Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>C(O)C.O.[C].[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccncc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)CCc1ccncc1
Yield: 65.1 %

Procedure:
tert-Butyl (E)-3-(4-Pyridyl)acrylate (0.88 g, 4.3 mmol) was dissolved in ethanol (10 ml), and 10% palladium-carbon (0.17 g) and a solution of ammonium formate (1.4 g, 21.4 mmol) in water (2.5 ml) were added thereto. The reaction mixture was refluxed for 3 hrs. Palladium-carbon was filtered off. The reaction mixture was combined with water, concentrated under reduced pressure to the half amount and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (20 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated to give the titled compound (0.58 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[O:19])=[CH:15][CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][OH:19])=[CH:15][CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C=O)cc2c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(CO)cc2c1=O
Yield: 56.8 %

Procedure:
To compound H (335 mg, 0.99 mmol) in ethanol (5 mL) cooled to 0° C. was added sodium borohydride (18.7 mg, 0.49 mmol). After ten minutes, the reaction was diluted with EtOAc and washed well with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 192 mg (57%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.25 (s, 1H), 7.76-7.72 (m, 2H), 7.61 (d, J=6 Hz, 1H), 7.54 (t, J=8.64, 8.68 Hz, 2H), 6.94 (d, J=8.68, 1H), 5.42 (t, J=5.68, 5.64 Hz, 1H), 4.62 (d, J=5.48 Hz, 2H), 4.23 (q, J=7.08 Hz, 2H), 1.27 (t, J=7.12, 7.04 Hz, 3H); ES-MS [M+1]+: 342.3.
Reaction SMILES: Cl.ClC1C=CC(NN)=CC=1.BrCCC1CCCC1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)N)=[CH:22][CH:21]=1.C(OC(OCC)CCCNC)C.ClC1C=C2[C:54](=CC=1)[N:53]([CH2:57][CH2:58][CH:59]1[CH2:63][CH2:62]CC1)C=C2CCNC.C=O.C(O)(C(F)(F)F)=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Cl:19][C:20]1[CH:25]=[C:24]2[C:23](=[CH:22][CH:21]=1)[N:26]([CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:63]1[CH2:62][N:53]([CH3:54])[CH2:57][CH2:58][C:59]2=1
Reactant: NN(CCC1CCCC1)c1ccc(Cl)cc1
Reactant: CNCCc1cn(CCC2CCCC2)c2ccc(Cl)cc12
Agent: BrCCC1CCCC1
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2c(n(CCC3CCCC3)c3ccc(Cl)cc23)C1

Procedure:
The title compound was prepared by following General Methods 2, 3 and 4 using 4-chlorophenylhydrazine hydrochloride, (2-bromoethyl)cyclopentane, and tetra-n-butylammonium chloride (General Method 2), 1-(4-chlorophenyl)-1-(2-cyclopentylethyl)hydrazine (Example 4) and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and 2-(5-chloro-1-(2-cyclopentylethyl)-1H-indol-3-yl)-N-methylethanamine (Example 13), formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:19]2[CH:18]=[C:17]([C:20]([O:22]C)=[O:21])[NH:16][C:15]=2[CH2:14][CH2:13]1.[OH-].[Li+].CO>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:19]2[CH:18]=[C:17]([C:20]([OH:22])=[O:21])[NH:16][C:15]=2[CH2:14][CH2:13]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc2ccccc2c1

