Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([OH:11])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(O)c1
Reactant: NCCc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Oc1cccc(CNCCc2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Combine 2-(3-chlorophenyl)ethylamine (1.866 gm; 15.28 mmol) and 3-hydroxybenzaldehyde (1.567 gm; 10.07 mmol) in 40 mL of methanol and stir at room temperature for 20 min and treat with sodium borohydride (0.950 gm; 25.1 mmol) in one portion. Stir the mixture at room temperature. After 15 h, add water (10 mL), and remove the methanol by rotary evaporation. Add to this slurry water (25 mL) and dichloromethane (50 mL), separate the layers and extract the aqueous layer with dichloromethane (50 mL). Wash the combined organic layers with saturated brine (3×), dry over MgSO4, and concentrate to give the title compound.
Reaction SMILES: CN1C2C(=CC(S(N3CCC[C@H]3COC3C=CC=CC=3)(=O)=O)=CC=2)C(=O)C1=O.[O:29]([CH2:36][C@@H:37]1[CH2:40][CH2:39][N:38]1[S:41]([C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][C:48](=[O:53])[C:47]2=[O:54])(=[O:43])=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[F:55][C:56]1[CH:63]=[CH:62][CH:61]=[CH:60][C:57]=1[CH2:58]Br>>[F:55][C:56]1[CH:63]=[CH:62][CH:61]=[CH:60][C:57]=1[CH2:58][N:49]1[C:50]2[C:46](=[CH:45][C:44]([S:41]([N:38]3[CH2:39][CH2:40][C@H:37]3[CH2:36][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:43])=[O:42])=[CH:52][CH:51]=2)[C:47](=[O:54])[C:48]1=[O:53]
Reactant: Fc1ccccc1CBr
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc2C1=O
Agent: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Product: O=C1C(=O)N(Cc2ccccc2F)c2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc21

Procedure:
(S)-1-(2-Fluorobenzyl)-5-(2-phenoxymethyl-azetidine-1-sulfonyl)-1H-indole-2,3-dione (18f) was prepared according to the same procedure for compound 11a, except using compound 17 and 2-fluorobenzyl bromide, and purified with solid, mp 147.1-148.0° C. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=1.8 Hz, 1H), 8.00 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 7.35 (m, 2H), 7.24-7.11 (m, 3H), 7.02-6.78 (m, 5H), 4.98 (s, 2H), 4.47 (m, 1H), 4.11 (m, 2H), 3.85 (m, 2H), 2.35-2.25 (m, 2H). Anal. Calcd for C25H21FN2O5S: C, 62.49, H, 4.41; N, 5.83. Found: C, 62.25, H, 4.47; N, 5.68.
Reaction SMILES: [CH2:1]([N:8]1[CH2:37][CH2:36][C:11]2([N:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:24][CH:23]=4)[C:19]([C:20]#[N:21])=[C:15]3[NH:14][C:13](=[O:35])[CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:38]>OP(O)(O)=O>[CH2:1]([N:8]1[CH2:37][CH2:36][C:11]2([N:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:24][CH:23]=4)[C:19]([C:20]([NH2:21])=[O:38])=[C:15]3[NH:14][C:13](=[O:35])[CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)CC21CCN(Cc2ccccc2)CC1
Agent: O=P(O)(O)O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)CC21CCN(Cc2ccccc2)CC1
Yield: 34.8 %

Procedure:
A solution of 1-benzyl-5′-oxo-2′-(4-phenoxyphenyl)-5′,6′-dihydro-4′H-spiro[piperidine-4,7′-pyrazolo[1,5-a]pyrimidine]-3′-carbonitrile (500 mg, 1.02 mmol) in H3PO4 (5 mL) was heated to 130° C. for 1 hr. The mixture was poured to water (20 mL) and extracted with EA (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated and purified by chromatography column on silica gel using 5% of MeOH in DCM as eluant to afford the product (180 mg, 34.8%) as a yellow solid. MS (ESI, m/e) [M+1]+ 507.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:17].C(O)(=O)C>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([O:13][CH3:17])=[O:12])=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1ccc(C(C)(C)CC(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CC(C)(C)c1ccc(OC)cc1
