Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH:8]1[O:13][CH:5]2[CH:6]=[CH:7]1.C1C[O:17][CH2:16]C1>CO>[F:12][C:11]1[CH:10]=[C:9]2[C:4](=[CH:3][C:2]=1[F:1])[C@H:5]([OH:13])[C@@H:6]([O:17][CH3:16])[CH:7]=[CH:8]2
Reactant: C1CCOC1
Reactant: Fc1cc2c(cc1F)C1C=CC2O1
Solvent: CO
Product: CO[C@H]1C=Cc2cc(F)c(F)cc2[C@@H]1O
Yield: 88 %

Procedure:
To a flame dried round bottom flask, [Rh(COD)Cl]2 (2.5 mg, 0.005 mmol), (S)-(R)-PPF-PtBu2 (5.4 mg, 0.010 mmol) and 24 (72 mg, 0.40 mmol) were added followed by addition of THF (1.0 mL) and methanol (1.0 mL). The mixture was heated to reflux for 1 hour. The solvents were then removed in vacuo. The resulting solid was purified by flash chromatography (20% ethyl acetate in hexanes) to give 27 as a white crystalline solid (74.9 mg, 88%). The ee was determined to be 96.4% using HPLC analysis on a CHIRALCEL OD column, λ=486 nm. Retention times in 4% isopropanol in hexanes were 8.9 min and 10.1 min (major). Rf=0.27 on silica gel (30% ethyl acetate:hexanes); mp 129-131° (Et2O); [α]25D=+134.4° (c=9.3, CHCl3); IR (KBr, cm−1) 3269 (br), 2937 (w), 1597 (m),1503 (s), 1306 (s), 1103 (s), 893 (s); 1H NMR (400 MHz, CDCl3) δ 7.40 (1H, ddd, JH−F=10.8, 7.8 Hz, JH−H=0.6 Hz), 6.85 (1H, dd, JH−F=10.9, 7.8 Hz), 6.31 (1H, dd, J=10.0, 2.0 Hz), 6.05 (1H, dd. J=10.0, 2.0 Hz), 4.79 (1H, d, J=1.0 Hz), 4.05 (1H, ddd, J=11.0, 2.0, 2.0 Hz), 3.49 (3H, s), 2.94 (1H, d, J=2.2 Hz); 13C NMR (400 MHz, CDCl3) δ 151.0 (d, JH−F=12.5 Hz), 148.5 (dd, JH−F=12.5, 2.9 Hz), 133.2 (dd, JH−F=5.2, 3.6 Hz), 128.9 (dd, JH−F=6.6, 4.4 Hz), 128.0 (d, JH−F=2.2 Hz), 126.5 (dd, JH−F=2.2, 1.5 Hz), 115.1 (d, JH−F=18.3 Hz), 114.8 (d, JH−F=19.8 Hz), 82.3, 72.0, 57.0. HRMS calcd for Cl H10O2F2 (M+): 212.0649. Found: 212.0658.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH3:7][N:8]([CH3:13])[S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>ClCCl>[CH3:7][N:8]([CH3:13])[S:9]([N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])(=[O:11])=[O:10]
Reactant: Cc1ncc[nH]1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nccn1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of 2-methyl-1H-imidazole (10 g, 121.8 mmol) in dichloromethane (100 mL) was added N,N-dimethylsulfamoyl chloride (14.4 mL, 133.7 mmol) and triethylamine (34 mL, 244.1 mmol). The reaction mixture was stirred overnight at room temperature, then quenched with 10 mL of water and extracted with 1×50 mL of DCM. The organic layer was washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) as the eluent to furnish 20 g (87%) of the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[OH:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:31]2[CH:32]=[N:27][CH:28]=[N:29][CH:30]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1

Procedure:
5-Bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 151.1, 59 mg, 0.136 mmol), pyrimidin-5-ylboronic acid (33.7 mg, 0.272 mmol), Pd(PPh3)2Cl2 (9.54 mg, 0.014 mmol) and Na2CO3 (57.6 mg, 0.544 mmol) were added to a MW vial and treated with a mixture of DME (576 μL), water (165 μL) and EtOH (82 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 min, diluted with DME (3 mL) and treated with Si-Thiol (Silicycle, 1.44 mmol/g, 56.6 mg, 0.082 mmol). The RM was centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column DEAP, from 10% to 15% in 10 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=0.92 min, m/z=434.3 [M+H]+, m/z=432.