Procedure:
The title compound was synthesized from methyl 4-(naphthalen-2-ylmethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.104 g, 0.34 mmol) and lithium hydroxide (0.148 g, 3.53 mmol in 5 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (10 mL) was used. The solvent was removed under reduced pressure, and the residue re-dissolved in ca. 5 mL H2O and acidified to pH 7 with 1 N HCl. The solids formed were collected, affording the title compound as a light pink solid: 77 mg, 76% yield. 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.16 (ddt, J=12.34, 8.74, 5.98, 5.98 Hz, 1H), 2.50-2.76 (m, 3H), 2.92-3.03 (m, 2H), 3.37-3.47 (m, 1H), 6.31 (d, J=1.71 Hz, 1H), 7.41-7.50 (m, 3H), 7.73 (s, 1H), 7.82-7.90 (m, 3H), 10.39 (br. s, 1H); LCMS-MS (ESI−) 290.0 (M−H); HPLC (UV=93.55%), (ELSD=100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.CCN(CC)CC.Br[CH:31]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([CH:31]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(c1ccccc1)N1CCc2c(cnc3c2cnn3Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
To a solution of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.506 g, 1.72 mmol) in dichloromethane (10 mL) and Et3N (0.72 mL, 5.16 mmol) was added ethyl 2-bromo-2-phenylacetate (0.41 mL, 1.89 mmol). The reaction mixture was stirred at room temperature for 16 hours followed by addition of aqueous NaHCO3 (30 mL). The reaction was extracted with EtOAc (60 mL) and the organic layer was then washed with brine (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using flash column chromatography (SiO2, 50% EtOAc in hexanes) to give the desired product, ethyl 2-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-phenylacetate as a yellow solid (0.134 g, 86%). 400 MHz 1H NMR (DMSO-d6) δ 8.25 (s, 1H), 8.10 (s, 1H), 7.5-7.34 (m, 5H), 7.19-7.4 (m, 2H), 6.86-6.8 (m, 2H), 5.76 (s, 1H), 5.56 (s, 2H), 4.46 (s, 1H), 4.13 (q, J=7.2 hz, 2H), 3.76 (s, 2H), 3.69 (s, 3H), 3.05 (t, J=6 hz, 2H), 2.88-2.72 (m, 2H), 1.64 (t, J=7.2 Hz, 3H); LCMS [M+H]:457.5.
Reaction SMILES: Cl.C(OCC)(=O)C.C(OC([NH:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:57]=[CH:58][CH:59]=1)[O:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]([CH2:43][CH2:44][CH2:45][NH:46][C:47](=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[F:55])[C:29](=[O:42])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)=O)(C)(C)C>>[ClH:27].[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:57]=[CH:58][CH:59]=1)[O:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]([CH2:43][CH2:44][CH2:45][NH:46][C:47](=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[F:55])[C:29](=[O:42])[C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N(CCCNC(=O)Cc2ccccc2F)C(=O)c2ccc(-c3ccccc3)cc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1cccc(Oc2cc(Cl)ccc2N(CCCNC(=O)Cc2ccccc2F)C(=O)c2ccc(-c3ccccc3)cc2)c1
Yield: 194.4 %

Procedure:
A 2 N hydrochloric acid/ethyl acetate solution (4 ml) of N-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]-N-[3-[(2-fluorophenyl)acetylamino]propyl]-4-phenylbenzamide (0.18 g, 0.25 mmols) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The solid precipitated was taken out through filtration, and washed with ethyl ether to give an amorphous solid of N-[2-[3-(aminomethyl)phenoxy]-4-chlorophenyl]-N-[3-[(2-fluorophenylacetyl)amino]propyl]-4-phenylbenzamide hydrochloride (0.16 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=2[O:28][CH3:29])=[N:12][CH:11]=1)[CH3:9])=O.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:15]3[C:10]([CH:11]=[N:12][C:13]([NH:16][C:17]4[CH:22]=[C:21]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=4[O:28][CH3:29])=[N:14]3)=[C:8]([CH3:9])[N:7]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)c1
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)c1
Yield: 27.9 %

Procedure:
In a similar manner as described for Example 9, 3-bromo-N-[1-(3-{[5-(ethylsulfonyl)-2-methoxyphenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 23) (0.11 g, 0.20 mmol) and 1,2,4-triazole (83 mg, 1.2 mmol) in pyridine (2 mL) and phosphorus oxychloride (0.056 mL, 0.6 mmol) gave 7-(3-bromophenyl)-N-[5-(ethylsulfonyl)-2-methoxyphenyl]-5-methylimidazo[5,1-f][1,2,4]triazin-2-amine (0.028 g) as a yellow solid. 1H NMR (CDCl3): δ8.89 (d, J=2.2 Hz, 1H), 8.85 (s, 1H), 8.69-8.60 (m, 1H), 8.43 (dd, J=1.8, 1.8 Hz, 1H), 7.81-7.75 (m, 2H), 7.63 (dd, J=8.5, 2.3 Hz, 1H), 7.58 (ddd, J=7.9, 2.0, 1.0 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 4.04 (s, 3H), 3.06 (q, J=7.4 Hz, 2H), 2.63 (s, 3H), 1.23 (t, J=7.4 Hz, 3H). MS m/z 502, 504 (M+1, M+3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18](C(C)(C)C(C)C)[O:19][SiH](C)C)[NH:15][C:12]2=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.C(=O)(O)[O-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH2:18][OH:19])[NH:15][C:12]2=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)c1cc2cc(OCc3ccccc3)cnc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cc2cc(OCc3ccccc3)cnc2[nH]1
Yield: 90.8 %

