Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[C:11]([CH3:13])([CH3:12])[O:10][C:9](=[O:14])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:20](Cl)(=[O:29])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>O1CCCC1>[C:23]1(/[CH:22]=[CH:21]/[C:20]([N:8]2[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]([CH3:12])([CH3:13])[O:10][C:9]2=[O:14])=[O:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)OC(=O)N[C@@H]1c1ccccc1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)N(C(=O)/C=C/c2ccccc2)[C@@H]1c1ccccc1
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Reaction of the auxiliary (15) (0.300 g, 1.57 mmol) in solution in tetrahydrofuran (10 ml) at -78° C. with butyllithium (1.5M, 1.06 ml, 1.59 mmol) and cinnamoyl chloride (0.228 ml, 1.73 mmol) for 10 minutes and then at room temperature for 2 hours, with work-up and flash column chromatography using 20% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (26) as a solid (0.503 g, 99%) which was recrystallised from ethyl acetate/40-60 petroleum ether; mp 149° C.; νmax (CDCl3) 1682 and 1771 cm-1 ; [α]D26 (c 1 in CHCl3)=+26.0; (Found: C, 74.79; H, 5.94; N, 4.28. C20H19NO3 requires C, 74.75; H, 5.96; N, 4.36%); δH (CDCl3 ; 200 MHz) 1.04 (3H, s, C(CH3)2), 1.65 (3H, s, C(CH3)2), 5.24 (1H, s, CHPh), 7.20-7.64 (10H, m, ArCH), 7.80 (1H, d, J=15.8, CH=CHPh), 8.07 (1H, d, J=15.8, CH=CHPh); δC (125 MHz; CDCl3) 23.78 (CH3), 28.99 (CH3), 67.24 (CH), 82.47 (C), 117.17 (CH), 126.37 (CH), 128.48 (CH), 128.90 (CH), 130.70 (CH), 134.54 (C), 136.38 (C), 146.53 (CH), 153.33 (CO), 165.04 (CO); m/z (CI+, NH3) 322 (M+ +1)
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[C:12]12([CH2:19][O:20][C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[CH:24]=[O:25])[O:18][CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13]2.C(#N)C.[Li]>C1COCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C>[C:12]12([CH2:19][O:20][C:21]3[CH:22]=[C:23]([CH:24]([OH:25])[CH2:2][C:1]#[N:3])[CH:26]=[CH:27][CH:28]=3)[O:18][CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13]2
Reactant: O=Cc1cccc(OCC23CCCCC2O3)c1
Reactant: CC#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: N#CCC(O)c1cccc(OCC23CCCCC2O3)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a −78° C. solution of acetonitrile (240 uL, 4.6 mmol) in THF under argon was added a solution of LDA (2.2 mL of a 2M solution in heptane/THF/ethylbenzene, 4.4 mmol). The resulting mixture was stirred at −78° C. for 30 min. In a separate flask, a solution of 3-(7-oxabicyclo[4.1.0]heptan-1-ylmethoxy)benzaldehyde (0.90 g, 4.1 mmol) in THF was cooled to −78° C. under argon. The freshly made lithium acetonitrile solution described above was added dropwise. The reaction mixture was stirred at −78° C. for 30 min then allowed to warm to room temperature overnight. The mixture was quenched with the addition of brine followed by 1M HCl (4 mL). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (10 to 75% EtOAc-hexanes gradient) gave 3-(3-(7-oxabicyclo[4.1.0]heptan-1-ylmethoxy)phenyl)-3-hydroxypropane-nitrile as an oil. Yield (0.340 g, 32%): 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J=8.0 Hz, 1H), 6.88-6.91 (m, 3H), 5.01 (br s, 1H), 3.92-4.02 (m, 2H), 3.01 (d, J=2.0 Hz, 1H), 2.76 (d, J=6.4 Hz, 2H), 2.34 (br s, 1H), 1.84-2.05 (m, 4H), 1.42-1.56 (m, 2H), 1.24-1.40 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([N:31]2[CH2:35][CH2:34][C@@H:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:9]=2)=[CH:6][CH:7]=1.[CH3:44]B(O)O.C([O-])(=O)C.[K+].O>C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:44][C:2]1[C:3]([N:31]2[CH2:35][CH2:34][C@@H:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CB(O)O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(-c3nn(COCC[Si](C)(C)C)c4cnc(-c5cccnc5)cc34)ccc2Br)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1N1CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 150 °C
Yield: 39 %

Procedure:
