Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH3:15])[C:8]([OH:10])=O)=[CH:5][S:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:21][CH:22]1[C:39](=[O:40])[N:24]2[C:25]([C:36]([OH:38])=[O:37])=[C:26]([CH2:29][S:30][C:31]3[NH:35][N:34]=[N:33][CH:32]=3)[CH2:27][S:28][C@H:23]12.C[Si](CC(N)=O)(C)C>O.C(OCC)(=O)C.CN(C)C=O>[O:1]1[C:6]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH3:15])[C:8]([NH:21][CH:22]2[C:39](=[O:40])[N:24]3[C:25]([C:36]([OH:38])=[O:37])=[C:26]([CH2:29][S:30][C:31]4[NH:35][N:34]=[N:33][CH:32]=4)[CH2:27][S:28][C@H:23]23)=[O:10])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CCCON=C(C(=O)O)C1=CSCCO1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12)C1=CSCCO1
Temperature: 40 °C
Yield: 69.3 %

Procedure:
2-(2,3-Dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetic acid (syn isomer, 1.6 g.), dry N,N-dimethylformamide (0.56 ml.), dry ethyl acetate (22.3 ml.) and phosphoryl chloride (0.69 ml.) were treated in a similar manner to that of Example 14 to give an activated acid solution. On the other hand, 7-amino-3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.0 g.) and trimethylsilylacetamide (5.9 g.) were added to dry ethyl acetate (40 ml.), and stirred at 40° C. for an hour. To the solution was added the activated acid solution at -15° C. and stirred at -10° to -20° C. for 50 minutes. Water (30 ml.) was added to the resultant solution, and the ethyl acetate layer was separated. Water (30 ml.) was added to the ethyl acetate solution and adjusted to pH 7.0 with sodium bicarbonate. The aqueous solution was separated, washed with ethyl acetate and adjusted to pH 2.7 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure. The product was added to diethyl ether (100 ml.) and stirred. The precipitates were collected by filtration and washed with diethyl ether to give 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetamido]-3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.33 g.).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:26]C=C)[C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:6]=1[Cl:30])[CH:2]=[CH2:3]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[CH3:16][O:15][C:13]([C@H:12]1[NH:17][C:18](=[O:29])[C:19]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:25][CH2:26][CH:3]=[CH:2][CH2:1][O:4][C:5]2=[CH:10][CH:9]=[C:8]([CH:7]=[C:6]2[Cl:30])[CH2:11]1)=[O:14]
Reactant: C=CCOc1ccc(C[C@H](NC(=O)c2ccccc2OCC=C)C(=O)OC)cc1Cl
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: COC(=O)[C@@H]1Cc2ccc(c(Cl)c2)OC/C=C/COc2ccccc2C(=O)N1
Solvent: ClCCl
Product: COC(=O)[C@@H]1Cc2ccc(c(Cl)c2)OCC=CCOc2ccccc2C(=O)N1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
In a 250 mL three-necked flask, Grubbs II catalyst (56.3 mg, 66.3 μmol, Eq: 0.30) was combined with dry DCM (50 mL) to give a brown solution. The reaction mixture was heated to 50° C. (reflux) under argon atmosphere. (S)-methyl 3-(4-(allyloxy)-3-chlorophenyl)-2-(2-(allyloxy)benzamido)propanoate (95 mg, 221 μmol, Eq: 1.00) dissolved in dry DCM (30 mL) was added dropwise. The reaction mixture was stirred at 50° C. for 2 h under argon atmosphere. The reaction mixture was stirred for 1 h at 50° C. to drive the reaction to completion. The crude reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 10 g, n-heptane/AcOEt 4/1, 3/1) to yield a brown oil (42 mg; 47%). m/z=402.2 [M+H]+.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH:12][C:19](=[O:21])[CH3:20])=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
To a solution of 8.0 g (42 mmol, 1.0 eq.) of (4-nitrophenyl)methanamine hydrochloride in 40 mL of methylene chloride and 28 mL (340 mmol, 8.0 eq.) of pyridine was added 16 mL (170 mmol, 4.0 eq.) of acetic anhydride. The mixture was stirred at room temperature for 16 h and diluted with 200 mL of methylene chloride. The organic solution was washed with sat. brine and dried (Na2SO4). The solvent was removed in vacuo to provide 8.0 g (41 mmol, 98%) of N-(4-nitrobenzyl)acetamide (I-21).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[C:5]2[CH2:10][N:9]([CH:11]([CH3:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1.[F:21][C:22]1[CH:23]=[C:24]([NH:37][C:38]([NH:40][CH2:41][CH2:42][F:43])=[O:39])[CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1.ClCCl.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].CCO.O.COCCOC>[F:21][C:22]1[CH:23]=[C:24]([NH:37][C:38]([NH:40][CH2:41][CH2:42][F:43])=[O:39])[CH:25]=[CH:26][C:27]=1[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[C:5]2[CH2:10][N:9]([CH:11]([CH3:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2F)OC1(C)C
Reactant: CC(C)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CC(C)N1Cc2nc(-c3ccc(NC(=O)NCCF)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 8.1 %