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.71 (s, 3H) 3.44-3.52 (m, 2H) 3.53-3.60 (m, 2H) 4.68 (t, J=5.14 Hz, 1H) 7.36 (d, J=8.41 Hz, 2H) 7.82-7.90 (m, 2H) 8.15 (d, J=2.38 Hz, 1H) 8.77 (d, J=2.38 Hz, 1H) 8.97 (s, 2H) 9.19 (s, 1H) 10.23 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([S:29]([C:32]5[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=5)(=[O:31])=[O:30])[CH2:24]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:5]=[CH:6][CH:7]=1.[C:39]([O:43][C:44]([NH:46][CH2:47][C:48](O)=[O:49])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCN(C(C)C)C(C)C.[Cl-].ClC1N(C)C=C[N+]=1C>C(Cl)Cl>[C:39]([O:43][C:44](=[O:45])[NH:46][CH2:47][C:48]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([S:29]([C:32]5[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=5)(=[O:31])=[O:30])[CH2:24]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:3]=1)=[O:49])([CH3:42])([CH3:40])[CH3:41]
Reactant: Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reaction time: 1.5 h
Yield: 55.5 %

Procedure:
The 4-[6-(3-aminophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-chlorophenyl)-sulfonyl]piperidin-3-yl}pyrimidin-2-amine (0.1 g, 0.177 mmol) and N-(tert-butoxycarbonyl)glycine (34 mg, 0.194 mmol) were dissolved in DCM (5 ml) and treated with Hunig's base (92 uL, 0.53 mmol) and 2-chloro-1,3-dimethyl-1H-imidazol-3-ium chloride (33 mg, 0.194 mmol). The mixture was kept at room temperature for 90 minutes then was diluted with DCM (10 ml). The organic phase was washed with water (2×10 ml) and with an aqueous sodium chloride solution (10 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo, giving a yellow oil. The product was purified by flash chromatography (gradient 70%-100% EtOAc/hexanes), affording the title compound as a pale yellow solid (71 mg). 400 MHz 1H NMR (DMSO-d6) δ: 9.86 (s, 1H), 8.73 (br. s, 1H), 8.11 (d, J=5.5 Hz, 1H), 7.84 (s, 1H), 7.79-7.75 (m, 2H), 7.70-7.65 (m, 3H), 7.45-7.37 (m, 2H), 7.26 (d, J=7.4 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.82 (br. s, 1H), 6.42 (d, J=6.9 Hz, 1H), 4.00-3.90 (m, 1H), 3.78-3.70 (m, 3H), 3.52-3.44 (m, 1H), 3.18 (s, 2H), 2.34 (t, J=10.2 Hz, 1H), 1.94-1.81 (m, 2H), 1.65-1.52 (m, 1H), 1.39 (s, 9H). LCMS: 723 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([CH:19]2[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:24].OO.[OH-].[Na+]>CCO.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[O:24][C@H:16]2[C:17]([CH:19]2[CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(/C=C/c1ccc(OCc2ccccc2)cc1)C1CC1
Reactant: CC(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C1CC1)[C@@H]1O[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
(2E)-3-[4-(Benzyloxy)phenyl]-1-cyclopropyl-2-propen-1-one (6.25 g) was suspended in EtOH (67.5 ml), acetone (22.5 ml) To this mixture was added hydrogen peroxide 30% aqueous solution (4.5 ml), and 3M NaOH (4.5 ml), and the mixture was stirred at ambient temperature for l day. The mixture was diluted with H2O. White precipitates were collected and washed with H2O, and air dried to give {(2R,3S)-3-[4-(benzyloxy)phenyl]-2-oxiranyl}(cyclopropyl)methanone (6.27 g).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:3][CH2:4][OH:5].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[S:21]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:14])[CH2:10][CH:11]([CH3:13])[CH3:12])([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: CC(=CCCC(C)CCO)CC(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=CCCC(C)CCOS(=O)(=O)c1ccc(C)cc1)CC(C)C
Temperature: 0 °C

Procedure:
