Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]([CH2:28][C:29](O)=[O:30])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[CH2:28][C:29]([NH:38][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:30])([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CN(c1cccc(Cl)c1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reactant: NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CN(c1cccc(Cl)c1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
The mixture of [[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-acetic acid 100 mg, 0.211 mmol), Cyclohexylamine (25 mg, 0.253 mmol), EDC.HCl (48 mmg, 0.253 mmol), HOBt (34 mmg, 0.253 mmol) and DIPEA (82 mmg, 0.633 mmol) in acetonitrile (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give 48 mg of rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide as a yellow solid. MS: [M+H]+=556.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C@@H:8]1[C:12]2[NH:13][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:11]=2[C:10](=[O:25])[NH:9]1.Br[C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[C:34]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:33]([CH2:42][C:43]([F:46])([F:45])[F:44])[C:32]2=[O:47]>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[C:38]([NH:37][C:34]1[N:33]([CH2:42][C:43]([F:46])([F:44])[F:45])[C:32](=[O:47])[C:31]2[C:36](=[C:27]([C:14]3[NH:13][C:12]4[C@@H:8]([CH3:7])[NH:9][C:10](=[O:25])[C:11]=4[CH:15]=3)[CH:28]=[CH:29][CH:30]=2)[N:35]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1CC(F)(F)F
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(CC(F)(F)F)c(NC(C)(C)C)nc34)[nH]c21
Yield: 26.6 %

Procedure:
2-(tert-Butylamino)-8-((6R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)-4(3H)-quinazolinone (501) as a yellow solid (32 mg, 26%) was prepared according the procedures described for 408, using 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (9.8 mg, 0.014 mmol, Sigma Aldrich), K2CO3 (153 mg, 1.111 mmol, Sigma Aldrich), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (146 mg, 0.555 mmol, 706), and 8-bromo-2-(tert-butylamino)-3-(2,2,2-trifluoroethyl)quinazolin-4(3H)-one (105 mg, 0.278 mmol, 501d). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.68 (1H, s) 7.89-7.96 (1H, m) 7.83-7.88 (1H, m) 7.59 (1H, s) 7.21 (1H, t, J=7.73 Hz) 6.62 (1H, d, J=1.37 Hz) 6.28 (1H, s) 5.28 (2H, q, J=8.93 Hz) 4.50 (1H, d, J=6.26 Hz) 1.45 (9H, s) 1.36 (3H, d, J=6.65 Hz). m/z (ESI, +ve) 434.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.CC(C1C=CC=C(Cl)C=1)=O.[NH2:27][C:28]1[C:32]([C:33]#[N:34])=[CH:31][NH:30][N:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:29]3[N:30]=[CH:31][C:32]([C:33]#[N:34])=[C:28]3[N:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(Cl)c1
Reactant: N#Cc1c[nH]nc1N
Agent: CC(=O)c1cccc(Cl)c1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(Cl)c3)nc12
Yield: 46.5 %

Procedure:
Reaction of 1-(3-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251 mg, 1.0 mmol), prepared from commercially available 3-chloro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (150 mg, 46%). MS (ISP) 323.1 [(M+H)+]; mp 204° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]([C:36]1[CH:40]=[C:39]([NH2:41])[O:38][N:37]=1)([CH3:35])[CH3:34].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.O>N1C=CC=CC=1.CC(=O)OCC>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:41][C:39]2[O:38][N:37]=[C:36]([C:33]([CH3:35])([CH3:34])[C:32]([F:31])([F:42])[F:43])[CH:40]=2)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2]
Reactant: CC(C)(c1cc(N)on1)C(F)(F)F
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cc(C(C)(C)C(F)(F)F)no2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a mixture of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (1.060 g, 2.58 mmol) and 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (0.5 g, 2.58 mmol) in pyridine (20 mL) was added T3P® (50% in EA, 5 mL, 2.58 mmol) dropwise and stirred at 25° C. for 1 h. The mixture was poured into stirring cold water (100 mL). The mixture was stirred for 0.5 h and left standing for 10 h. The resulting solid was filtered, washed with H2O (200 mL×3) and TBME (200 mL×2) and dried in vacuo to give an off white solid 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (1.5 g, 2.298 mmol, 89% yield): 1H NMR (400 MHz, CD3OD): δ 7.96 (s, 1H), 7.40-7.32 (m, 3H), 7.28 (d, J=9.6 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.45 (s, 1H), 6.38 (s, 1H), 5.27 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.83 (s, 2H), 3.79 (s, 3H), 1.53 (s, 6H), 1.37 (t, J=6.8 Hz, 3H). ES-LCMS m/z: 588 (M+H).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C([Li])CCC.[B:21](OC)([O:24]C)[O:22]C.Cl>C1COCC1>[CH:14]1[C:15]2[C:10](=[CH:9][C:8]3[C:3]([C:2]=2[B:21]([OH:24])[OH:22])=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=[CH:12][CH:13]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1c2ccccc2cc2ccccc12
Temperature: -80 °C
Reaction time: 2 h

