O:25][CH3:24])=[O:27])[CH:11]=3)=[O:14])[CH2:16][CH2:17]1
Reactant: O=C(Nc1cc2ccc(O)cc2cn1)C1CC1
Reactant: CCOC(=O)[C@H](C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](C)Oc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(7-hydroxyisoquinolin-3-yl)cyclopropanecarboxamide (68.7 mg, 0.301 mmol) in tetrahydrofuran (3.0 mL, 37 mmol) was added ethyl L-(-)-lactate (44 uL, 0.39 mmol) and triphenylphosphine (108.4 mg, 0.4133 mmol), followed by dropwise addition of diethyl azodicarboxylate (62 uL, 0.39 mmol). The resulting mixture was stirred at room temperature for 1 hour, and then ethyl L-(-)-lactate (13 uL, 0.11 mmol) and diethyl azodicarboxylate (19 uL, 0.12 mmol) were added. After an additional 2.5 hours, the reaction mixture was poured into ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-80% ethyl acetate in heptanes) to provide a quantitative yield of (R)-methyl 2-(3-(cyclopropanecarboxamido)isoquinolin-7-yloxy)propanoate. LCMS (ESI): M+H=329.2.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[CH:16](O)[CH3:17])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([NH:26][O:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.CCOCC>[C:19]([O:23][C:24]([N:26]([CH:16]([CH3:17])[CH:15]=[CH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)[O:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Reactant: CC(O)/C=C/c1cccc(Oc2ccccc2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C=Cc1cccc(Oc2ccccc2)c1)N(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
(-)-(E)-1-3(-Phenoxyphenyl)but-1-en-3-ol from step (d) (2.6 g), N,O-bis(t-butoxycarbonyl)hydroxylamine (2.65 g), and triphenylphosphine (4.25 g) were taken up in toluene (30 ml) and cooled to -78° C. under N2. A solution of DEAD (2.9 g) in toluene (10 ml) was then added and the mixture allowed to warm to room tempterature. 40/60 pet.ether (60 ml) was added to precipitate Ph3P=O as a dark gummy mass. The mother liquor was decanted off and stripped to give a tan/orange oil which was eluted through a silica gel column using methylene chloride. The eluate was stripped to give a pale yellow oil which was eluted through a second silica gel column using ether/methylene chloride/40-60 pet.ether (1:1:8) and the eluate stripped to give the desired product as a colourless oil which was dried under high vacuum. Yield 1 97 g.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].N1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1)(=[O:28])=[O:27]
Reactant: COC(=O)c1ccccc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.6 %

Procedure:
To a solution of 2.00 g (0.013 mol) of methyl anthranilate dissolved in 20 mL of chloroform was added 3.2 mL (0.039 mol) of pyridine followed by 2.733 g (0.013 mol) of p-methoxybenzenesulfonyl chloride. The reaction mixture was stirred at room temperature for 5 h and then washed with 3N HCl and water. The organics were then dried over Na2SO4, filtered and concentrated in vacuo. The resulting white solid was washed with ether and dried in vacuo to provide 3.7 g (87%) of the desired sulfonamide. CI Mass Spec: 322 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH2:45][CH2:44]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 47.9 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.21 mmol), 2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (60 mg, 0.19 mmol), and p-toluenesulfonic acid (98 mg, 0.51 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (67 mg, 0.091 mmol, 46%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.39 (d, J=2.01 Hz, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.19 (s, 1H), 8.01-8.07 (m, 1H), 7.78-7.83 (m, 1H), 7.68-7.75 (m, 1H), 7.56-7.63 (m, 1H), 7.36-7.47 (m, 3H), 7.16-7.23 (m, 2H), 6.93-7.01 (m, 1H), 6.67 (s, 1H), 6.45 (d, J=4.40 Hz, 2H), 3.79 (s, 3H), 3.31-3.36 (m, 2H), 3.10-3.18 (m, 4H), 3.03 (s, 3H), 2.71-2.78 (m, 2H), 2.53-2.61 (m, 4H). MS (ESI): 739 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Br:27]N1C(=O)CCC1=O>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][C:17]=3[Br:27])[CH:10]=[N:9]2)=[CH:25][CH:26]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4ccccn4)n3)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)sc3Br)cn2)cc1
Yield: 95.7 %

Procedure:
According to Scheme 5 Step 1: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-2-amine (4.20 mmol, 1.53 g) and N-bromosuccinimide (4.40 mmol, 782 mg) in DMF (76 mL) was stirred for 1.5 hour at 50° C. The reaction mixture was diluted with a saturated solution of Na2CO3 and water. The precipitate formed was recovered and washed with DCM. The aqueous phase was extracted with DCM and the organic phase was washed. The organic phase was dried over MgSO4, was filtered and was concentrated to yield with the addition of the precipitate N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-bromothiazol-2-yl)pyridin-2-amine (4.02 mmol, 1.78 g, 96%) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13]CC1C2SC3C(=CC=CC=3)C(=O)C=2C(NCCN(CC)CC)=CC=1.O.[OH-].[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccccc3c(=O)c12
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3,4-dichlorobenzenesulfonyl chloride (1.84 g, 7.5 mmol) in 35 mL of dry pyridine was added 2.5 g (7 mmol) of 4-(aminomethyl)-1-[[2-(diethylamino)ethyl]amino]-thioxanthen-9-one (prepared by the method described in Example 4) under nitrogen and the reaction mixture was stirred at room temperature for 15 min. and then was allowed to stand for approximately 72 hours. The reaction mixture was poured into 75 mL of water containing 0.75 g of NaOH, and extracted into chloroform. The organic layer was washed with water (2x) and brine, and dried over sodium sulfate. Chloroform was removed in vacuo, the residue was recrystallized from ethanol to afford 1.24 g of N-[[1-[[2-(diethylamino)]ethyl]amino]-9-oxothioxanthen-4-yl]methyl]-3,4-dichlorobenzenesulfonamide, m.p. 95° C. (dec.). The free base was dissolved in methanol and treated with methanesulfonic acid in methanol to afford the methanesulfonate·1/2 hydrate, m.p. 55° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:37])[F:38])[CH:30]=2)=[CH:40][CH:41]=1
Reactant: Cn1c(=O)n(CCC(=O)OC(C)(C)C)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n(CCC(=O)O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
tert-Butyl 3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoate (0.23 g, 0.383 mmol, Example 397) was dissolved in DCM (4 mL) and TFA (0.57 mL, 7.66 mmol) was added. The reaction was stirred at room temperature for 1 h; then the solvent was removed under reduced pressure to leave a golden oil (0.21 g). The oil was purified using a 12 g silica gel column eluted with 5% methanol/DCM to give 34744-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoic acid (0.13 g, 63% yield) as an white solid. LCMS retention time=3.903 min and 99% purity, LCMS MH+=539. 1H NMR (CDCl3) δ 7.14-7.47 (m, 8H), 5.41 (s, 2H), 4.35 (t, 2H, J=8 HZ), 3.44 (s, 3H), 2.77 (t, 2H, J=8 HZ).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([OH:16])=[O:15].[Cl:17][C:18]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:19]=1[C:20]([N:22]=[C:23]=[O:24])=[O:21]>C(#N)C>[Cl:17][C:18]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:19]=1[C:20]([NH:22][C:23](=[O:24])[NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[S:4][C:3]=1[C:14]([OH:16])=[O:15])=[O:21]
