Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:46])[CH2:19][CH:20]1[CH2:25][NH:24][C@H:23]([C:26]([N:28]2[CH2:32][CH2:31][CH:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:29]2)=[O:27])[C@@H:22]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:21]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:46])[CH2:19][CH:20]1[CH2:25][NH:24][C@H:23]([C:26]([N:28]2[CH2:32][CH2:31][CH:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:29]2)=[O:27])[C@@H:22]([C:39]([OH:41])=[O:40])[CH2:21]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CC(CC(=O)NCCCCCNC(=O)OCc2ccccc2)CN[C@@H]1C(=O)N1CCC(c2ccccc2)C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CC1CN[C@H](C(=O)N2CCC(c3ccccc3)C2)[C@@H](C(=O)O)C1)NCCCCCNC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of tert-butyl (2S,3S)-5-{2-[(5-{[(benzyloxy)carbonyl]amino}pentyl)amino]-2-oxoethyl}-2-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidine-3-carboxylate (40 mg, 0.063 mmol) in methylene chloride (2 mL) was added a drop of water and trifluoroacetic acid (4 mL). After stirring the reaction mixture overnight, the volatiles were removed in-vacuo and the residue was azeotropically washed with benzene (2×3 mL) and heptane (2×3 mL). The crude product was dried under high vacuum and used directly in the following coupling reaction without purification. MS (ESI): 579 (M+H).
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[F:44][C:45]1[C:53]([N:54]2[CH2:58][CH2:57][CH2:56][C:55]2=[O:59])=[CH:52][C:51]([C:60]([F:63])([F:62])[F:61])=[CH:50][C:46]=1[C:47]([OH:49])=O.[CH:64]12[CH2:70][CH:67]([CH2:68][CH2:69]1)[CH2:66][CH:65]2[NH:71][C:72](=[O:87])[C@H:73]([CH3:86])[CH2:74][C@H:75]([OH:85])[C@@H:76]([NH2:84])[CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>>[CH2:77]([C@H:76]([NH:84][C:47](=[O:49])[C:46]1[CH:50]=[C:51]([C:60]([F:63])([F:62])[F:61])[CH:52]=[C:53]([N:54]2[CH2:58][CH2:57][CH2:56][C:55]2=[O:59])[C:45]=1[F:44])[C@@H:75]([OH:85])[CH2:74][C@H:73]([C:72](=[O:87])[NH:71][CH:65]1[CH2:66][CH:67]2[CH2:70][CH:64]1[CH2:69][CH2:68]2)[CH3:86])[C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(N2CCCC2=O)c1F
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(C(F)(F)F)cc(N2CCCC2=O)c1F)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6 from 2-fluoro-3-(2-oxopyrrolidin-1-yl)-5-trifluoromethyl benzoic acid (D25) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: C(O)C.[BH4-].[Na+].[F:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][N:23]([CH:25]([CH:31]=[O:32])[C:26](OCC)=[O:27])[CH:24]=2)[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:37])([C:33]([F:36])([F:35])[F:34])[C:9]=2[CH:8]=1>O1CCCC1>[F:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][N:23]([CH:25]([CH2:31][OH:32])[CH2:26][OH:27])[CH:24]=2)[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:37])([C:33]([F:36])([F:35])[F:34])[C:9]=2[CH:8]=1
Reactant: CCOC(=O)C(C=O)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCC(CO)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 17 h
Yield: 61.4 %

Procedure:
To a mixture of ethanol (80 ml) and sodium borohydride (16.2 g), a solution of an optically active form (13.2 g) of ethyl 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-oxo-propionate in tetrahydrofuran (80 ml) was added dropwise over 25 min. At this time, the temperature of the reaction mixture was controlled with an ice-bath not to exceed 30° C. The ice-bath was changed to a water-bath, and the mixture was stirred for 17 hr. Then, the water-bath was removed and the mixture was further stirred for 4 hr. The reaction mixture was ice-cooled, 2N hydrochloric acid was added and the mixture was stirred. To this mixture were added ethyl acetate and water, and the mixture was partitioned in a separatory funnel. The aqueous layer was further extracted with ethyl acetate, and the extract was combined with the organic layer obtained earlier. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=30/1 to 15/1) to give the title compound (7.38 g, 84%).