Procedure:
A solution of (S)-4-(2-chloro-6-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 22) (120 mg, 0.404 mmol), 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-fluoroethyl)urea (intermediate 31) (145 mg, 0.445 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (16 mg, 0.02 mmol) and sodium carbonate (128 mg, 1.21 mmol) in 2 ml of a 7:3:1 mixture of DME:H2O:EtOH respectively was heated in the microwave at 140° C. for 1 hour. The reaction was filtered through celite and purified via preparative HPLC at high pH to yield the title compound (15 mg, 8%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:21][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[S:13][C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(F)cccc2s1
Product: Fc1cccc2sc(CCC#Cc3ccccn3)nc12
Yield: 2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (291 mg, 1.84 mmol) and 2-but-3-ynyl-4-fluoro-benzo[d]thiazole (378 mg, 1.84 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 10 mg (37 μmol, 2%) of 4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:16])[C@H:4]([CH2:14][SH:15])[NH:5][C:6](=[O:13])[C@@H:7]1[CH2:11][CH2:10][C:9](=O)[NH:8]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1.[OH-].[Na+]>>[S:26]=[C:9]1[NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:16])[CH2:14][SH:15])=[O:13])[CH2:11][CH2:10]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@H](CS)NC(=O)[C@@H]1CCC(=O)N1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H](CS)NC(=O)[C@@H]1CCC(=S)N1

Procedure:
Thionation of N-(5-oxo-L-prolyl)-L-cysteine methyl ester with the Lawesson's reagent and the subsequent alkali hydrolysis with two sodium hydroxide equivalents in aqueous solution yields N-(5-thioxo-L-prolyl)-L-cysteine.
Reaction SMILES: C[O:2][C:3]1[N:4]([CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:6]=2.Cl.[OH-].[Na+]>CO.O1CCOCC1.O>[NH2:12][C:9]1[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:6]=[C:5]2[C:10]=1[NH:11][C:3](=[O:2])[N:4]2[CH2:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: COCCOc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: COCCOc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.4 %