79.5 g. of 3,7,9-trimethyl-6-decen-1-ol and 75 ml. of pyridine are treated portionwise with 76 g. of toluene-4-sulphonic acid chloride while cooling with ice and stirring. The thus-obtained thick, cream-colored mass is then stirred for a further 5 hours at 0°-5° C. For the working-up, the mixture is poured on to 420 ml. of ice-water and 140 ml. of concentrated aqueous hydrochloric acid and extracted twice with 300 ml. of ether each time. The extracts are washed twice with water, then with semisaturated aqueous sodium chloride solution and finally with saturated sodium chloride solution dried over sodium sulphate/potassium carbonate and evaporated. There is obtained 1-tosyloxy-3,7,9-trimethyl-6-decene.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11]Br)=[O:4].[CH:26]12[NH:33][C:30]([C:34]([OH:36])=[O:35])([CH2:31][CH2:32]1)[CH2:29][O:28][CH2:27]2.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@H:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:10]([CH2:11][N:33]2[C@@:30]3([C:34]([OH:36])=[O:35])[CH2:31][CH2:32][C@@H:26]2[CH2:27][O:28][CH2:29]3)[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7]1
Reactant: O=C(O)C12CCC(COC1)N2
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1=C(CN2[C@@H]3CC[C@@]2(C(=O)O)COC3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of methyl (4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (compound C, 61 mg, 0.138 mmol), 3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid 81a (20 mg, 0.127 mmol) and DIPEA (0.07 mL, 0.4 mmol) in DCM (5 mL) was stirred at 25° C. for 16 h. Then the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford a pair of diastereomers, Example 81 and Example 82.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:5][N:4]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>C(Cl)Cl>[Si:18]([O:11][CH2:10][C@@H:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1)[OH:12])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ncc([C@@H](O)CO)cn1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: COc1ncc([C@@H](O)CO[Si](C)(C)C(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-1-(2-methoxypyrimidin-5-yl)ethane-1,2-diol (3.46 g, 20.3 mmol) and imidazole (3.08 g, 44.7 mmol) was dissolved in methylene chloride (40 mL). The mixture was cooled to 0° C. and tert-butyldimethylsilyl chloride (3.48 g, 22.4 mmol) dissolved in methylene chloride (40 mL) was added. The reaction was stirred for 30 minutes at 0° C. and then reacted at room temperature overnight. The mixture was treated with water (200 mL) and extracted with methylene chloride (2×200 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:10][C@@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)(C)(C)C.CCOC(C)=O.C1CCCCC1.[Cl:31]CCl>>[ClH:31].[F:17][C:14]1[CH:13]=[CH:12][C:11]([C@H:9]2[CH2:10][C@H:8]2[NH2:7])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H]1c1ccc(F)cc1
Reactant: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Cl
Product: N[C@@H]1C[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
cis-2-(4-Fluoro-phenyl)-cyclopropyl-carbamic acid tert-butyl ester (0.239 g, 0.951 mmol) was dissolved in dichloromethane (5 ml). Under argon HCl (4 M in dioxan, 2.38 ml, 9.5 mmol) was added and the clear solution stirred at room temperature. After 3 hours a precipitate had formed and the reaction was complete according to tlc (30% EtOAc/cyclohexane) and LC/MS. The solvent was evaporated and the residue stirred with tBuOMe. The solid was filtered off and washed twice with tBuOMe and dried to yield 155 mg (87%) of the product as a white solid.