Procedure:
In a 500 mL three-neck flask, 7.7 g (30 mmol) of 9-bromoanthracene was placed, and the air in the flask was replaced with nitrogen. Then, 200 mL of THF was added into the flask and the solution was cooled to −80° C. under nitrogen stream. After cooling, 18 mL (30 mmol) of 1.6 M n-butyllithium was dripped into the solution and stirred at the same temperature for 2 hours. After a certain period, 6.8 mL (60 mmol) of trimethyl borate was added into the solution, the temperature of the solution was raised to room temperature, and then, the solution was stirred for 17 hours. After a certain period, 100 mL of 1.0 M hydrochloric acid was added to the solution and stirred for 1 hour. An aqueous layer of the obtained mixture was extracted with ethyl acetate. The resulting extracted solution and the organic layer were combined and washed with saturated saline, and then the organic layer was dried with magnesium sulfate. The obtained mixture was gravity filtered, and the filtrate was condensed to give a solid. The solid was recrystallized with toluene, so that 5.2 g of target white powder was obtained in a yield of 80%.
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[CH2:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]#[CH:28]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:25][C:4]1[C:3]([C:28]#[C:27][CH2:26][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[N:8][CH:7]=[N:6][C:5]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:12]([CH3:24])[CH:11]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#CCNC(=O)OC(C)(C)C)c3N)cc2C)cn1
Yield: 73.8 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydriodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl 2-propynylcarbamate (166 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) and copper(I) iodide (10.2 mg) were sequentially added. The title compound (303 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]C)[CH:6]=1)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)=[O:4]
Reactant: COc1cccc(C(=O)CBr)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(CBr)c1cccc(O)c1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
2-Bromo-1-(3-methoxyphenyl)ethan-1-one (2 g, 8.7 mmol) was taken in a round bottomed flask equipped with magnetic stir bar. The flask was put under a N2 atmosphere and CH2Cl2 was introduced into the flask. The resulting solution was cooled in a dry ice acetone bath and BBr3 (27 mL, 1M in CH2Cl2) was introduced dropwise. The resulting solution was allowed to warm up to room temperature over-night. The solvents were removed under vacuum and the residue was purified by passing through a short pad of silica gel (50 g) to give 1.3 g (69%) of 2-bromo-1-(3-hydroxyphenyl)ethan-1-one as an oil. 1H-NMR (CDCl3; 300 MHz) δ4.47 (s, 2H), 6.21 (s, 1H), 7.08-7.19 (m, 1H), 7.23-7.48 (m, 1H), 7.52-7.82 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl.O>[CH3:18][S:19]([O:10][CH2:9][C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:21])=[O:20]
Reactant: COc1ccc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COS(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
A solution of (6-methoxypyridin-3-yl)methanol (2.9 g, 20.93 mmol) and triethylamine (4.35 mL) in dichloromethane (20 mL) was treated with methanesulfonyl chloride (2.9 g, 25.1 mmol) dropwise and the reaction mixture stirred at rt overnight. After this time, the reaction was diluted with water and extracted with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford the title compound (1.4 g, 49%) as a yellow oil. MW=217.24. 1H NMR (CDCl3, 300 MHz) δ 8.16-8.14 (m, 1H), 7.68-7.59 (m, 1H), 6.76 (d, J=8.6 Hz, 1H), 4.55 (s, 2H), 3.94 (s, 3H), 3.19 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:11]([OH:13])=O)[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:24]C=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40](N)[CH2:41][C@H:42]([OH:64])[C@@H:43]([NH:51][C:52](=[O:63])[C@H:53]([C@H:59]([CH2:61][CH3:62])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH:39]([NH2:24])[N:40]([C:11](=[O:13])[C@H:7]([CH:8]([CH3:9])[CH3:10])[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:41][C@H:42]([OH:64])[C@@H:43]([NH:51][C:52](=[O:63])[C@H:53]([C@H:59]([CH2:61][CH3:62])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1
Reactant: On1nnc2ccccc21
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N[C@H](C(=O)N(C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)[C@@H](C)CC)C(N)c1ccc(-c2cncs2)cc1)C(C)C