Reaction SMILES: N([Si](C)(C)C)=[N+]=[N-].[CH3:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=1.[I:16]I>N1C=CC=CC=1.ClCCl.C(OCC)(=O)C>[I:16][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH2:14][C:9]=1[CH3:8]
Reactant: CC1=CC(=O)CCC1
Reactant: II
Agent: C[Si](C)(C)N=[N+]=[N-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC1=C(I)C(=O)CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Freshly distilled azidotrimethylsilane (2.65 mL, 20 mmol) was added to a stirred solution of 3-methyl-2-cyclohexen-1-one (Compound 1, 1.13 mL, 10 mmol) and dichloromethane (15 mL) at 0° C. under argon. The solution was stirred for 2 hours at 0° C. before adding a solution of iodine (5.08 g, 20 mmol) in 15 mL of pyridine and 15 mL of dichloromethane. The resulting solution was stirred for 4 hours at room temperature, diluted with ethyl acetate, and was washed successively with 20% aqueous Na2S2O3, 10% aqueous HCl, water, and brine. The solvents were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (7:1, hexanes: ethyl acetate) to give the title compound as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH3:34])[CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH3:26])[C:18]2=[C:27]3[C:32](=[N:33][C:17]=12)[CH:31]=[CH:30][CH:29]=[CH:28]3)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:34][N:11]([CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH3:26])[C:18]2=[C:27]3[C:32](=[N:33][C:17]=12)[CH:31]=[CH:30][CH:29]=[CH:28]3)[CH2:10][CH2:9][CH2:8][NH2:7]
Reactant: CN(CCCNC(=O)OC(C)(C)C)CCCNc1c2nc3ccccc3c-2n(C)c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCCN)CCCNc1c2nc3ccccc3c-2n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
To a solution of [3-[methyl-[3-(5-methyl-5H-indolo[3,2-b]quinolin-11-ylamino)-propyl]amino]propyl)-carbamic acid tert-butyl ester (49 mg, 0.1 mmol) in CH2Cl2 (10 ml), was added trifluoroacetic acid (12_l). This mixture was stirred at room temperature for 16 h, at which point the reaction was completed by TLC. All solvents were removed under reduced pressure to give N1-methyl-N1-[3-(5-methyl-5H-indolo[3,2-b]quinolin-11-ylamino)propyl]propane-1,3-diamine (38 mg, 92%) as an oil, which was used directly. 1H-NMR [MeOD,_, ppm]: 8.52 (d, J=8.5 Hz, 1H), 8.35-7.73 (m, 4H), 7.63-7.60 (m, 2H), 7.31 (m, 1H), 4.45 (s, 3H, NCH3), 3.60 (m, 2H, CH2NO), 3.02 (m, 2H, CH2N(CH3)), 2.92 (s, 3H, N(CH3)), 2.36 (m, 4H, 2CH2CN(CH3)), 2.14 (m, 2H, CH2N(CH3)), 1.90 (m, 2H, CH2CN(CH3)).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([OH:31])[CH:25]=[CH:26][CH:27]=2)[N:22]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH3:54][CH:55]([CH3:62])[CH2:56][CH2:57][CH:58](O)[CH2:59][CH3:60]>>[CH2:59]([CH:58]([O:31][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[N:22]=[C:21]([NH2:20])[CH:30]=[CH:29]2)[CH2:57][CH2:56][CH:55]([CH3:62])[CH3:54])[CH3:60]
Reactant: Nc1ccc2cccc(O)c2n1
Reactant: CCC(O)CCC(C)C
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCC(CCC(C)C)Oc1cccc2ccc(N)nc12
Reaction time: 0.17 h

Procedure:
A 7.5 mL conical microwave vessel (Personal Chemistry) equipped with a septum cap and a magnetic stirring bar was charged with PS-PPh3 resin (Aldrich Chemical Co., Inc, 140 mg, 4.40 equiv), 2-amino-8-hydroxyquinoline (15.0 mg, 0.0960 mmol) and DBAD (69 mg, 3.2 equiv) and purged by passing a stream of N2 for 45 seconds. Anhydr. THF (1.5 mL) was added and contents of the vessel were stirred for 10 min. Then, neat 6-methyl-3-heptanol (4 equiv) was added to the vessel and the resulting suspension was irradiated in Personal Chemistry Smith Synthesizer (150° C. for 330 s; 300 W). The suspension was then filtered, and the resin washed with THF (3×3.0 mL). The filtrate and washings were combined and evaporated in vacuo. The residue was then treated with 6.0 mL of 4 M HCl in dioxane at room temperature for 4 h. The resulting solution was evaporated in vacuo. The residue was dissolved in 1.5 mL of a 1:1 mixture of DMSO/MeOH and purified by preparative reverse-phase HPLC. 1H NMR (500 MHz, CDCl3) δ ppm 7.96 (d, 1H), 7.29 (t, 1H), 7.19 (m, 1H), 7.10 (d, 1H), 7.05 (br d, 1H), 4.37 (m, 1H), 1.91 (m, 2H), 1.78 (m, 2H), 1.55 (m, 1H), 1.35 (m, 1H), 1.24 (m, 1H), 0.98 (t, 3H), 0.87 (m, 6H); MS (DCI/NH3) m/z 273 [M+H]+.