Procedure:
To the solution of 0.53 g (1.3 mmol) 5-benzyloxy-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-1H-pyrrolo[2,3-b]pyridine in 3 ml tetrahydrofuran 1.6 ml (1.6 mmol) tetra-n-butylammonium fluoride (1M solution in THF) were added. After 75 min. the solution was poured on saturated aqueous sodium bicarbonate solution and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was stirred in tert-butyl methyl ether, filtered and washed with tert-butyl methyl ether to give 0.3 g (88%) of the product as a brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CS[C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16]>>[N+:15]([NH:14][C:13]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[NH:18])([O-:17])=[O:16]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCSCc1nccs1
Product: N=C(NCCSCc1nccs1)N[N+](=O)[O-]

Procedure:
Reaction of 2-[(2-aminoethyl)thiomethyl]thiazole with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(2-thiazolylmethylthio)-ethyl]guanidine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[CH:13]([C:29]1[CH:34]=[C:33]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:32]([OH:39])=[CH:31][C:30]=1[CH3:40])[CH2:14][CH:15]([C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20]([OH:27])=[CH:19][C:18]=1[CH3:28])[CH3:16].C1([O:47][C:48](=[O:56])[O:49]C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1(O)C=CC=CC=1>>[C:48](=[O:47])([OH:56])[OH:49].[CH3:40][C:30]1[CH:31]=[C:32]([OH:39])[C:33]([C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:34][C:29]=1[CH:13]([C:3]1[CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:8])=[CH:7][C:2]=1[CH3:1])[CH2:14][CH:15]([C:17]1[CH:22]=[C:21]([C:23]([CH3:24])([CH3:26])[CH3:25])[C:20]([OH:27])=[CH:19][C:18]=1[CH3:28])[CH3:16]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: Cc1cc(O)c(C(C)(C)C)cc1C(C)CC(c1cc(C(C)(C)C)c(O)cc1C)c1cc(C(C)(C)C)c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Product: O=C(O)O

Procedure:
27.2g (0.05 mole) of 1,1,3-tris(2'-methyl-4'-hydroxy -5'-t-butylphenyl) butane, 8.6g (0.04 mole) of diphenylcarbonate and 0.05g of potassium carbonate were reacted under N2 atmosphere at 150° C for 3 hours, and then phenol was distilled off under reduced pressure (max. 160° C/3 mm Hg) to obtain a glassy solid. Distilled phenol residue after cooling was 100% of the calculated quantity and the molecular weight of the product was 2740 (calculated value: 2824).
Reaction SMILES: [NH2:1][C:2]([C:20]#[N:21])=[C:3]([N:6]=[CH:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[Cl:19])[C:4]#[N:5].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(#N)C>[Cl:14][C:13]1[CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=[C:9]([Cl:19])[C:8]=1[C:7]1[NH:1][C:2]([C:20]#[N:21])=[C:3]([C:4]#[N:5])[N:6]=1
Reactant: N#CC(N)=C(C#N)N=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC#N
Product: N#Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1C#N
Yield: 42.3 %