Reactant: Nc1cc(-c2ccc(F)cc2)sc1C(=O)O
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Solvent: CC#N
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1cc(-c2ccc(F)cc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Amino-5-(4-fluorophenyl)thiophene-2-carboxylic acid (50 mg) is initially charged in 3 ml of acetonitrile. The equimolar solution of 2-chloro-4,5-difluorobenzoyl isocyanate in acetonitrile is added and the mixture is stirred at RT. After 3 hours, the solid is filtered off with suction, stirred once more with methanol, filtered off with suction and dried under reduced pressure.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[N-:11]=[N+:12]=[N-:13].[Na+].O>CN(C=O)C>[N:11]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCCCCBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCN=[N+]=[N-]
Temperature: 75 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
Methyl 6-azidohexanoate was synthesized via a modified literature procedure. A reaction mixture of methyl 6-bromohexanoate (6 g, 29 mmol) and NaN3 (9.4 g, 144 mmol) in 30 ml of DMF was stirred at 75° C. for 14 h under N2. After cooling down, the reaction mixture was poured into water. The product was extracted with hexane, washed with brine, and dried under MgSO4. Solvent was evaporated to give transparent liquid. Yield: 95%.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Cl[CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]3([C:10]([F:13])([F:11])[F:12])[O:21][CH2:20][CH2:19][O:14]3)=[N:6][C:5]=2[CH:15]=1
Reactant: OCCCl
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)C1(c2nc3cc(Cl)c(Cl)cc3[nH]2)OCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (1.14 g; 4.02 mmol), 2-chloroethanol (0.83 mL; 12.4 mmol) and potassium carbonate (1.68 g; 12.2 mmol) were dissolved in DMF (18 mL). The reaction mixture was stirred for 18 hrs at ambient temperature, then diluted with ethyl acetate (80 mL), washed with water (50 mL) and brine (2×50 mL). The extracts were dried over Na2SO4, filtered, concentrated to a light brown solid and the light brown solid purified by column chromatography (SiO2; 30% ethyl acetate/hexanes) to yield the title compound as a tan solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:21]([O:20][C:18]([C:13]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C1CCCC1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(Cc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
A solution of diisopropylamine (1.0 mL, 7.7 mmol) in 20 mL of dry THF was cooled to −78° C. in a dry ice-acetone bath under argon. n-Butyl lithium in hexanes (2.5 M, 3.6 mL, 7.7 mmol) was added all at once and the mixture was stirred for 0.5 hour and transferred to a precooled (−30° C.) solution of 1.0 g (7.0 mmol) of ethyl cyclopentane carboxylate in 10 mL of THF. After a further 45 min, benzyl bromide (0.92 mL, 7.7 mmol) was added and the mixture was allowed to warm to room temperature over night. The resulting mixture was concentrated, and the residue was taken up in 70 mL of ether, washed with water, 1 N HCl, water, saturated brine and was dried (MgSO4). The residue obtained after filtration and evaporation was purified by flash chromatography over 100 g of silica gel, eluting with 3% ethyl acetate-hexane to give 1-benzylcyclopentane carboxylic acid ethyl ester (0.80 g, 45%) as a colorless oil.