Procedure:
8-(Methoxy)-2-{[2-(methoxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (0.1434 g) was dissolved in methanol (5 mL) and treated with 4N hydrogen chloride in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to give a solid, which was suspended in water (1 mL) and methanol (2-3 mL) before 2N sodium hydroxide was added to neutralise (to pH 7). After evaporating the suspension to near dryness under reduced pressure, the solid was suspended in water (3 mL) and filtered under suction and then washed with a few drops of methanol. This solid was dried to constant weight under vacuo at 50° C. after being initially air-dried under suction. This gave the title compound as a white solid (94 mg).
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9]N2CCN(C3C(OC)=CC=CN=3)CC2C)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:40][O:41][C:42]1[C:43]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH:49]2[CH3:54])=[N:44][CH:45]=[N:46][CH:47]=1>>[ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][N:51]2[CH2:52][CH2:53][N:48]([C:43]3[C:42]([O:41][CH3:40])=[CH:47][N:46]=[CH:45][N:44]=3)[CH:49]([CH3:54])[CH2:50]2)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2
Reactant: COc1cccnc1N1CCN(CCCc2csc3ccccc23)C(C)C1
Reactant: COc1cncnc1N1CCNCC1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: COc1cncnc1N1CCN(CCCc2csc3ccccc23)CC1C

Procedure:
The title compound was prepared (0.44 g, 62%, mp 183°-186° C.) in a manner analogous to the preparation of 1-[3-(benzo[b]thien-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)-2-methylpiperazine hydrochloride (Example 41) by the reaction of 3-benzo[b]thienepropanol tosylate with 1-(5-methoxy-4-pyrimidinyl)-2-methylpiperazine.
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:7][CH2:6][C:5](=[O:8])[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)=[CH:3]1.[BH4-].[Na+].CO>[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-].C(O)C>[F:15][C:2]1([F:1])[CH2:7][CH2:6][C@H:5]([OH:8])[C@@H:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: Cn1nccc1C1=CC(F)(F)CCC1=O
Agent: [Pd+2]
Agent: [BH4-]
Agent: [C+4]
Solvent: CCO
Solvent: CO
Product: Cn1nccc1[C@H]1CC(F)(F)CC[C@@H]1O
Yield: 28.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 67d by using the 4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohex-2-en-1-one (170 mg, 0.80 mmol) prepared in Example 88f, sodium borohydride (60 mg, 1.59 mmol), methanol (3.0 mL), palladium hydroxide carbon (10%; 150 mg) and ethanol (4.0 mL), to yield the title compound (50 mg, 29%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.[OH-].[Na+]>>[Br:1][C:2]1[CH:18]=[CH:17][C:16]2[C:9](=[O:11])[C:8]3[C:7]([CH2:6][O:5][C:4]=2[CH:3]=1)=[N:15][CH:14]=[CH:13][CH:12]=3
Reactant: O=C(O)c1cccnc1COc1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C1c2ccc(Br)cc2OCc2ncccc21
Yield: 26.7 %