Reaction time: 0.75 h

Procedure:
3-(4-methoxyphenyl)-3-methylbutanoic acid (513 mg, 2.463 mmol) was dissolved in toluene (13.3 ml) and methanol (2 ml). TMS-diazomethane (1.848 ml, 3.70 mmol) was added dropwise. Evolution of gas was observed, and a yellow color persisted. After 45 minutes, the reaction was quenched with acetic acid (200 uL, 3.5 mmol). The reaction was concentrated, and the residue was purified by flash chromatography on silica gel with 0 to 75% EtOAc/hexanes to afford methyl 3-(4-methoxyphenyl)-3-methylbutanoate. 1H NMR (CDCl3, 500 MHz) δ 7.28 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 3.79 (s, 3H), 3.54 (s, 3H), 2.59 (s, 2H), 1.43 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1C
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1sc2nc(-c3cnccn3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyrazin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3-nitrobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([C:15](O)=[O:16])=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][CH:19]=3)[N:10]2[CH3:30])=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:33])=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([C:15]([Cl:33])=[O:16])=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][CH:19]=3)[N:10]2[CH3:30])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: Cn1c(-c2ccc(-c3ccccn3)cc2)c(C(=O)O)c(=O)n1-c1ccc(C#N)cc1
Product: Cn1c(-c2ccc(-c3ccccn3)cc2)c(C(=O)Cl)c(=O)n1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.6 g of 1-(4-cyanophenyl)-4-hydroxycarbonyl-2-methyl-3-[4-(2-pyridyl)phenyl]-2H-pyrazol-5-one and 16 ml of thionyl chloride was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was crystallized in a liquid mixture of n-hexane-toluene to give 1.65 g of the desired compound as a pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH:20]1[CH2:23][CH:22]([N:24]2[CH2:29][CH2:28][NH:27][C:26](=[O:30])[CH2:25]2)[CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:20]3[CH2:21][CH:22]([N:24]4[CH2:29][CH2:28][NH:27][C:26](=[O:30])[CH2:25]4)[CH2:23]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Reactant: O=C1CN(C2CNC2)CCN1
Product: O=C1CN(C2CN(Cc3ccc4nc(Cl)nc(N5CCOCC5)c4n3)C2)CCN1

Procedure:
4-(6-(bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.201 g) was reacted with 4-(azetidin-3-yl)piperazin-2-one via General Procedure B to afford 0.18 g 4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)piperazin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([NH2:23])=O)[NH:6]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:33])[NH2:23])[NH:6]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN(c1ccc(Cl)c2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Solvent: C1CCOC1
Product: CN(c1ccc(Cl)c2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
A mixture of 4-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.54 g), Lawesson's reagent (0.59 g) and tetrahydrofuran (20 ml) was stirred at 60° C. for 3 hr. The reaction mixture was concentrated, toluene was added, and the resulting crystals were filtrated, washed with toluene, and dried to give the title compound (0.51 g, yield 87%) as yellow crystals. melting point >248° C. (decomposition).
