Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:17]=[O:18]>CN(C=O)C>[OH:18][CH2:17][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:8]#[N:9]
Reactant: C=O
Reactant: CCCCCC(C#N)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(C#N)(CO)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
5.14 g (27.4 mmol) of 2-phenylheptanenitrile are added to a suspension of 1.34 g of 60% NaH in 50 ml of DMF cooled to 0° C. After stirring for 30 minutes, 7.6 g (220 mmol) of paraformaldehyde are added portionwise. The reaction medium is left to stir at ambient temperature for 6 hours and then hydrolysed with ice and extracted with diethyl ether. The organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulphate, filtered and evaporated under pressure. The crude product obtained is purified by silica gel chromatography (eluent 8/2 heptane/ethyl acetate). 4.24 g in the form of a pale yellow oil are obtained with a yield of 71%.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.BrC[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([CH3:37])(=[O:36])=[O:35]>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([CH3:37])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)c1ccccc1CBr
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: CS(=O)(=O)c1ccccc1CSc1c(Cl)ccc2c1CCNCC2
Product: Cl

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 1-bromomethyl-2-methanesulfonyl-benzene to give, after deprotection by the General Procedure 1-4, the title compound and as a white solid. MS (APCI+) m/z: 382 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:12]2[C:7](=[C:8]([CH2:36][CH2:37][CH3:38])[C:9]3[O:29][C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][C:26](=[O:35])[C:10]=3[CH:11]=2)[N:6]=1)=[O:4].[C:39](=O)([O-])[O-].[K+].[K+].CI.O>CN1CCCC1=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([N:15]([CH3:39])[S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[C:12]2[C:7](=[C:8]([CH2:36][CH2:37][CH3:38])[C:9]3[O:29][C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][C:26](=[O:35])[C:10]=3[CH:11]=2)[N:6]=1)=[O:4]
Reactant: CCCc1c2nc(C(=O)OC)cc(NS(=O)(=O)c3ccc(C)cc3)c2cc2c(=O)cc(C(=O)OCC)oc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CI
Product: CCCc1c2nc(C(=O)OC)cc(N(C)S(=O)(=O)c3ccc(C)cc3)c2cc2c(=O)cc(C(=O)OCC)oc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The product of step (a) (5.38 g, 0.01 mol) was suspended in N-methyl pyrrolidone (40 ml), and potassium carbonate (1.38 g, 0.01 mol) added, to give on stirring at room temperature for five minutes a deep red solution. Methyl iodide (2 ml) was then added, and the whole warmed to 40° C., and stirring continued for one hour. The solution was poured into water (150 ml), to give the sub-title compound on filtration, as a white powder, 5.44 g, (98.6%), m.p. 173°-174° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)([CH3:4])[CH3:3].[I-].[Mg+2].[I-].[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[CH:24]1[C:28](=[O:29])[CH:27]=[CH:26][C:25]1=[O:30]>>[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[CH:24]1[C:25](=[O:30])[CH:26]2[CH:27]([CH:10]3[O:9][CH:8]2[CH:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[CH2:11]3)[C:28]1=[O:29]
Reactant: Cc1cc(C)c(C2C(=O)C=CC2=O)c(C)c1
Reactant: C[Si](C)(C)C#Cc1ccoc1
Agent: [I-]
Agent: [Mg+2]
Product: Cc1cc(C)c(C2C(=O)C3C4CC(C#C[Si](C)(C)C)C(O4)C3C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3-(Trimethylsilylethynyl)furan (10.0 g, 61 mmol) and magnesium iodide (1.11 g, 4 mmol) are added to 2-(2,4,6-trimethylphenyl)cyclopent-4-ene-1,3-dione (4.34 g, 20 mmol) and the mixture is stirred at room temperature for 3 days. The reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7RS)-4-(2,4,6-trimethylphenyl)-8-trimethylsilylethynyl-10-oxatricyclo-[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>[Zn].ClCCl>[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[C:1]([Br:5])[Br:2])=[CH:31][CH:30]=1
Reactant: BrC(Br)(Br)Br
Reactant: COCOc1ccc(C=O)cc1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCOc1ccc(C=C(Br)Br)cc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 66.2 %