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.C1(CC([NH:16][C@@H:17]2[C:41](=[O:42])[N:19]3[C:20]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)=[O:30])=[C:21]([CH:24]4[CH2:28][CH2:27][CH2:26][O:25]4)[CH2:22][S:23][C@H:18]23)=O)C=CC=CC=1.CN1CCOCC1.CO>ClCCl.O>[NH2:16][C@@H:17]1[C:41](=[O:42])[N:19]2[C:20]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=[O:30])=[C:21]([C@@H:24]3[CH2:28][CH2:27][CH2:26][O:25]3)[CH2:22][S:23][C@H:18]12
Reactant: COc1ccc(COC(=O)C2=C(C3CCCO3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COC(=O)C2=C([C@@H]3CCCO3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 37.5 %

Procedure:
Phosphorus pentachloride (2.15 g, 10.32 mmol) in dichloromethane (108 ml) was added to 4-methoxybenzyl (6R,7R)-7-phenylacetamido-3-[(RS)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (3.40 g, 6.69 mmol) and N-methylmorpholine (1.50 ml, 13.64 mmol) in dichloromethane (30 ml) at -25° C. The reaction was stirred at -10±5° C. for 45 min., then methanol (14 ml) was added, and stirring continued for 45 min. at room temperature. Water (27 ml) was then added, and the mixture vigorously stirred for a further 1 h. The dichloromethane was evaporated in vacuo, the aqueous residue washed with diethyl ether, then adjusted to pH7 with ammonium hydroxide in the presence of ethyl acetate. The mixture was extracted with ethyl acetate (x2), dried and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 50, 70, 80% ethyl acetate in hexane yielding 4-methoxybenzyl (6R,7R)-7-amino-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (980 mg, 38%) as a yellow foam; νmax (CH2Cl2) 1777, 1721, 1613, 1516, 1152 cm-1 ; δH (CDCl3, 250 MHz) 1.53-1.71 (1 H, m), 1.84-2.02 (4 H, m, 2 exch.), 2.25-2.40 (1 H, m), 3.31 and 3.60 (2 H, ABq, J 18.5 Hz), 3.78-3.98 (2 H, m), 3.81 (3 H, s), 4.72 (1 H, d, J 5.0 Hz), 4.86-4.93 (2 H, m), 5.19 (2 H, s), 6.88 (2 H, d, J 8.6 Hz), 7.33 (2 H, d, J 8.6 Hz). [Mass spectrum: M+ (390)].
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.C(#N)C>O>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:13]2)=[CH:18][CH:17]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)Cc1ccccc1
Solvent: CC#N
Solvent: O
Product: O=C(Cc1ccccc1)Nc1ccc2ccc(Cl)nc2n1
Temperature: 4 °C
Yield: 63.1 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with phenylacetic acid (10.9 g), N,N'-carbonyldiimidazole (13 g) and 2-amino-7-chloro-1,8-naphthyridine (10.8 g). The product obtained by precipitation in water (13.5 g; m.p. 184° C.) is dissolved in boiling acetonitrile (210 cc). After cooling for 1 hour at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (10 cc) and dried at 45° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)phenylacetamide (11.3 g), m.p. 187° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[C:24]=1[CH:25]=O>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:25]([C:24]3[C:27]([O:31][CH3:32])=[CH:28][CH:29]=[CH:30][C:23]=3[O:22][CH3:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1cccc(OC)c1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1cccc(OC)c1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Br)cnc2[nH]1
Yield: 68.4 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 2,6-Dimethoxy-benzaldehyde (27 mg, 0.163 mmol) were reacted to produce 49 mg (68%) of the title compound. mp: 194-197° C., 1H NMR (300 MHz, DMSO-d6): 12.6 (s, 1H), 8.00 (s, 1H), 7.57 (s, 1H), 7.45 (t, J=8 Hz, 1H), 7.12 (s, 1H), 6.80 (d, J=8 Hz, 2H), 6.23 (br s, 1H), 6.17 (br s, 1H), 5.14 (t, J=8 Hz, 1H), 3.73 (s, 6H), 2.84 (s, 1H), 2.69 (s, 1H), 2.54 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 2.09 (s, 1H), 1.38 (d, J=8 Hz, 1H). MS: 484, 486 (M+H), HPLC: 2.33 min (G method)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.Cl[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23](C(C)=C)[C:22]1=[O:33].C(=O)(O)[O-].[Na+].N>O1CCCC1.CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:33])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: C=C(C)n1c(=O)n(CCCCCl)c2ccccc21