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:18]=2[N+:25]([O-])=O)[C@@H:13]([C:28]([OH:30])=O)[CH2:12]1)(OCC1C=CC=CC=1)=O>C(O)(=O)C.[Fe]>[Cl:24][C:20]1[CH:19]=[C:18]2[C:17](=[CH:22][C:21]=1[Cl:23])[N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C@@H:13]1[C:28](=[O:30])[NH:25]2
Reactant: O=C(O)[C@H]1CN(C(=O)OCc2ccccc2)CCN1c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cc(Cl)c(Cl)cc2N2CCNC[C@H]12
Temperature: 60 °C
Yield: 113.5 %

Procedure:
To a solution of 8.0 g (R)-4-carbobenzyloxy-1-(4,5-dichloro-2-nitrophenyl)-piperazine-2-carboxylic acid in 200 mL of acetic acid is added 6.0 g of iron powder. With good stirring, the mixture is heated at 60° C. for 2 hours, followed by concentrated under reduced pressure (1-2 mm, <40° C.) to a gray-black residue. This material was slurried with 400 mL of ethyl acetate and filtered. This process was repeated. The combined ethyl acetate filtrates are washed with 150 mL of 1 N HCl, 200 mL of water (2×), 200 mL of brine and dried over MgSO4. Filtration and concentration of the solvent gave a semi-solid material that is crystallized from ethyl acetate-hexane to afford 5.44 g (76.1%) of title compound as a white solid, mp 136-138° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:24]([C:20]3[O:19][CH:23]=[CH:22][CH:21]=3)=[O:25])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: O=C(Cl)c1ccco1
Product: Cc1noc(-c2sc(NC(=O)c3ccco3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and furan-2-carbonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[CH:21]=[CH:20][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.9 %

Procedure:
To a solution of ethyl 4-{2-[(tert-butoxycarbonyl)amino]ethyl}benzoate (4 g) in tetrahydrofuran (30 ml) was added lithium aluminum hydride (0.82 g), and the mixture was stirred at 0° C. for 30 min. Water (3.6 ml) and 1N aqueous sodium hydroxide solution (1 ml) were added to quench the reaction, and the precipitate was filtered off. The filtrate was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (3.8 g) as a colorless oil.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[Si:15]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)=[O:38])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Si:45]([O:52][CH2:53][CH:54]=[O:55])([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>O1CCCC1.CCCCCC>[Si:45]([O:52][CH2:53][CH:54]([OH:55])[CH:36]([C:37](=[O:38])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1)[CH2:35][CH2:34][CH2:33][O:32][Si:15]([C:28]([CH3:29])([CH3:30])[CH3:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:48]([CH3:50])([CH3:51])[CH3:49])([CH3:47])[CH3:46]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC(C)(C)[Si](OCCCCC(=O)c1cccnc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCC(O)C(CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)c1cccnc1
Temperature: 0 °C

Procedure:
To a solution of 0.93 ml (0.0044 mole) of hexamethyldisilazane in 14 ml of tetrahydrofuran, 2.15 ml (0.0044 mole) of 2.06 molar solution of n-butyllithium in hexane is added dropwise with stirring under argon at 0° C. The mixture is cooled to -20° C. and a solution of 1.68 g (0.004 mole) of 5-(t-butyldiphenylsilyloxy)-1-(3-pyridyl)pentan-1-one in 10 ml of tetrahydrofuran is added dropwise over a period of 15 min. The mixture is stirred at -20° C. for 15 min and a solution of 0.74 g (0.0042 mole) of t-butyldimethylsilyloxy acetaldehyde in 15 ml of tetrahydrofurane is added over a period of 1 min. The mixture is stirred at -20° C. for 15 min, quenched with 6 ml of concentrated aqueous ammonium chloride, diluted with ether and washed with water and brine, dried and evaporated. The residue is purified by flash chromatography using ethyl acetate-methylene chloride (1:1) as eluent to give 1-(t-butyldimethylsilyloxy)-6-(t-butyldiphenylsilyloxy)-3-nicotinoylhexan-2-ol described in example 3.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([C@@:18]1([CH2:32][C:33](=[CH2:36])[CH2:34]Br)[CH2:22][C:21](=[O:23])[N:20]([C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:11]([O:15][C:16]([C@@:18]12[CH2:32][C:33](=[CH2:36])[CH2:34][C@@H:22]1[C:21](=[O:23])[N:20]([C@@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:25])[CH2:19]2)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C=C(CBr)C[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1C[C@@H]2C(=O)N([C@H](C)c3ccccc3)C[C@]2(C(=O)OC(C)(C)C)C1
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
A 1 M solution of lithium hexamethyldisilazide in THF (9.15 ml, 9.15 mmol) was added to a solution of (3S)-3-(3-bromo-2-methylene-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (3.22 g, 7.62 mmol) in tetrahydrofuran (76.2 ml) under cooling with ice-acetone in a nitrogen atmosphere, and the mixture was stirred for 10 minutes. A 10% citric acid solution (120 ml) was added to the reaction solution, followed by extraction with ethyl acetate (100 ml×2). The organic layer was washed with brine (200 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→83:17→80:20→75:25) to give 2.47 g of the title compound as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[N:19][CH:18]=[CH:17][CH:16]=3)([NH2:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.CO[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#N)[CH:27]=1)=[NH:25].C(Cl)(Cl)Cl>CO>[C:24]([C:26]1[CH:27]=[C:28]([C:32]2[NH:10][CH2:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([C:12]3[CH:13]=[N:14][C:15]4[C:20]([CH:21]=3)=[N:19][CH:18]=[CH:17][CH:16]=4)[N:11]=2)[CH:29]=[CH:30][CH:31]=1)#[N:25]
Reactant: COC(=N)c1cccc(C#N)c1
Reactant: NCC(N)(c1ccc(F)cc1)c1cnc2cccnc2c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N#Cc1cccc(C2=NC(c3ccc(F)cc3)(c3cnc4cccnc4c3)CN2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 33.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-1-(1,5-naphthyridin-3-yl)-1,2-ethanediamine (17 mg) in methanol (1 mL) was added 3-cyanobenzeneimidic acid methyl ester (23 mg), and the mixture was stirred at room temperature for 19 hrs. To the reaction mixture was added chloroform and insolubles were removed by filtration, followed by concentration of the filtrate in vacuo. The residue was purified by preparative thin-layer chromatography (100% ethyl acetate) to give the objective compound (8.0 mg).