Procedure:
To a mixture of carbon tetrabromide (56.58 g), triphenylphosphine (44.61 g) and zinc powder (11.18 g) was added dichloromethane (300 ml), and the mixture was stirred for 25 hours at room temperature. To the mixture was then added p-methoxymethoxybenzaldehyde (13.91 g), which was stirred for 30 hours. The reaction mixture was subjected to filtration through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 4-(2,2-dibromoethenyl)phenol methoxymethyl ether (17.84 g) (Compound B-25). The physical properties are shown in Table 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH2:9][C:10]([O:12]CC)=[O:11])=O)=[CH:5][CH:4]=1.Cl.O[NH2:19]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]2[NH:19][O:12][C:10](=[O:11])[CH:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(=O)o[nH]2)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To 110 ml of acetic acid were added 16 g (72 mmol) of ethyl 4-methoxybenzoylacetate and 5 g (72 mmol) of hydroxyamine hydrochloride, followed by stirring at 100° C. for 2 hours. The resulting mixture was allowed to stand overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Crystals thus precipitated were collected by filtration, washed with water and then dried under reduced pressure, whereby the title compound was obtained as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:8]CC(N)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:13]1([C:16]2[N:20]([CH3:21])[C:19]([CH:22]=[O:23])=[CH:18][N:17]=2)CC1>>[CH2:1]([O:8][CH2:13][C:16]1[N:20]([CH3:21])[C:19]([CH:22]=[O:23])=[CH:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C=O)cnc1C1CC1
Reactant: NC(=O)COCc1ccccc1
Product: Cn1c(C=O)cnc1COCc1ccccc1

Procedure:
2-Benzyloxymethyl-3-methyl-3H-imidazole-4-carbaldehyde was prepared from 2-benzyloxy-acetamide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: CC(C)(O)CCNc1ccc2ncc(Br)n2n1
Product: CC(C)(O)CCNc1ccc2ncc(-c3ccc(CN)cc3)n2n1
Yield: 78 %

Procedure:
The 4-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)-2-methylbutan-2-ol was coupled with (4-(aminomethyl)phenyl)boronic acid as described in example 5.6.19 to afford the titled compound in 78% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.29 (s, 6H) 1.84-1.94 (m, 2H) 3.49-3.58 (m, 2H) 4.24 (s, 2H) 7.25 (d, J=9.85 Hz, 1H) 7.67 (d, J=8.59 Hz, 2H) 7.97 (d, J=9.85 Hz, 1H) 8.22-8.29 (m, 3H); LRMS (ESI) m/e 326.0 [(M+H)+, calcd for C18H23N5O 325.0].
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1([C:25]2[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[N:19]1([C:25]2[N:30]=[CH:29][C:28]([NH:31][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:27][CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1ccc(N2CCOCC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCOCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (1.58 g, 6.14 mmol), 6-morpholin-4-yl-pyridin-3-ylamine (1.0 g, 5.58 mmol), N-hydroxybenzotriazole (1.27 g, 8.37 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.6 g, 8.37 mmol) in anhydrous dichloromethane (20 mL) was stirred at room temperature overnight. After the reaction was complete, solvent was evaporated. The resulted mixture was mixed with water and extracted twice with ethyl acetate. The organic layers were collected, combined, washed with brine, dried over sodium sulfate, and then concentrated to give a solid. The crude product was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-100% ethyl acetate in hexane) to gave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide (1.15 g, 50%) as an off-white solid. LCMS calcd for C20H17F3N4O3 (m/e) 418, obsd 419 (M+H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@:6]1([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][Si](C(C)(C)C)(C)C)=[CH:36][CH:35]=2)[CH:27]=1)OC)(=[O:3])[CH3:2].O.C([SiH](CC)CC)C.C(OC(=O)C)C>C(#N)C>[C:16]([O:15][C@H:9]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([CH2:33][C:34]3[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=3)[CH:27]=2)[O:7][C@@H:8]1[CH2:19][O:20][C:21](=[O:23])[CH3:22])(=[O:18])[CH3:17]
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
To a solution of (2S,3R,4S,5R,6R)-6-(acetoxymethyl)-2-(3-(4-((tert-butyldimethylsilyl)oxy)benzyl)-4-chlorophenyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (44.0 g, 0.064 mol) in acetonitrile (200 mL), water (1.15 mL, 0.064 mol), triethylsilane (32.45 mL, 0.203 mol) and borontrifluoroetherate (15.94 mL, 0.127 mol) were added at 10° C. The resulting mixture was stirred at r.t. for 16 h. Additional amounts of triethylsilane (3.25 mL, 0.020 mol) and borontrifluoroetherate (1.59 mL, 0.013 mol) were added at 10° C. and heated at 30° C. for 6 h. Ethylacetate (1 L) was added to the reaction mixture, washed it with saturated NaHCO3 solution (2×500 mL), water (500 mL) and brine (500 mL) successively. The organic layer was dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 4:6 Ethyl acetate:Pet.Ether) to provide title compound (30 g, 86.27%) as off-white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([NH:20][CH2:21][CH2:22][O:23][CH3:24])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:25]>CO>[NH2:25][C:2]1[C:11]2[N:12]=[C:13]([NH:20][CH2:21][CH2:22][O:23][CH3:24])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: COCCNc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Solvent: CO
Product: COCCNc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Temperature: 150 °C