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2n1CCCCN1CCC(c2c[nH]c3ccccc23)CC1
Reaction time: 2 h

Procedure:
A mixture consisting of 3.0 gm of 4-(3-indolyl)-piperidine, 4.0 gm of 1-(4-chloro-butyl)-3-isopropenylbenzimidazolone, 1.3 gm of sodium bicarbonate, 30 ml of dimethyl-formamide and 30 ml of tetrahydrofuran was refluxed for 16 hours. Thereafter, the reaction mixture was poured into a mixture of ice and ammonia, the aqueous mixture was extracted with ethyl acetate, and the extract solution was washed with water, dried and evaporated to dryness in vacuo. The residue was dissolved in ether, etheric hydrogen chloride was added to the solution, and the precipitate formed thereby was collected by filtration, dried and dissolved in 100 ml of ethanol. The resulting solution was cooled, 16 ml of concentrated sulfuric acid were carefully added while stirring, and the mixture was allowed to stand at 20° C. for two hours, whereupon it was poured into a mixture of ice and ammonia. The precipitate formed thereby was collected by filtration and recrystallized from ethanol, yielding 3.2 gm (55% of theory) of the compound of the formula ##STR13## having a melting point of 196° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[C:5]([C@@H:10]([C@H:12]([C:14]([O:16]CC)=O)[OH:13])[OH:11])([O:7]CC)=O.O>CO>[CH2:1]([NH:4][C:5](=[O:7])[C@@H:10]([C@H:12]([C:14]([NH:4][CH2:1][CH2:2][CH3:3])=[O:16])[OH:13])[OH:11])[CH2:2][CH3:3]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: CCCN
Solvent: O
Solvent: CO
Product: CCCNC(=O)[C@H](O)[C@@H](O)C(=O)NCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
N,N′-Di-n-propyl L-tartaramide was prepared by the reaction of n-propyl amine with diethyl L-tartrate. Diethyl L-tartrate (20.027 g, 1.0 eq) and HPLC grade methanol (40 mL) were weighed into a 250 mL round-bottomed flask equipped with a teflon coated magnetic stir bar. n-Propyl amine (12.038 g, 2.0 eq) was slowly poured into the stirring diethyl L-tartrate solution. Some fuming and a color change from water-white to pale yellow were observed. Additional methanol (10 mL) was used to rinse all of the amine into the reaction flask. After stirring the solution for 30 min at ambient temperature, the product began to crystallize from solution. The reaction mixture was allowed to sit at ambient temperature for two hours. The flat, white crystals were filtered, washed with methanol (2×50 mL), washed with diethyl ether (2×30 mL), and dried under vacuum. The first crop of product was obtained in 35% yield (7.977 g, 34.34 mmole). Subsequently, a second crop of crystals (1.80 g, 7.75 mmole) was isolated from the mother liquor.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH2:34]([NH:37][C:38]([C@@H:40]1[CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41]1)=[O:39])[CH2:35][CH3:36]>O1CCCC1.C(Cl)Cl>[CH2:34]([NH:37][C:38]([C@@H:40]1[CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]1[C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][CH3:17])=[O:39])[CH2:35][CH3:36]
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCNC(=O)[C@@H]1Cc2ccccc2N1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCNC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@H](CC)NC(=O)OCc1ccccc1
Reaction time: 0.75 h

Procedure:
0.439 g (1.85 mmol) of N-benzyloxycarbonyl-2(S)-aminobutyric acid prepared as in Example 3 a) is dissolved, under nitrogen, in tetrahydrofuran (50 ml) and the solution is cooled in an ice/water bath. 0.213 g (1.85 mmol) of N-ethylmorpholine is added, followed by 0.253 g (1.85 mmol) of isobutyl chloroformate. After 45 minutes, 0.378 g (1.85 mmol) of the compound obtained in step b) is added and stirring is continued for 12 hours. The suspension is poured into CH2Cl2 (100 ml) and the mixture is washed with 10% citric acid (3×100 ml) and then with 5% NaHCO3 (3×100 ml). After drying and evaporation, a white solid is obtained which crystallizes from CCl4.