Reaction SMILES: C[N:2]([C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][N:12]([Si](C(C)C)(C(C)C)C(C)C)[C:9]2=[N:10][CH:11]=1)[C:3](=O)[CH3:4].Cl.[OH-].[Na+]>C1COCC1>[CH2:3]([NH:2][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1)[CH3:4]
Reactant: CC(=O)N(C)c1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCNc1cnc2[nH]ccc2c1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
Acetyl chloride (75 μL, 1.0 mmol) was added to a solution of 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (230 mg, 0.8 mmol) and 4-dimethylaminopyridine (5 mg) in pyridine (1.6 mL). The mixture was stirred at RT for 24 h and a saturated solution of ammonium chloride (30 mL) and ethyl acetate (30 mL) were added. The separated aqueous layer was extracted with ethyl acetate (3×25 mL) and the combined organic layers were dried, filtered and concentrated to provide an oil which was purified by preparative HPLC to afford N-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-acetamide (140 mg, 53%) as an oil: LCMS; m/z 332 (M+H+). B. At RT under argon, a solution of borane-dimethylsulfide complex (665 μL, 6.6 mmol, 10 M) was added to N-methyl-N-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-acetamide (110 mg, 0.33 mmol) in THF (3.0 mL). The mixture was heated to 65° C. for 2 h., cooled down and a 6N hydrochloric acid solution was slowly added. The mixture was heated to 100° C. and vigorously stirred for 12 h., cooled down and a 6 N sodium hydroxide solution was added until pH 7 was reached. The mixture was extracted with ethyl acetate (3×15 mL) and the combined organic layers were dried, filtered and evaporated to provide an oil which was purified through silica gel-SCX column (arylsulfonic acid with washes with methanol and 2N NH3 in methanol) to afford ethyl-(1H-pyrrolo[2,3-b]pyridin-5-yl)-amine. LCMS; m/z 203 (M+AcCN), 162 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][N:33]([CH3:39])[CH2:34][CH2:35][CH2:36][NH:37][CH3:38]>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:37]([CH2:36][CH2:35][CH2:34][N:33]([CH3:39])[CH3:32])[CH3:38])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CNCCCN(C)C
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N(C)CCCN(C)C)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 27.9 mg (0.24 mmol) N,N,N′-trimethyl-1,3-propanediamine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 24 mg (36.6%) product as an orange powder. MS (ESI) m/z 547.3 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5](=[O:18])[N:4]2[C@H:19]([C:23]([OH:25])=O)[CH2:20][CH2:21][CH2:22][N:3]12.C(OC([NH:32][CH:33]([CH:47]=[O:48])[CH2:34][CH2:35][C:36](=[N:42][NH:43][C:44]([NH2:46])=[O:45])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=O)C=C.[SnH](CCCC)(CCCC)CCCC.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CCOC(C)=O.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>[C:10]([NH:9][CH:6]1[C:5](=[O:18])[N:4]2[CH:19]([C:23]([NH:32][CH:33]([CH:47]=[O:48])[CH2:34][CH2:35][C:36](=[N:42][NH:43][C:44]([NH2:46])=[O:45])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:25])[CH2:20][CH2:21][CH2:22][N:3]2[C:2](=[O:1])[CH2:8][CH2:7]1)(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Reactant: C=CCOC(=O)NC(C=O)CCC(=NNC(N)=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(CCC(C=O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)=NNC(N)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