Procedure:
A solution of 1-amino-2-(2,6-dichloro-4-trifluoromethylbenzylideneamino)-1,2-dicyanoethylene (3.3 g, 0.01 mol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.3 g, 0.01 mol) in acetonitrile (75 ml) was stirred at reflux for 48 hours. Evaporation of the solvent yielded a brown solid which was continuously extracted with boiling toluene. The solution was evaporated under reduced pressure and the red-brown residue was dissolved in a mixture of ethyl acetate and dichloromethane (1:10) and filtered through silica. Evaporation of the liltrate gave a brown solid which was triturated with hexane and the solid was removed by filtration to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4,5-dicyanoimidazole (1.4 g) as a light brown solid, m.p. 194°-195° C.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[CH:21].CCOCC>C(#N)C.[Cu]I>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: C#CCCCCOCCCCCCBr
Reactant: Brc1cnccn1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCOCC
Product: BrCCCCCCOCCCCC#Cc1cnccn1
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A mixture of bromopyrazine (1.64 g), 6-[(6-bromohexyl)oxy]-1-hexyne (2.69 g) N,N-dicyclohexylamine (1.88 g), BTPC (130 mg) and copper (I) iodide (13 mg) in acetonitrile (30 ml) was stirred at 22° under nitrogen for 1 h. Ether (150 ml) was added, the mixture filtered and evaporated in vacuo to an oil which was purified by FCC eluting with hexane-ether (3:2→1:1) followed by ether to give the title compound as a dark yellow oil (2.79 g), t.l.c. (ether) Rf 0.5.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[C:16]([OH:18])=O>C1C=CC=CC=1>[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[C:16]([Cl:3])=[O:18]
Reactant: O=C(O)c1cnc2ccccc2c1O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1cnc2ccccc2c1O

Procedure:
3.8 ml of thionyl chloride were added to a suspension of 8.2 g of 4-hydroxy-quinoline-3-carboxylic acid in 160 ml of benzene and the mixture was refluxed for an hour and then cooled. The mixture was vacuum filtered and the precipiate was empasted with a little anhydrous benzene and was dried to obtain 9 g of 4-hydroxy-quinoline-3-carboxylic acid chloride melting at 260° C. The said product was then reacted with 4.35 g of 2-aminothiazole as in Example 1 to obtain 4.3 g of N-(2-thiazolyl)-4-hydroxy-quinoline-3-carboxamide melting at 349°-350° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]2[C:15]3[C:16]([CH3:30])=[C:17]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([CH3:21])=[C:19]([CH3:20])[C:14]=3[O:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[CH2:31]([O:33][C:34](=[O:37])[CH2:35]Br)[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.[I-].[K+]>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([NH:22][C:17]1[C:18]([CH3:21])=[C:19]([CH3:20])[C:14]2[O:13][CH2:12][CH:11]([C:4]3[CH:5]=[CH:6][C:7]([CH:8]([CH3:10])[CH3:9])=[C:2]([CH:3]=3)[O:1][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:37])[C:15]=2[C:16]=1[CH3:30])=[O:29]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)c(O)c1)CO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)COc1cc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)ccc1C(C)C
Yield: 90.6 %

Procedure:
A mixed solution of N-(3-(3-hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (500 mg, 1.22 mmol) obtained in Example 186, ethylbromoacetate (245 mg, 1.47 mmol), potassium carbonate (253 mg, 1.83 mmol) and potassium iodide (10 mg) in acetone (10 mL) was heated for 16 hours under an argon atmosphere. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 548 mg (yield: 91%) of the title compound. Melting point: 149-150° C. (ethyl acetate-hexane).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13]1(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[O:1]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccnc(CO)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(COc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Methyl 2-(hydroxymethyl)isonicotinate (2.232 g, 13.35 mmol) dissolved in THF (15 mL) and phenol (1.426 mL, 16.02 mmol) and triphenylphosphine (3.71 mL, 16.02 mmol) were added. The mixture was cooled to 0° C. (E)-diisopropyl diazene-1,2-dicarboxylate (3.24 g, 16.02 mmol) was added dropwise, the ice-bath removed and the reaction stirred at room temperature for 2 h. The solvent was evaporated and the residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column. 4:1 of EtOAc in heptane over 10 CV was used as mobile phase. Methyl 2-(phenoxymethyl)isonicotinate (2.65 g, 82%) was isolated. 1H NMR (400 MHz, cdcl3) δ 3.96 (s, 3H), 5.26 (s, 2H), 6.95-7.04 (m, 3H), 7.27-7.34 (m, 2H), 7.76-7.80 (m, 1H), 8.10 (s, 1H), 8.75 (d, 1H). MS m/z 244 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[N:5]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:4](=[O:21])[CH2:3]1.CC(C1C=C(C(C)C)C(S([N:37]=[N+:38]=[N-:39])(=O)=O)=C(C(C)C)C=1)C>C1COCC1>[N:37]([CH:3]1[C:4](=[O:21])[N:5]([CH2:17][CH:18]2[CH2:19][CH2:20]2)[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]([CH2:9][CH:10]2[CH2:11][CH2:12]2)[C:2]1=[O:1])=[N+:38]=[N-:39]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: O=C1CC(=O)N(CC2CC2)c2ccccc2N1CC1CC1
Solvent: C1CCOC1
Product: [N-]=[N+]=NC1C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Temperature: -30 °C