Reaction SMILES: C(O)[C@@H](O)[C@H:3]1[O:8][C:6](=[O:7])[C:5]([OH:9])=[C:4]1[OH:10].[CH:13](P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:15])[CH3:14].C([Li])CCC.O=C[C@@H]([C@@H](CO)O)O>O1CCCC1.C(OCC)(=O)C>[CH3:14][C:13]1([CH3:15])[O:9][C@@H:5]2[C@@H:4]([CH2:3][O:8][CH:6]2[OH:7])[O:10]1
Reactant: CC(C)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1O[C@H]([C@H](O)CO)C(O)=C1O
Agent: O=C[C@H](O)[C@H](O)CO
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2COC(O)[C@@H]2O1
Temperature: -40 °C
Reaction time: 20 h

Procedure:
2,3-O-Isopropylidene-D-erythrose was prepared by literature procedures (Cohen, N. et al, J. Am. Chem. Soc. 1983, 105, 3661) from D-isoascorbic acid. To a suspension of isopropyltriphenylphosphine (121 g, 2.4 equiv, 0.314 mol) in tetrahydrofuran (1.5 L) at -40° C. under nitrogen was added n-butyllithium (1.6M solution in hexanes) (197 mL, 2.4 equiv) dropwise. The erythrose (21 g, 1 equiv, 0.131 mol) in tetrahydrofuran (231 mL) was also added dropwise maintaining the temperature at -40° C. The mixture was then allowed to warm to room temperature and stirred under nitrogen for 20 hours and then quenched by the addition of ammonium chloride (77 g). The insoluble material was removed by filtration through Celite and the filtrate concentrated at reduced pressure to afford a residue which was extracted (4×) with ether. The combined ether extracts were washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo to afford a yellow oil. Chromatography on silica gel eluting with 20% ethyl acetate in hexanes afforded the title compound (13.0 g, 53%). 1H NMR (CDCl3, 300 MHz) δ 1.4 (s, 3H), 1.50 (s, 3H), 1.73 (s, 3H), 1.78 (s, 3H), 3.57 (t of d, J=1.5 Hz, J=6 Hz, 2H), 4.20 (q, J=6 Hz, 8 Hz, 1H), 4.44 (q, J=9 Hz, 9 Hz, 1H), and 5.75 (d, J=9 Hz, 1H). MS (DCI/NH3) m/e 204 (M+H+NH3)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[CH:14][N:13]=[N:12]2)=[N:9][CH:10]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][N:18]=1>C(#N)C>[I:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([CH:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([N:11]4[CH:15]=[CH:14][N:13]=[N:12]4)=[N:9][CH:10]=3)[N:16]=2)[CH:19]=1
Reactant: Nc1ccc(I)cn1
Reactant: O=C(CBr)c1ccc(-n2ccnn2)nc1
Solvent: CC#N
Product: Ic1ccc2nc(-c3ccc(-n4ccnn4)nc3)cn2c1
Temperature: 100 °C
Yield: 45.4 %

Procedure:
66.4 mg (corresponding to 0.249 mmol) of 5-(2-bromoacetyl)-2-(1H-1,2,3-triazole-1-yl)pyridine and 54.8 mg (corresponding to 0.249 mmol) of 2-amino-5-iodopyridine were dissolved in 2.0 mL of acetonitrile. The resulting solution was heated under reflux for 1.5 hours in an oil bath at 100° C. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 2 mL of water and 2 mL of methanol. Then, about 1 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 44.0 mg (corresponding to 0.113 mmol) of 6-iodo-2-[2-(1H-1,2,3-triazole-1-yl)pyridine-5-yl]imidazo[1,2-a]pyridine (FIG. 1, step 3).
Reaction SMILES: [C:1](Cl)(=[O:19])[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][CH3:18].[CH3:21][N:22]([CH2:26][C:27]([O-:29])=[O:28])[C:23]([NH2:25])=[NH:24].[K+]>>[C:1]([O:28][C:27](=[O:29])[CH2:26][N:22]([CH3:21])[C:23]([NH2:25])=[NH:24])(=[O:19])[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][CH3:18]
Reactant: CN(CC(=O)[O-])C(=N)N
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: [K+]
Product: CCCCCCCCCCCCCCCCCC(=O)OC(=O)CN(C)C(=N)N
Temperature: 0 °C

Procedure:
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 21.27 g (70 mmol) of the prepared stearoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 23.40 g (77 mmol) of potassium 2-(1-methylguanidino)acetate. The round bottomed flask is placed in an ice bath and the stearoyl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-(1-methylguanidino)acetic stearic anhydride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20]C)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of 9-bromo-5-methoxycarbonylmethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (25.0 g, 0.071 mol) in a mixture of THF (350 mL) and methanol (350 mL) was added aqueous 1N NaOH (440 mL). The mixture was stirred for 2 h at room temperature, concentrated to ca. 500 mL, and acidified by addition of aqueous 1N HCl. The precipitates formed were collected by filtration, washed with distilled water, and dried in vacuo to give 22.9 g of the title compound (95%).