Procedure:
1-{4-Chloro-2-[(2-methoxyethyl)amino]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (2.1 g, 6.2 mmol) and ammonia (25 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated overnight in an oven at 150° C. and then allowed to cool to ambient temperature. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (eluting with 2% methanol in dichloromethane with 1% ammonium hydroxide added.) The isolated product was dried under high vacuum overnight to provide 1.08 g of 1-{4-amino-2-[(2-methoxyethyl)amino]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as a white solid, mp 176-178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][C:11](O)([C:13](=O)[CH3:14])[CH3:12].C(O)(=O)C.C1(C)C=CC=CC=1>O>[CH3:14][C:13]1[C:11]([CH3:12])([CH3:10])[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=2[N:9]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)C(C)(C)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(C)(C)C(C)=N2
Temperature: 220 °C
Reaction time: 3 h

Procedure:
246 parts of p-anisidine, 204 parts of 2-methyl-2-hydroxy-butan-3-one and 10 parts of acetic acid in 650 parts of toluene are heated, with removal of water from the system, until no more water separates off. The solvent is then distilled off and the residue is heated for 5 hours at 220° C. After cooling to 160° C., 10 parts of concentrated sulfuric acid are added; the mixture is kept at 160° C. for 3 hours, whilst distilling off the water formed. Distillation under reduced pressure (21 mbar) gives 318.7 parts of 5-methoxy-2,3,3-trimethyl-indolenine (melting point 53°-54° C.), corresponding to 84.3% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:15]([NH:16][C:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[O:18])[C:14](=[O:29])[NH:13][C:12]3[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH:15]([NH:16][C:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[O:18])[C:14](=[O:29])[N:13]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:12]3[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C2Sc3ccccc3NC(=O)C2NC(=O)c2ccc3ccccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(NC(=O)c2ccc3ccccc3c2)C(c2ccc(OC)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In the same manner as in (iv) of Example 1, 1.5 g of 2-p-methoxyphenyl-3-(2-naphthalenecarboxamido)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is dissolved in 30 ml of dimethylformamide, whereto 0.145 g of 60% sodium hydride is added under ice-cooling. After the mixture is stirred at room temperature for 30 minutes, 5 ml of dimethylformamide containing 0.45 ml of ethyl bromoacetate is added dropwise. The mixture is stirred at room temperature for 3 hours, and then the reaction mixture is concentrated under reduced pressure. Chloroform and water are added to the residue to separate the organic layer. The chloroform layer is washed with water and dried. The solvent is distilled off under reduced pressure. A mixed solvent of isopropyl alcohol-isopropyl ether is added thereto. The resulting crystals are collected by filtration to give 1.8 g of ethyl 2-p-methoxyphenyl-3-(2-naphthalenecarboxamido)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5acetate, m.p. 183°-186° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:13][P:14](Cl)(Cl)=[O:15]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][P:14]([CH3:13])(=[O:15])[O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CP(=O)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CP(=O)(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Yield: 88 %

Procedure:
Methylphosphonic acid bis-(4-nitrophenyl) ester is prepared according to procedure E using 1 g of 4-nitrophenol, 12 ml of THF, 345 mg of sodium hydride at 50% in oil and 478 mg of methylphosphonic dichloride. 1.07 g of crude methylphosphonic acid bis-(4-nitrophenyl) ester are obtained.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][O:16][C:17](=[O:25])[NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1COCC1.[Cl:33][CH2:34][CH2:35][CH2:36][CH2:37]I>CCCCCCC.C(OCC)(=O)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][O:16][C:17](=[O:25])[NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:37][CH2:36][CH2:35][CH2:34][Cl:33])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(NCCOCCO)OCc1c2ccccc2cc2ccccc12
Reactant: ClCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCCOCCOCCCCCl)OCc1c2ccccc2cc2ccccc12
Reaction time: 0.08 h
Yield: 31.4 %

Procedure:
A 50 ml round bottom flask was charged with [2-(2-Hydroxyethoxy)-ethyl]-carbamic acid anthracen-9-ylmethyl ester (0.25 g, 0.74 mmol) and fresh sodium hydride, 60% dispersion in mineral oil (150 mg, 3.75 mmol) under inert atmosphere. 10 ml anhydrous THF was added and the reaction allowed to stir for 5 minutes. After this point, 1-chloro-4-Iodobutane (180 μl, 1.5 mmol) is added via syringe. The reaction is stirred at room temperature for 24 hours. Silica gel 60 is co-absorbed onto the reaction mixture with loss of solvent under reduced pressure. Silica gel column chromatography takes place initially with heptane as eluent, followed by 10%, 20%, and 30% ethyl acetate. A total of 0.1 g (32% yield) of product is isolated from appropriate fractions: 1H NMR (CDCl3) δ 8.50 (s, H-10), 8.40 (d, H-1, 8), 8.03 (d, H-4, 5), 7.53 (dt, H-2, 3, 6, 7), 6.15 (s, CH2-anth), 5.19 (m, exchangeable, NH), 3.93-3.32 (m, 12H) 1.69-1.25 (m, 4H). Mass spectrum, m/e Calcd for C24H28ClNO4.H2O: 447.18 (100.0%), 448.18 (27.1%). Found: 447.17, 448.41.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH2:15].C(=O)([O-])[O-].[K+].[K+].Cl[C:29]1[N:34]=[C:33]([S:35][C:36]#[N:37])[C:32]([N+:38]([O-:40])=[O:39])=[CH:31][N:30]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:29]1[N:34]=[C:33]([S:35][C:36]#[N:37])[C:32]([N+:38]([O-:40])=[O:39])=[CH:31][N:30]=1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: COc1ccc(CNc2ccc(C#N)cc2N)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(SC#N)n2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 6.5 %