Procedure:
For this substrate General Procedure 8-K was modified in the following manner. Initially the product from Step A was suspended (not a solution) in THF at −78° C., and following addition of the KN(TMS)2 solution, this suspension was allowed to warm to −30° C., during which the suspension became a solution, and was re-cooled to −78° C. Upon re-cooling to −78° C. a precipitate began to form, therefore the reaction flask containing the mixture was partially raised above the cooling bath until the internal temperature rose to −50° C.; then the trisyl azide solution was added. The cooling bath was removed and the mixture allowed to warm to −20° C. whereupon the mixture had become a nearly homogenous solution, and the AcOH was added. Then, treated as described in the general procedure. 3-Azido-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was purified by trituration with hot to room temperature EtOAc, followed by recrystalization from hot to −23° C. CHCl3/EtOAc/EtOH (5:5:1) and isolated as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[NH:23][C:22](=[O:28])[CH2:21]2>>[Cl:27][C:25]1[CH:26]=[C:18]([CH3:17])[CH:19]=[C:20]2[C:24]=1[NH:23][C:22](=[O:28])[C:21]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1
Reactant: Cc1cc(Cl)c2c(c1)CC(=O)N2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3c(Cl)cc(C)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-methyl-7-chloro-2-oxindole to give 0.35 g of 7-chloro-3-(3,5-diisopropyl-4-methoxybenzylidene)-5-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23]Cl>C(Cl)Cl>[CH:1]([C:4]1[N:5]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ncc[nH]1
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCn1ccnc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
A mixture of 2-isopropylimidazole (3.0 g, 27.2 mmol) and DIEA (5.28 g, 40.9 mmol) in DCM (75 mL) was treated drop-wise with methoxyethoxymethyl chloride [MEM-Cl] (4.24 g, 34.0 mmol) and stirred at RT for 16 h. The mixture was washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford 2-isopropyl-1-((2-methoxyethoxy)methyl)-1H-imidazole (3.91 g, 72%). 1H NMR (400 MHz, DMSO-d6): δ 7.11 (d, J=1.3 Hz, 1H), 6.74 (d, J=1.3 Hz, 1H), 5.30 (s, 2H), 3.47-3.46 (m, 2H), 3.38-3.37 (m, 2H), 3.19 (s, 3H), 3.08-3.07 (m, 1H), 1.18 (d, J=6.8 Hz, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[O:19])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:23][C:24]([CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:28][CH2:27]1)=[O:25].Cl.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[N:1]1[CH:2]=[CH:3][C:4]([C:7](=[O:19])[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=2)[CH2:23][C:24](=[O:25])[CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:33])[CH2:28][CH2:27]2)=[CH:5][CH:6]=1
Reactant: O=C(CCl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CS(C)=O
Product: O=C(CC(C(=O)c1ccncc1)c1cccc(C(F)(F)F)c1)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
Under Ar, a solution of 33 (5.2 g, 19.6 mmol) in DMSO (65 mL) was stirred at room temperature and treated with 95% NaH (0.58 g, 22.8 mmol). After 1 h, a solution of 5 (5.8 g, 19.6 mmol) in DMSO (25 mL) was added dropwise. After 18 h, the reaction was poured into 2N HCl (100 mL) and then basified with saturated Na2CO3 and then extracted with EtOAc (3×). The combined EtOAc extracts were backwashed with H2O, brine, dried, filtered and concentrated to dryness. The residue was chromatographed on a Still column to yield 3.3 g of crude 34.