A microwave reaction vial was charged with (R)-tert-butyl 1-(3-bromo-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate (124.5 mg, 0.1867 mmol), Methyl boronic acid (111.76 mg, 1.867 mmol), 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (15.2 mg, 0.01876 mmol), 1.00 M of Potassium acetate in Water (0.28 mL, 0.28 mmol), 1.00 M of Sodium carbonate in Water (0.28 mL, 0.28 mmol), and Acetonitrile (10 mL). The reaction mixture was heated under microwave at 150° C. for 5 minutes. The mixture was concentrated, and the residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford (R)-tert-butyl 1-(3-methyl-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate (43.8 mg, 39%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28](OC)=[O:29])=[CH:25][C:24]=4[CH:32]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:34][NH2:35]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([NH:35][CH3:34])=[O:29])=[CH:25][C:24]=4[CH:32]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(C(C)(C)C)c4)n3)ccc2o1
Agent: Cl
Product: CNC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(C(C)(C)C)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, N4-(3-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine and methylamine hydrochloride were reacted to give N4-(3-tert-butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofur-5-yl]-2,4-pyrimidinediamine. LCMS: ret. time: 23.05 min.; purity: 100%; MS (m/e): 434 (MH+); 1□□□ (DMSO-d6): δ 9.6 (1H, s), 9.57 (1H, s), 8.75 (1H, m), 8.25 (1H, s), 8.15 (1H, s), 7.93 (1H, d, J=8.5 Hz), 7.47 (3H, m), 7.44 (1H, s), 7.36 (1H, t, J=8.5 Hz), 7.25 (1H, d, J=8.5 Hz), 2.89 (3H, d, J=4.5 Hz), 1.33 (9H, s).
Reaction SMILES: CO.N1CC[CH2:6][CH2:5][CH2:4]1.[ClH:9].Cl.C[O:12][C:13]([C:15]1[CH:38]=[CH:37][C:18]([CH2:19][NH:20][C:21]([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[NH:25])=[NH:22])=[CH:17][CH:16]=1)=[O:14]>CC(C)=O>[ClH:9].[CH3:4][C:5]1([CH3:6])[N:22]=[C:21]([NH:20][CH2:19][C:18]2[CH:37]=[CH:38][C:15]([C:13]([OH:12])=[O:14])=[CH:16][CH:17]=2)[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N:25]1
Reactant: CCCCCCCCCCNC(=N)NC(=N)NCc1ccc(C(=O)OC)cc1
Reactant: C1CCNCC1
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Product: CCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(C(=O)O)cc2)N1

Procedure:
50 ml of methanol, 100 ml of acetone and 1.6 ml of piperidine were added to 5.0 g (10.8 mmol) of N1-(4-methoxycarbonylbenzyl)-N5-decyl-biguanide dihydrochloride. The mixture was refluxed for 24 hours, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution with a mixture of chloroform/methanol/acetic acid (8:0.7:0.7→8:1:1)). 4.0 g of the purified product was dissolved in 60 ml of ethanol, and to the solution were added 60 ml of water and 2.4 ml of 5N aqueous sodium hydroxide. The mixture was refluxed for 2 hours, and 5 ml of concentrated hydrochloric acid was added thereto. The mixture was concentrated under reduced pressure, and extracted with chloroform. The aqueous layer was separated, and the solvent was distilled off under reduced pressure. The residue was dried well under reduced pressure, heated and extracted with methanol. The extract was filtered, and cooled. The resulting precipitates were filtered, and the solvent of the filtrate was distilled off under reduced pressure. The residue was extracted with ethanol under heating, and filtered. The solvent of the filtrate was distilled off under reduced pressure, and ether was added to the residue to obtain 3.4 g of a white yellow solid.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:28][S:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]=O.C(=O)(O)[O-].[Na+]>CCOCC>[CH3:28][S:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]=[CH2:2]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CSc1ccccc1C=O
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOCC
Product: C=Cc1ccccc1SC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methyl triphenylphosphonium iodide (1.57 g, 3.88 mmol) was dissolved in 25 mL ether in a 50 mL round-bottomed flask under dry nitrogen. To the mixture was added in one portion at 0° C. potassium tert-butoxide (0.47 g, 4.19 mmol) and it was stirred for 10 min at room temperature. 2-(methylsulfanyl)benzenecarbaldehyde (2.77 mmol) was added in one portion at 0° C. and the reaction mixture was stirred until complete disappearance of the reactants (2 hr) at room temperature (followed by TLC). The mixture was added to 50 mL of saturated sodium bicarbonate solution, followed by extraction with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using petroleum ether 60-80 as eluent. Yield: 0.33 g, 79%, colorless oil. 1H NMR (200 MHz, CDCl3): δ 2.43 (s, 3H), 5.32 (dd, J1=10.9, J2=1.2, 1H), 5.67 (dd, J1=17.4, J2=1.2, 1H), 7.05-7.26 (m, 4H), 7.46 (d, 1H) ppm.