Reaction SMILES: [F:1][CH2:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.CO.C1C(=O)N(Br)C(=[O:16])C1>O>[F:1][CH2:2][S:3]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(SCF)cc1
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)CF)cc1
Yield: 87.7 %

Procedure:
(Fluoromethyl)(p-tolyl)sulfane (52.09 g, 320.06 mmol) was added to a mixture of methanol (250 mL) and water (50 mL). The resulting mixture was cooled to a temperature between 0° C. and 5°. NBS (68.36 g, 1.2 eq) was added in small portions, maintaining the same temperature range. The reaction mixture was stirred at the same temperature range until the reaction was complete. After that, the reaction mixture was quenched by the addition of Na2SO3 (10%, 150 mL). The pH of the reaction mixture was adjusted to a value between 7 and 8, with saturated NaHCO3 solution. The mixture was concentrated under vacuum at a temperature between 20° C. and 25° C. The residue was extracted with dichloromethane (200 mL, 150 mL). The combined organic layer was washed with water (2×300 ml) and concentrated to 1/3 of the volume. Heptane (50 mL) was added and then removed by distillation. The crude product was purified by flash chromatography (Ethyl Acetate/Hexane 30:70) to give 48.32 g (88%) of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[NH:11][C:10](=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1.[Br-].BrC1C(C2C=CC(Cl)=CC=2)=CC(=O)NC=1C>CO>[Br:23][C:9]1[C:10](=[O:15])[NH:11][C:12]([CH3:14])=[CH:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1[nH]c(=O)cc(-c2ccc(Cl)cc2)c1Br
Agent: [Br-]
Solvent: CO
Product: Cc1cc(-c2ccc(Cl)cc2)c(Br)c(=O)[nH]1
Temperature: 40 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A suspension of 4-(4-chlorophenyl)-6-methylpyridin-2(1H)-one (0.44 g, 2.0 mmol) in methanol (30 mL) was refluxed until a clear solution formed. The solution was allowed to cool to 40° C., then NBS (285 mg, 1.6 mmol) was added in small portions over 30 min. After completion of the addition, analysis by HPLC/MS indicated about 40% of the starting 4-(4-chlorophenyl)-6-methylpyridin-2(1H)-one remained. Additional NBS (142 mg, 0.8 mmol) was added in portions over 10 min. The reaction mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure. The residue was triturated with a mixture of water (50 mL) and EtOAc (50 mL), and filtered to obtain a solid product which contained mainly the regioisomeric bromide, 5-bromo-4-(4-chlorophenyl)-6-methylpyridin-2(1H)-one. The filtrate was extracted with EtOAc (30 mL×3). The combined extracts were washed with aqueous saturated NaCl solution, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified using a silica gel cartridge (80 g) eluted with a gradient of EtOAc (30-100%) in hexanes to afford 280 mg (47%) of the title product as a white solid. HPLC/MS: retention time=3.15 min, [M+H]+=298.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22]>ClCCl>[C:1]([O:5][C:6]([C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:20](=[O:23])[CH:21]=[CH2:22])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 100.3 %

Procedure:
To a stirred solution of 5.0 g (29.2 mmol) D-Proline tert-butyl ester and 4.5 ml (32.1 mmol) triethylamine in 180 ml dichloromethane at 0° C. was added dropwise 3.6 ml (43.8 mmol) acryloyl chloride and stirring continued for 48 h at room temperature. The reaction mixture was then washed sequentially with water, saturated ammonium chloride solution, once more with water and then with saturated brine, and the aqueous phases back-extracted with dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated in vacuo to afford 6.6 g (100%) of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:23])([F:22])[C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOC(C)=O>[F:22][C:11]([F:23])([C:8]1[N:6]2[N:7]=[C:2]([C:28]3[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2
Reactant: FC(F)(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cn1cc(-c2ccc3ncc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Temperature: 150 °C

Procedure:
A microwave tube was charged with 6-[(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-difluoro-methyl]-quinoline (Stage 6.1, 10 mg, 0.03 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (10 mg, 0.045 mmol), tetrakis-(triphenylphosphine)palladium (1.7 mg), 2M Na2CO3 (0.054 mL) and DME (1 mL). It was heated at 150° C. under microwave irradiation for 20 min. The RM was taken up with EtOAc (2 mL) and washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by HPLC to afford the title compound as a brown solid (tR 1.379 min (conditions 1), MH+=376.8, 1H-NMR in DMSO-d6: 9.00 (m, 1H); 8.65 (d, 1H); 8.52 (s, 1H); 8.30 (s, 1H); 8.21 (d, 1H); 8.14 (d, 1H); 7.99 (m, 2H); 7.87 (s, 1H); 7.66 (m, 2H); 3.86 (s, 3H)).