Procedure:
[step 1] 4-Azaphthalide (15.0 g, 111.0 mmol) and 3-bromophenol (21.0 g, 121.4 mmol) were suspended in xylene (450 mL), and 28% sodium methoxide methanol solution (31.5 mL, 166.5 mmol) was added dropwise at 140° C. After stirring at 140° C. for 1 hr, DMF (10 mL) was added and the mixture was further stirred for 3 hr. Water and toluene were added to the reaction mixture, and the mixture was partitioned. The aqueous layer was neutralized with hydrochloric acid and the precipitated solid was collected by filtration to give 2-(3-bromophenoxymethyl)nicotinic acid (16.75 g, 49%). [step 2] 2-(3-Bromophenoxymethyl)nicotinic acid (10.0 g, 32.5 mmol) obtained in step 1 and polyphosphoric acid (70 g) were stirred at 170° C. for 3 hr. The reaction mixture was added to ice, and the mixture was neutralized with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 8-bromo-5-oxo-5,11-dihydrobenzooxepino[3,4-b]pyridine (2.52 g, 27%). [step 3] Using 8-bromo-5-oxo-5,11-dihydrobenzooxepino[3,4-b]pyridine (3.70 g, 12.8 mmol) obtained in step 2 and in the same manner as in Reference Example B10, step 2, (Z)-2-(8-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiononitrile (0.086 g, 2%) and (E)-2-(8-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiononitrile (0.224 g, 6%) were obtained. [step 4] Using (Z)-2-(8-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiononitrile (0.084 g, 0.30 mmol) obtained in step 3 and in the same manner as in Reference Example B2, the title compound (0.056 g, 63%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6]P(=O)(OCC)OCC.C[O-].[Na+].C1OCCOCCOCCOCCOCCOC1.[Br:39][C:40]1[N:45]=[C:44]([CH:46]=O)[CH:43]=[CH:42][CH:41]=1>CN(C)C=O>[Br:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44](/[CH:46]=[CH:6]/[C:5]2[CH:15]=[CH:16][CH:17]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:45]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CCOP(=O)(Cc1cccc(OC)c1)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(/C=C/c2cccc(Br)n2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of diethyl 3-methoxybenzylphosphonate (0.5 g, 1.94 mmol) in dimethylformamide (5 mL) at room temperature was added sodium methoxide (0.209 g, 3.87 mmol) and 18-Crown-6 (0.205 g, 0.77 mmol). After stirring at room temperature for 5 min, the reaction was cooled to 0° C. and treated with a solution of 6-bromopicolinaldehyde (0.432 g, 2.32 mmol) in dimethylformamide (2 mL) dropwise. When addition was complete, the ice bath was removed and the reaction stirred at room temperature for 1 h. The reaction was heated to 120° C. and held there for 2 h. The reaction was cooled to room temperature and stirred overnight. The resulting suspension was poured into water (70 mL) with vigorous stirring. The resulting suspension was extracted with diethyl ether (2×), washed with brine, dried over magnesium sulfate, and concentrated. The resulting residue was suspended in ethanol (ca. 10 ml). The resulting solution was placed in the freezer and held there for 3 h. The resulting precipitate was collected by filtration to give 150 mg (27%) as a white powder. 1H-NMR (CDCl3, 500 MHz) δ 7.61 (d, J=15.9, 1H), 7.49 (dd, J=7.6, 7.6, 1H), 7.22-7.36 (m, 3H), 7.16 (d, J=7.6, 1H), 7.10 (m, 1H), 7.07 (d, J=15.9, 1H), 6.87 (dd, J=8.2, 2.1, 1H), 3.84 (s, 3H). 13C-NMR (CDCl3, 126 MHz) δ 160.0, 157.1, 142.3, 138.9, 137.7, 134.4, 129.8, 126.7, 126.3, 120.7, 120.1, 114.8, 112.3, 55.4. Mass spec.: 290.01 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:18]([C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[C:21]=1[CH:22]=O)[CH3:19].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:13]([C:9]1[N:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([NH:1][CH2:22][C:21]3[C:20]([CH2:18][CH3:19])=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:28][CH3:29])[C:3]2=[N:11][C:10]=1[CH3:12])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCc1cccc(CC)c1C=O
Reactant: CCOC(=O)c1c(C)nc2c(N)cc(C)cn12
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1c(C)nc2c(NCc3c(CC)cccc3CC)cc(C)cn12