Reaction SMILES: CS([Cl:5])(=O)=O.C(N1CCNCC1)=O.C([N:16]1[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]1)=O.Cl>C(N(CC)CC)C.C(Cl)Cl>[ClH:5].[CH3:25][S:22]([N:19]1[CH2:20][CH2:21][NH:16][CH2:17][CH2:18]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)N1CCN(C=O)CC1
Agent: Cl
Agent: O=CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (3.65 ml) was added to a methylene chloride (50 ml) solution containing N-formylpiperazine (5.08 g) and triethylamine (6.85 ml) under ice-cooling, and the mixture was stirred at room temperature for 18 hours to undergo reaction, thereby obtaining 1-formyl-4-methanesulfonylpiperazine. This compound was acid-treated with hydrochloric acid to obtain 1-methanesulfonylpiperazine.hydrochloride. Also, 1-(phenylsulfonyl)piperazine.hydrochloride was obtained in the same manner as mentioned above by using the corresponding starting material.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:12]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCOCC2)nc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 70.6 %

Procedure:
A mixture of methyl 6-chloronicotinate (1.02 g, 5.93 mmol), morpholine (0.57 ml, 6.52 mmol), potassium carbonate (1.06 g, 7.71 mmol) and DMF (20 ml) was stirred at 100° C. for 6 hrs. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and concentrated under reduced pressure. The obtained solid was collected by filtration and washed with diisopropyl ether to give the title compound (0.93 g, 71%) as a colorless powder.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[CH:29](=[NH:33])OCC.[OH-].[Na+]>O1CCOCC1>[CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][N:19]1[CH:29]=[NH:33])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCOC=N
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(C=N)C1
Reaction time: 0.5 h
Yield: 5.3 %

Procedure:
A stirred suspension of 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (153 mg, 0.34 mmol, 1 equiv) and ethyl formimidate (Aldrich) (44 mg, 0.40 mmol, 1.2 equiv.) in dioxane (1 mL) was treated with 1M aqueous NaOH (0.74 mL, 0.74 mmol, 2.2 equiv). After 1 h additional ethyl formimidate (44 mg, 0.40 mmol, 1.2 equiv) was added to the reaction mixture, and stirring was continued for 30 min. The reaction mixture was frozen and lyophilized. The lyophilized powder was purified by column chromatography to furnish the title compound (8 mg): TLC Rf=0.48 CHCl3/MeOH/32% aqueous AcOH (5:3:1); MS (ESPOS): 447.7 [M+H]+, 469.7 [M+Na]+; MS (ESNEG): 481.6 [M−H+HCl]−.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[S:5][C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:1][C:2]1[N:3]=[C:4]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)[S:5][C:6]=1[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(N)c(C(=O)c4cccc(F)c4)s3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(Nc2ccc(N3CCNCC3)cc2)sc1C(=O)c1cccc(F)c1
Reaction time: 8 h
Yield: 100.6 %

Procedure:
A mixture of 4-[4-[[4-amino-5-(3-fluorobenzoyl)-2-thiazolyl]amino]phenyl]1-piperazinec acid, 1,1-dimethylethyl ester (75 mg, 0.15 mmol) (from Step A above) and a solution of TFA/CH2Cl2 (1:1; 1.5 mL) was gently shaken for 1.5 h. The solution was evaporated in vacuo. To the residue was added resin-bound N,N-diisopropylethylamine (2.5 g, loading capacity: 3.8 mmol/g from Argonaut, Inc.) and CH2Cl2 (15 mL). After shaking overnight, the mixture was filtered and washed successively with CH3OH and CH2Cl2. The solvent was evaporated in vacuo and the residue was triturated by diethyl ether/hexanes (1/9) to afford [4-amino-2-[[4-(1-piperazinyl)phenyl]amino]-5-thiazolyl](3-fluorophenyl)methanone (60 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1>C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[Br:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C2CCC(=O)NC2)cn1
Solvent: CC#N
Product: Nc1ncc(C2CCC(=O)NC2)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(6-aminopyridin-3-yl)piperidin-2-one (132 mg, 0.690 mmol) in Acetonitrile (8.00 mL) was added NBS (98 mg, 0.552 mmol) at 0° C. The reaction mixture was stirred for 30 min upon warming-up to room temperature. LCMS 0.28 min, MH+270/272; 0.7 min, MH+400.1/402.1 (SEM protected one). After quenched with Na2S2O3 solution, the reaction mixture was extracted with EtOAc, which was washed with NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4, filtered off, concentrated in vacuo. The crude 5-(6-amino-5-bromopyridin-3-yl)piperidin-2-one was used for the next step.