Reaction SMILES: OC1C=CC(CC(OCC)=O)=CC=1.C1C(C(CBr)=O)=CC=C(Cl)C=1.C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[O:46][C:45]([CH2:47][C:48]([O:50]CC)=[O:49])=[C:41]3[CH:42]=[CH:43][CH:44]=[C:40]3[CH:39]=2)=[CH:34][CH:33]=1.[OH-].[Na+]>O.C(OCC)C.C(O)C.C(COC)OC>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]2[O:46][C:45]([CH2:47][C:48]([OH:50])=[O:49])=[C:41]3[CH:42]=[CH:43][CH:44]=[C:40]3[CH:39]=2)=[CH:36][CH:37]=1
Reactant: CCOC(=O)Cc1oc(-c2ccc(Cl)cc2)cc2cccc1-2
Agent: CCOC(=O)Cc1ccc(O)cc1
Agent: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: COCCOC
Solvent: CCO
Product: O=C(O)Cc1oc(-c2ccc(Cl)cc2)cc2cccc1-2

Procedure:
In 200 ml. of glyme are placed 28.6 g. (0.159 mole) of ethyl (4-hydroxyphenyl)acetate, 37.2 g. (0.159 mole) of 4-chloro-α-bromoacetophenone and 28.6 g. of potassium carbonate. The mixture is heated at its reflux temperature for five hours, then diluted with water and diethyl ether. The ether layer is washed with water, cold 0.5N sodium hydroxide solution and saturated sodium chloride solution and treated with decolorizing charcoal, then dried. The solution is evaporated to provide a residue which is recrystallized from methanol yielding 24.4 g. of yellow crystals of condensation product, m.p. 87°-92° C. This product is mixed with 165 g. of polyphosphoric acid and heated at 110° C. for 1.5 hours. The mixture is poured into ice and water. This mixture is extracted with diethyl ether. The ether layer is washed with water and saturated sodium chloride solution, then dried. Evaporation provides 20.7 g. of ethyl 3-(4-chlorophenyl)-5-benzofuranacetate. This ester is hydrolyzed in 210 ml. of ethanol with 21 ml. of water and 20.7 g. of sodium hydroxide by heating at reflux for two hours. The solution is evaporated, and the residue is partitioned into water and diethyl ether. The water layer is poured into cold dilute hydrochloric acid to provide a yellow, gummy solid. The solid is dissolved in diethyl ether. The ether layer is washed with water and saturated sodium chloride solution, then dried. Evaporation provides a solid which is recrystallized twice from aqueous ethanol, then from benzene to yield 3-(4-chlorophenyl)-5-benzofuranacetic acid, m.p. 136°-140° C.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([C@@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C.CO[CH:42]1[N:46]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:45]([CH3:55])([CH3:54])[CH2:44][CH2:43]1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:8]([C@@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:30])[C@@H:22]([C@H:42]1[N:46]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:45]([CH3:55])([CH3:54])[CH2:44][CH2:43]1)[C:23]1[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cc1ccc(Br)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COC1CCC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H]([C@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(Br)cc2)CCC1(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 85.1 %

Procedure:
TiCl4 in toluene (3.52 mL, 3.52 mmol) was added to a solution of (R)-4-benzyl-3-(2-(4-bromophenyl)acetyl)oxazolidin-2-one (1.26 g, 3.35 mmol) in DCM (30 mL) at −78° C. DIEA (0.64 mL, 3.69 mmol) was then added to the cold stirring solution. The reaction was stirred at −78° C. for 15 minutes, followed by the addition of a solution of tert-butyl 5-methoxy-2,2-dimethylpyrrolidine-1-carboxylate (1.00 g, 4.36 mmol, see Example F) in DCM (10 mL). The reaction was then warmed to −10° C. and stirred for 2 hours. The reaction was quenched with a saturated NH4Cl solution (20 mL), and the organic fraction was isolated, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to give (S)-tert-butyl 5-((R)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(4-bromophenyl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.63 g, 85%) as a solid.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([C:13](OC)=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.CC(C[AlH]CC(C)C)C.C(O)(C)C.O>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][OH:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(C)O2