Procedure:
Analogously to Example 7, 175 mg (0.92 mmol) of N-ethoxycarbonyl-(L)-valine, 332 mg (1.7 mmol) of EDC and 156 mg (1.15 mmol) of HOBT in 2.5 ml of DMF and 483 μl (3.47 mmol) of TEA are reacted with 0.578 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane (Example 11b) in 5.2 ml of DMF to form the title compound: m.p: 200°-203° C.; HPLC20-100 : tRet =14.6; FAB MS (M+H)+ =711.
Reaction SMILES: [N:1]1[C:9]([S:10][CH2:11][C:12]2[O:13][C:14](=[O:28])[C:15]3[C:20]([C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.BrCC1OC(=O)C2C(C=1C1C=CC=CC=1[F:47])=CC=CC=2.O.N1C(S)=C2C(NC=N2)=NC=1.C([O-])([O-])=O.[K+].[K+]>>[N:1]1[C:9]([S:10][CH2:11][C:12]2[O:13][C:14](=[O:28])[C:15]3[C:20]([C:21]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[F:47])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: O=c1oc(CSc2ncnc3[nH]cnc23)c(-c2ccccc2)c2ccccc12
Reactant: O=c1oc(CBr)c(-c2ccccc2F)c2ccccc12
Agent: O=C([O-])[O-]
Agent: Sc1ncnc2[nH]cnc12
Agent: [K+]
Solvent: O
Product: O=c1oc(CSc2ncnc3[nH]cnc23)c(-c2ccccc2F)c2ccccc12
Yield: 73.5 %

Procedure:
The title compound was made in a similar way as that of the compound of example 10, 3-(bromomethyl)-4-(2-fluorophenyl)-1H-isochromen-1-one (intermediate C2, 37 mg, 0.111 mmol), 9H-purine-6-thiol hydrate (18.90 mg, 0.111 mmol) and K2CO3 (15.35 mg, 0.111 mmol) to give the title compound (33 mg, 73.5%).
Reaction SMILES: [C:1](=[O:4])(O)[O-:2].[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.C1COCC1.[CH2:20](C(Cl)=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.O>[CH2:20]([O:2][C:1](=[O:4])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C([O-])O
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccc(CO)cc1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(CO)cc1)OCc1ccccc1
Reaction time: 1 h
Yield: 57.4 %