Procedure:
A solution of 4-(2,4-dimethoxybenzylamino)-3-aminobenzonitrile (3.9 g) in acetonitrile (100 mL) was cooled to 0° C. and treated with potassium carbonate (6.3 g) followed by a solution containing 3 g of 2-chloro-5-nitro-4-thiocyanatopyrimidine (WO 2003/032994) in acetonitrile (50 mL). The mixture was stirred for 30 minutes at 0° C. and 30 minutes at room temperature resulting in the formation of a precipitate. The mixture was quenched at 0° C. by the addition of 4% acetic acid (150 mL) and filtered. The precipitate was swirled in 100 mL acetonitrile and filtered again. The precipitate was washed with acetonitrile, which resulted in the slow dissolution of product into the filtrate. After air-drying, 1.5 g of the title compound remained as the precipitate cake. The filtrate was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (0→20% EtOAc/DCM) and recrystallization from acetonitrile provided 0.415 g of additional title compound.
Reaction SMILES: [CH2:1]([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[H-].[Na+].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>CN(C=O)C>[CH3:23][CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34]([NH:18][S:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:16])=[O:17])=[O:35])[CH3:22]
Reactant: CCCCCCCCCCCCCCS(N)(=O)=O
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCS(=O)(=O)NC(=O)Nc1c(C(C)C)cccc1C(C)C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
A solution of 1-tetradecylsulfonamide (9.0 g, 32.4 mmoles) in DMF (90 mL) was added dropwise to a stirred suspension of NaH (1.63 g, 68 mmoles) in 30 mL of DMF. The solution was stirred 60 minutes, then 2,6-diisopropylphenyl isocyanate (7.0 mL, 33 mmoles) was added dropwise. The mixture was stirred overnight at room temperature, then quenched by dropwise addition of 1M HCl. The mixture was then partitioned between H2O and ethyl acetate (500 mL each). The aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate extracts were diluted with hexane (100 mL) and then washed exhaustively with H2O. The organic extracts were dried, filtered, and concentrated to a solid residue, which was triturated with ether and the solid isolated by suction filtration and dried. Isolated 9.70 g of solid, m.p. 135-137° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: c1ccc(COCCOc2ccc(C3CCCCC3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: OCCOc1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 103 %

Procedure:
3.2 g of 1-[2-(Benzyloxy)ethoxy]-4-cyclohexylbenzene was dissolved in 100 ml of ethanol, and 300 mg of 20% palladium hydroxide was added, and the mixture was stirred at room temperature under hydrogen atmosphere for 25 hours. The catalyst was filtered off and washed with ethyl acetate. The filtrate was evaporated, and the residue was subjected to azeotropy with toluene (×2), to give 2.34 g of the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([NH:18][NH2:19])=[O:17])[N:13]=2)=[N:6][CH:7]=1.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[O:17][C:32]([OH:33])=[N:19][N:18]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Solvent: C1CCOC1
Product: Oc1nnc(CCc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)o1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
To a mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanehydrazide (0.150 g, 0.345 mmol) in THF (5 mL) was added TEA (0.04814 mL, 0.3454 mmol) and cooled in an ice bath. To this mixture was added. CDI (0.0672 g, 0.414 mmol) in one portion. The mixture was allowed to warm to ambient temperature and was then heated at 50° C. overnight. The reaction was concentrated to dryness, dissolved in CH2Cl2 and washed with water, dried over Na2SO4, concentrated to a residue that was purified by preparative HPLC to give the title compound (0.045 g, 28.31% yield) was white solids. 1H NMR (d6 DMSO) δ 2.91 (s, 4H), 6.75 (s, 1H), 7.10 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.4 Hz, 1H), 7.40 (d, J=2.1 Hz, 1H), 7.44 (t, J=7.9 Hz, 2H), 8.22 (d, J=2.1 Hz, 1H), 11.03 (br s, 1H), 12.04 (br s, 1H).