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1Oc2ccc(CO)cc2NC1=O
Temperature: -15 °C
Reaction time: 0.75 h

Procedure:
10.3 g (46.6 mmol) of (±)-2-methyl-3-oxo-6-(methoxycarbonyl)-3,4-dihydro-2H-1,4-benzoxazine is dissolved in 164 ml of tetrahydrofuran. After 330 ml of toluene is added, the solution is cooled to −15° C. At this temperature, 144.2 ml of a 20% DIBAH solution in toluene is added in drops within 30 minutes. A color change from yellow to orange takes place. After 45 minutes of stirring at −15° C., 31 ml of isopropanol is added in drops at this temperature, and 68 ml of water is added in drops at 0° C. After 2½ hours of vigorous stirring at room temperature, the precipitate that is produced is suctioned off, washed with tetrahydrofuran, and the filtrate is spun in. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[C:7]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([NH:15][CH3:16])=[O:14])[CH:6]=[N:5]2.C1C(=O)N([Br:27])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:27][C:3]1[N:4]2[N:5]=[CH:6][C:7]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([NH:15][CH3:16])=[O:14])=[CH:8][C:9]2=[N:1][CH:2]=1
Reactant: CNC(=O)c1cccc(-c2cnn3ccnc3c2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(-c2cnn3c(Br)cnc3c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Imidazo-[1,2-b]-pyridazin-7-yl-N-methyl-benzamide (1 eq, 0.595 mmol, 150 mg) is dissolved in DMF (5 ml) at 0° C. and NBS (1.1 eq, 0.654 mmol, 116 mg) is added. The reaction mixture is stirred for 1 h at 0° C. and then is diluted with EtOAc. The reaction mixture is washed with NaHCO3 and brine, dried over MgSO4, filtered and evaporated to yield 3-(3-Bromo-imidazo-[1,2-b]-pyridazin-7-yl)-N-methyl-benzamide as a pale yellow solid which did not require further purification; [M+H]+=333
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.Br[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:7]=1
Reactant: BrCCc1ccccc1
Reactant: OCc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1cc(Cl)ccc1CO)c1ccccc1
Temperature: 100 °C
Yield: 76.7 %

Procedure:
Charged 5-chloro-2-(hydroxymethyl)phenol (787 mg, 4.96 mmol), (bromoethyl)benzene (1.01 g, 5.46 mmol), K2CO3 (1.37 g, 9.93 mmol) and DMF (8 mL) to a flask, heated to 100° C. overnight. Poured into ice water, and extracted with ethyl acetate twice, and washed the organic phase with water twice, brine and dried with anhydrous Na2SO4. Solvent was then removed and purified by flash column chromatograph to give 1.0 g of the title compound (77%).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH2:5]([O:7][C:8](=[O:13])[CH2:9][C:10]([CH3:12])=[O:11])[CH3:6]>O.C(O)(=O)C>[CH2:5]([O:7][C:8](=[O:13])[C:9](=[N:1][OH:3])[C:10](=[O:11])[CH3:12])[CH3:6]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A solution of sodium nitrite (36.9 g, 0.534 mol) in 70 mL of water was added dropwise to a stirred solution of ethylacetoacetate (70 g, 0.538 mol) in 1401 mL of glacial acetic acid at 0° C. After the addition was complete, the light yellow reaction mixture was allowed to warm to room temperature. After 30 minutes, all the starting material had been consumed, the reaction was quenched with 350 mL of water and extracted with ethyl acetate (2×125 mL). The organic extracts were combined and washed with water (2×125 mL) and saturated sodium hydrogen carbonate aqueous solution (2×105 mL). The organic layer was dried with sodium sulfate and concentrated in vacuo to give 84.2 g (98%) of ethyl-2-Hydroxyimino-3-oxobutanoate 1b as a pale yellow oil. 1H NMR (CDCl3) δ 10.3 (s, 1H), 4.2 (q, 2H), 2.3 (s, 3H), 1.3 (t, 3H) ppm.