Procedure:
A stirred mixture of 8-amino-3-carboethoxy-2,6-dimethylimidazo[1,2-a]pyridine (2.02 g, 8.6 mmol), zinc(II)chloride (1.48 g, 10.8 mmol) and 2,6-diethylbenzaldehyde (2.17 g, 13.4 mmol) in 50 ml methanol was treated with sodium cyanoborohydride (0.65 g, 10.3 mmol) and was refluxed overnight. The mixture was allowed to cool and then poured over 80 ml 1M sodium hydroxide. The precipitate formed was filtrated and washed with water and then purified by column chromatography on silica gel with dichloromethane:methanol (95:5) as eluent. The yield was 2.1 g (64%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N:24]=[C:25]=[O:26].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:25]([NH:24][C:18]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=3[F:16])=[O:26])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: Nc1ccc(Sc2ccnc(Cl)c2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Sc3ccnc(Cl)c3)cc2)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 4-(2-Chloro-pyridin-4-ylsulfanyl)-phenylamine (300 mg, 1.27 mmol) in anhydrous THF (10 ml) was added 2-fluoro-5-methyl-phenylisocyanate (210 mg, 1.39 mmol). The mixture was stirred at 60° C. for 5 hours, and poured into 100 ml of water. The precipitates were filtered, washed with water (50 ml), and dried to give the crude, which was purified by silica gel chromatography eluting with 2-3% MeOH/CHCl3 to give 1-[4-(2-Chloro-pyridin-4-ylsulfanyl)-phenyl]-3-(2-fluoro-5-methyl-phenyl)-urea as white solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH:46]([N:57]=[N+]=[N-])[CH2:45]2)[CH:7]([CH3:61])[CH2:6][CH2:5][C:4]1=[O:62])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH:46]([NH2:57])[CH2:45]2)[CH:7]([CH3:61])[CH2:6][CH2:5][C:4]1=[O:62])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccccc4)C(N=[N+]=[N-])C3)C(C)CCC1=O)C(C)CC2OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccccc4)C(N)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.5 %

Procedure:
17-Ethyl-1-hydroxy-12-[2'-(3"-azido-4"-phenoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone (24 mg) in THF (1 ml) containing 1 drop of water was treated with triphenylphosphine (9 mg) and the mixture stirred at room temperature for 72 hours. The reaction mixture was purified directly by preparative thin layer chromatography eluting eith 90% dichloromethane:10% methanol to give the title compound (5 mg, 20%) as a white solid. (1H NMR analysis was consistent with the desired structure).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=3)[CH2:8][CH2:9][O:10][C:11]=2[N:12]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C.CN(C)C(=O)C>>[CH:21]([N:20]1[C:16]([C:14]2[N:15]=[C:6]3[C:5]4[CH:4]=[CH:3][C:2]([N:28]5[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]5)=[N:12][C:11]=4[O:10][CH2:9][CH2:8][N:7]3[CH:13]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CN1CCNCC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Cl)nc1OCC2
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCN(C)CC3)nc1OCC2

Procedure:
A solution of 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine (66.0 mg, 0.200 mmol;), 1-methyl-piperazine, (88.5 uL, 0.798 mmol) and Triethylamine (167 uL, 1.20 mmol) in N,N-Dimethylacetamide (3.00 mL, 32.3 mmol) was heated in microwave at 160 C for 20 min. The reaction was filtered thru celite then rinsed with EtOAc. The filtrate was washed water, brine. The organic layer was dried Na2SO4, concentrated. The crude product was purified by rHPLC to give 323. MS: (ESI+)=395.2. 1H NMR (400 MHz, DMSO) δ 8.50 (d, J=8.7 Hz, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 6.72 (d, J=8.8 Hz, 1H), 5.88 (dt, J=13.2, 6.7 Hz, 1H), 4.49 (m, 4H), 3.61-3.48 (m, 4H), 2.42-2.34 (m, 4H), 2.21 (s, 3H), 1.47 (d, J=6.6 Hz, 6H)
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([NH2:45])=[N:43][CH:44]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:32])[NH:45][C:42]5[CH:41]=[CH:40][C:39]([Cl:38])=[CH:44][N:43]=5)=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Cl)cn3)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.5 %

Procedure:
A solution of the product of Example 19C (471 mg, 0.861 mmol) in anhydrous tetrahydrofuran (8 mL) was treated with 5-chloro-2-aminopyridine (125 mg, 0.972 mmol) and diisopropylethylamine (0.232 mL, 1.332 mmol), and stirred at room temperature under a nitrogen atmosphere for 18 hours. The solvent was removed by rotary evaporation in vacuo, the residue taken up in ethyl acetate (250 mL) and washed with saturated aqueous sodium bicarbonate (50 mL), water (2×50 mL), and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration with methylene chloride provided the title compound as a yellow solid (373 mg, 61%).