Reaction SMILES: [C:1]([OH:24])(=O)[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].CCN=C=[N:29][CH2:30][CH2:31][CH2:32]N(C)C.C1C=CC2N([OH:45])N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[OH:45][CH2:32][CH2:31][CH2:30][NH:29][C:1](=[O:24])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (3.3 g, 10 mmol) in 50 mL of anhydrous CH2Cl2 were added EDCI (2.2 g, 11.0 mmol), HOBt (1.5 g, 11.0 mmol), and Et3N at 0° C. The reaction mixture was allowed to warm to room temperature, and stirred overnight. The reaction mixture was diluted with 50 mL of CH2Cl2 and washed successively with water (3×20 mL), brine (30 mL). The resulting organic layer was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography (gradient elution from 2:1 pentane/EtOAc to 1:2 pentane/EtOAc) to afford 3.0 g of (4Z,7Z,10Z,13Z,16Z,19Z)—N-(3-hydroxypropyl)docosa-4,7,10,13,16,19-hexaenamide (78% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N([CH2:29][CH3:30])CC)C.C([ClH][C:35](=[O:44])[CH:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37])(=O)C.C([O-])(O)=[O:46].[Na+]>C(Cl)Cl>[C:29]([O:37][CH:36]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:35]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)=[O:44])(=[O:46])[CH3:30]
Reactant: CCN(CC)CC
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC(C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.30 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is added 0.15 g of triethylamine followed by 0.27 g of O-acetylmandelic acid chloride. The mixture is stirred at room temperature for 1 hour and then diluted with 50% NaHCO3. The methylene chloride is evaporated and the residue is extracted with ethyl acetate. The separated organic layer is washed with saturated NaHCO3 and brine and then dried with Na2SO4 followed by filtering through a pad of hydrous magnesium silicate. The filtrate is evaporated to a residue which is stirred with ether-hexane to give 0.54 g of beige solid. MS(CI): 480(M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2[CH:26]=[CH:27][CH:28]=[N:29][C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1.CCN(CC)CC>C(Cl)Cl>[O:12]=[C:10]([N:29]1[CH2:28][CH2:27][CH2:26][CH2:24]1)[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH3:14]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
To a mixture of (S)-2-(tert-butoxycarbonylamino)butanoic acid (1.4 g, 6.89 mmol), HATU (3.14 g, 8.27 mmol), and pyrrolidine (1.216 mL, 13.78 mmol) in DCM (50 mL) was added Et3N (1.920 mL, 13.78 mmol). The reaction mixture was stirred at room temperature for 5 h and then washed with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4 and concentrated. Purification by silica column chromatography (MeOH/DCM, 0-10%) afforded the title compound as a light yellow oil (1.75 g, 99%). 1H NMR (500 MHz, CDCl3) δ 0.94 (t, J=7.57 Hz, 3 H) 1.34-1.48 (m, 9 H),1.49-1.68 (m, 1 H) 1.68-1.81 (m, 1 H) 1.81-1.92 (m, 2 H) 1.92-2.03 (m, 2 H) 3.34-3.47 (m, 2 H) 3.52 (dt, J=12.08, 7.14 Hz, 1 H) 3.65 (dt, J=10.13, 6.65 Hz, 1 H) 4.30-4.42 (m, 1 H) 5.35 (d, J=8.30 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]>C(O)C>[ClH:13].[N+:20]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6])([O-:22])=[O:21]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCO
Product: Cl
Product: O=C(O)c1cccc(Nc2ccncc2[N+](=O)[O-])c1
Yield: 70.5 %

Procedure:
A solution of ethyl 3-aminobenzoate (3.3 g, 20 mmol) and 4-chloro-3-nitropyridine (3.17 g, 20 mmol) in ethanol (150 ml) was stirred at room temperature for 16 hours and then cooled in an ice-bath. The resulting precipitate was collected, washed with ice-cold ethanol and dried to give ethyl (3-(3-nitro-4-pyridylamino)benzoate hydrochloride (4.17 g) as a yellow crystalline solid, m.p. 201°-204° C. Found: C,5.2; H,4.4; N,12.9. C14H13N3O4. HCl requires C,51.9; H,4.3; N,13.0%. The mother liquors were evaporated and the residue recrystallised from ethanol to give a further 1.2 g of product.