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][S:22][CH3:23])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][S:22][CH3:23])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OCCCSC)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSCCCOc1ccc2oc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)c(C)c2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{3-methyl-5-[3-(methylsulfanyl)propoxy]-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)amino]propanoate (0.25 g) synthesized in the above-mentioned (1) was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (2.0 mL) was added to the solution at room temperature, and the mixture was stirred at 50° C. for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (2.0 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title object compound (0.07 g, 31%) as a colorless solid.
Reaction SMILES: [I-].C[SH2+].[C:4]([NH:11][C@H:12]([C:17]([NH:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18])[CH2:13][CH2:14]SC)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[H-].[Na+]>CN(C=O)C>[C:24]([O:23][C:21]([NH:20][N:19]1[CH2:14][CH2:13][C@H:12]([NH:11][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[C:17]1=[O:18])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)OC(C)(C)C
Agent: C[SH2+]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
A solution of tert-butyl 2-(Boc-L-methionyl)-1-hydrazine carboxylate methylsulfonium iodide (18 g) in DMF (200 ml) was combined with sodium hydride (3.93 g, in oil) with cooling on ice, and then stirred at room temperature for 3 hours The reaction mixture was combined with ice-water, and extracted with ethyl acetate, and the organic phase was washed with water and brine, dried and concentrated to obtain a residue, which was triturated from isopropyl ether/hexane (1/1) solution, collected by filtration, washed with isopropyl ether/hexane (1/1) solution and dried to obtain the title compound (5.7 g) as a colorless solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C@@H:19]([NH:21][C:22]2[CH:27]=[N:26][CH:25]=[C:24]([Cl:28])[N:23]=2)[CH3:20])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:28][C:24]1[N:23]=[C:22]([NH:21][C@H:19]([C:15]2[CH:14]=[C:13]([NH:12][S:8]([C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)(=[O:10])=[O:9])[CH:18]=[CH:17][CH:16]=2)[CH3:20])[CH:27]=[N:26][CH:25]=1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](Nc1cncc(Cl)n1)c1cccc(NS(=O)(=O)c2cccnc2)c1
Reaction time: 17 h
Yield: 28.2 %

Procedure:
To a suspension of pyridine-3-sulfonylchloride hydrochloride (94 mg, 0.44 mmol) and N-[(1S)-1-(3-aminophenyl)ethyl]-6-chloropyrazin-2-amine (100 mg, 0.4 mmol) in dichloromethane (5 mL) was added triethylamine (0.17 mL, 1.2 mmol) dropwise at room temperature and the mixture was stirred for 17 hours. After this time the mixture was diluted with ethyl acetate (20 mL), washed successively with saturated aqueous sodium hydrogen carbonate (2×20 mL) and brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure to give a yellow oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give N-(3-{(1S)-1-[(6-chloropyrazin-2-yl)amino]ethyl}phenyl)pyridine-3-sulfonamide (44 mg, 28%) as a pale yellow foam.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])=[O:7].S(Cl)([Cl:24])=O>>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([Cl:24])=[O:11])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Product: O=C(Cl)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 2-(3-trifluoromethylbenzoyl)nicotinic acid (1.8 g) and thionyl chloride (10 ml) was heated at reflux for 3.5 hours. Excess reagent was removed by evaporation to yield 2-(3-trifluoromethylbenzoyl)nicotinoyl chloride as a red-brown gum (2 g) which was used in the next step without further purification.