Procedure:
Sodium bicarbonate (1.0 g, 12.2 mmol) was added portion-wise to a stirred solution of (4-amino-phenyl)-methanol (0.5 g, 4.06 mmol) in a 1:1 mixture of THF:H2O (16 ml) and the mixture was stirred at room temperature for 5 minutes. After this time, benzyl carbonyl chloride (0.69 g, 4.06 mmol) was added dropwise, followed by a further portion of sodium bicarbonate (0.5 g, 6.1 mmol) and stirring was continued for 1 hour. The reaction mixture was then diluted with DCM (50 ml) and washed sequentially with HCl (1M solution, 10 ml) then NaOH (1M solution, 10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 50% EtOAc, 50% heptane) to give the title compound (0.6 g, 57% yield) as an off-white solid. δH (500 MHz, DMSO) 9.63 (s, 1 H) 7.01-7.39 (m, 9 H) 4.90-5.11 (m, 3 H) 4.30 (d, J=5.63 Hz, 2 H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:5].[H-].[Na+].[H][H].[CH2:18](Cl)[CH:19]=[CH2:20]>C1(C)C=CC=CC=1>[CH2:20]([N:6]([CH:4]([CH3:5])[CH:3]([O:2][CH3:1])[O:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:19]=[CH2:18]
Reactant: CCOC(=O)NC(C)C(OC)OC
Reactant: [H][H]
Reactant: C=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCN(C(=O)OCC)C(C)C(OC)OC
Temperature: 90 °C
Reaction time: 8 h

Procedure:
131 g (0.686 mol) of N-(1,1-dimethoxyprop-2-yl)-urethane are added dropwise to 25 g of sodium hydride (80% strength) in 700 ml of absolute toluene at 90° C. When the evolution of hydrogen has ended, 61.2 g (0.8 mol) of allyl chloride are added dropwise at 90° C. and the mixture is stirred overnight at 90° C. The sodium chloride which has precipitated out is dissolved with water, the organic phase is separated off, dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2(OC)[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C:10]([CH2:19][OH:20])([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.CC1CCCO1.C1(C)C(S(O)(=O)=O)=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:9][C@@:10]([CH2:19][OH:20])([CH2:17][O:18]2)[C@@H:11]([OH:16])[C@H:12]([OH:15])[C@H:13]3[OH:14])=[CH:4][C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)OC(CO)(CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Solvent: CC1CCCO1
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of (2S,3R,4S,5S)-2-[4-Chloro-3-(4-hydroxy-benzyl)-phenyl]-6,6-bis-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol (580 mg, 1.32 mmol) in a mixture of dichloromethane (5 mL) of and 2-methyl-tetrahydrofuran (5 mL) was added Silicycle® Si-Tosic acid derivatized silica gel (40-63 micrometer, 0.68 mmol/g) Silicagel bound toluenesulfonic acid (1 g) and the reaction mixture was allowed to stir at room temperature overnight (˜16 hours). The mixture was filtered through a plug of Celite® and the plug rinsed with dichloromethane:2-methyl-tetrahydrofuran (40 mL; 1:1 volume). The crude material was purified by preparative HPLC on a Phenomenex Gemini NX 150×21.2 5 mm column eluting with a flow rate of 28 mL/minute; mobile phases A: water with 1% ammonium hydroxide modifier and B: methanol with 1% ammonium hydroxide modifier. The product was eluted using a gradient of 5% methanol with 1% ammonium hydroxide modifier for 1.5 minutes and increased in a linear gradient to 100% methanol with 1% ammonium hydroxide modifier over 8.5 minutes to give the product (375 mg; 69.7% yield, retention time=9.8 minute). LCMS 407 (M−H+, negative mode). 1H NMR (500 MHz, METHANOL-d4) delta ppm 3.56 (d, J=7.8 Hz, 1H), 3.61 (d, J=7.3 Hz, 1H), 3.66 (t, J=8.2 Hz, 1H), 3.69 (d, J=12.4 Hz, 1H), 3.79 (d, J=8.3 Hz, 1H), 3.85 (d, J=12.4 Hz, 1H), 4.01 (s, 2H), 4.16 (d, J=7.3 Hz, 1H), 6.69 (d, J=8.3 Hz, 2H), 7.02 (d, J=8.3 Hz, 2H), 7.34-7.37 (m, 1H), 7.37-7.41 (m, 1H), 7.45 (d, J=1.5 Hz, 1H).
Reaction SMILES: [C:1](=[O:22])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[CH2:32]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:32]([N:39]1[CH2:44][CH2:43][N:42]([C:1]([O:2][CH2:3][CH2:4][N:5]2[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]2)=[O:22])[CH2:41][CH2:40]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCOC(=O)N2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.8 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (Intermediate 4; 567 mg, 1.8 mmol) was dissolved in DMF (15 mL). DIPEA (0.52 mL, 3.0 mmol) and 4-benzyl-piperazine (0.296 mL, 1.7 mmol) were added. The reaction mixture was stirred at room temperature for 24 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (40 mL) and washed with 1 M aq Na2CO3 solution (6×50 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by reverse phase chromatography (gradient eluting with MeOH in water, 0-100%) to give 2-(4-methylpiperazin-1-yl)ethyl 4-benzylpiperazine-1-carboxylate (352 mg, 60% yield) as a colourless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:29][CH3:30])[CH2:11][S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].[I-:31].[Na+]>C(C(C)=O)C>[CH2:13]([S:12][CH2:11][CH:10]([O:29][CH3:30])[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:31])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: [I-]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Yield: 86.6 %