A solution of (1S,9S) 6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-9-(benzoylamino)-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid (212e) (345 mg, 1.0 mmol), (4S) t-butyl N-(allyloxycarbonyl)-4-amino-5-oxopentanoate semicarbazone (208a) (361 mg, 1.1 mmol, 1.1 equiv) and (Ph3P)2PdCl2 (20 mg) in CH2Cl2 (5 ml), was treated dropwise with n-Bu3SnH (0.621 ml, 2.3 mmol, 2.1 equiv). The resulting orange brown solution was stirred at 25° C. for 10 min and then 1-hydroxybenzotriazole (297 mg, 2.2 mmol, 2 equiv) was added. The mixture was cooled to 0° C. and ethyldimethylaminopropyl carbodiimide (253 mg, 1.3 mmol, 1.2 equiv) added. After stirring at 0° C. for 10 min and then at room temperature overnight, the mixture was diluted with EtOAc (50 ml) and the resulting solution washed successively with 1M HCl (3×25 ml), 10% NaHCO3 (3×25 ml) and sat. aq. NaCl, dried (MgSO4) and concentrated. Flash chromatography on silica gel (2-10% methanol in CH2Cl2) afforded compound 233e (280 mg, 49%) as a tan solid: [α]D20 −95 (c 0.09, MeOH); IR (KBr) 3477, 3333, 2968, 2932, 1633, 1580, 1535, 1423, 1378, 1335, 1259, 1156, 1085, 709; 1H NMR (CDCl3) δ 9.32 (1H, s), 7.83-7.39 (6H, m), 7.11-7.09 (1H, m), 6.30-5.30 (2H, brs), 5.17-5.05 (2H, m), 4.62-4.38 (2H, m), 3.30-3.15 (1H, m), 3.13-2.65 (2H, m), 2.46-2.19 (3H, m), 2.15-1.54 (8H, m), 1.42 (9H, s).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Br:5][C:6]1[C:7]([OH:16])=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([CH:13]=1)[CH:11]=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:16][C:7]1[C:8]([O:14][CH3:15])=[CH:9][C:10]([CH:11]=[O:12])=[CH:13][C:6]=1[Br:5]
Reactant: COc1cc(C=O)cc(Br)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)cc(Br)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
1,2-Dibromoethane (37 mL, 0.43 moles) was added to a mixture of 5-bromovanillin (10 g, 43 mmoles) and potassium carbonate (30 g, 216 mmoles) in DMF (150 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours followed by vigorously stirring at 60° C. for 16 hours. The cooled mixture was poured into water (1 L) and extracted with ethyl acetate (3×250 mL). The combined organic phases were washed with saturated sodium chloride (300 mL), dried over MgSO4 and evaporated in vacuo to afford 13.7 g (94%) of 4-(2-bromoethoxy)-3-bromo-5-methoxybenzaldehyde.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:16]1[CH2:20][O:19][CH2:18][CH2:17]1>>[CH2:2]([C:18]1[O:19][CH:20]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCBr
Reactant: C1CCOC1
Product: CCCCCCCCCCCCCCc1ccco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Bromotetradecane (2.05 g, 8.17 mmol) in THF (4 mL) was added dropwise and the resulting solution was warmed to room temperature and stirred overnight. The reaction was quenched with a saturated solution of NH4Cl (5 mL). The organic layer was removed and the aqueous layer extracted with ether (3×5 mL). The combined organic layers were washed with a saturated solution of NaHCO3 (1×5 mL), brine (1×5 mL), dried over MgSO4, filtered and concentrated. The crude residue was passed through a small silica gel plug and recrystallized in methanol to afford the 2-(tetradecyl)furan, compound (20) (1.50 g, 77% yield).