Procedure:
To a solution of 1.03 g (2.12 mM) of 3-(3-chloropropylsulfonylamino)-1-hexadecylthio-2-methoxypropane IIIa2 in 20 ml of methyl ethyl ketone is added 636 mg (4.24 mM) of sodium iodide and the mixture is refluxed or 3 hours with stirring. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (4:1) mixture as an eluent to give 1.06 g (1.835 mM) of 1-hexadecylthio-3-(3-iodopropylsulfonylamino)-2-methoxypropane IIa2 as an oil in 87% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14](=[NH:18])OCC)[CH:11]=[CH:10][C:9]=1[C:19](=[O:28])[NH:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[NH3:32].CO>>[C:14]([C:12]1[CH:11]=[CH:10][C:9]([C:19]([NH:20][CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:28])=[C:8]([NH:7][CH2:6][CH2:5][C:4]2[CH:29]=[CH:30][CH:31]=[C:2]([F:1])[CH:3]=2)[N:13]=1)(=[NH:32])[NH2:18]
Reactant: CCOC(=N)c1ccc(C(=O)NCc2cccnc2)c(NCCc2cccc(F)c2)n1
Reactant: N
Solvent: CO
Product: N=C(N)c1ccc(C(=O)NCc2cccnc2)c(NCCc2cccc(F)c2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of the ethyl 6-(3-fluorophenethylamino)-5-(pyridin-3-ylmethylcarbamoyl)picolinimidate and NH3/MeOH (7N, 0.76 mL) was stirred at 50° C. for 1 hour. The reaction mixture was concentrated to dryness to give 6-carbamimidoyl-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide. LC/MS (M+H+) m/z 394.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]([O:20]CC)=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.CO.[OH-].[Na+].Cl>O.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]([OH:20])=[O:19])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12
Temperature: 70 °C
Yield: 79.8 %

Procedure:
Ethyl 6-bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxylate (394 mg, 1.09 mmol) was dissolved into MeOH (10 mL) and THF (10 mL) and then 1M aqueous NaOH (7.5 mL, 7.50 mmol) was added and the reaction was heated at 70° C. for 1 h. The reaction was treated with aqueous 1M HCl (8 mL) (white prec. formed), cooled to rt, diluted with water (30 ml) and filtered to collect the precipitate (rinsed with water). The solid was dried overnight under vacuum to yield 6-bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxylic acid (290 mg, 0.87 mmol, 80% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 13.40 (br s, 1H), 9.53 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.78 (d, J=9.5 Hz, 1H), 7.73 (dd, J=9.5, 1.5 Hz, 1H), 7.30 (d, J=8.9 Hz, 1H), 7.28 (d, J=8.9 Hz, 1H). LC-MS retention time 0.94 min; m/z 334, 336 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% TFA and solvent B was 10% 2O/90% acetonitrile/0.1% TFA. MS data was determined using a Micromass Platform for LC in electrospray mode.