Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=3[F:37])=[O:25])=[CH:19][CH:18]=2)=[C:11]([C:14]([NH2:16])=[O:15])[NH:12][CH:13]=1)=O)(C)(C)C.[ClH:38]>O1CCOCC1.CCCCC>[ClH:38].[NH2:8][C:9]1[C:10]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=[CH:29][C:28]=3[F:37])=[O:25])=[CH:19][CH:18]=2)=[C:11]([C:14]([NH2:16])=[O:15])[NH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1c[nH]c(C(N)=O)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Agent: Cl
Solvent: CCCCC
Solvent: C1COCCO1
Product: NC(=O)c1[nH]cc(N)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To 0.15 g (0.288 mmol) of 4-tert-butyloxycarbonylamino-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-2-carboxamide suspended in 1 cm3 of dioxane is added, at a temperature in the region of 20° C., 0.72 cm3 of a 4N solution of hydrogen chloride in dioxane. After stirring for 5 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue, which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (gradient of from 90/5/5 to 80/10/10 by volume)]. After concentrating the fractions under reduced pressure, 85 mg of a yellow solid are obtained, and are then stirred in 4 cm3 of pentane for 16 hours. After filtering through a No 3 sinter funnel, the solid is washed with twice 1 cm3 of pentane and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. for 4 hours to give 47 mg of 4-amino-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-2-carboxamide hydrochloride in the form of a yellow solid melting at about 174° C.; 1H NMR (400 MHz, DMSO d6, δ in ppm) from 5.30 to 8.00 (very broad m, 2H); 6.34 (d, J=2.5 Hz, 1H); 7.27 (d, J=8.5 Hz, 2H); 7.39 (m, 1H); 7.50 (partially masked m, 1H); 7.53 (d, J=8.5 Hz, 2H); 8.63 (broad d, J=7.0 Hz, 1H); 8.96 (broad s, 1H); 9.29 (s, 1H); 10.7 (broad s, 1H):; ES+: m/z=422: [M+H]+; ES−: m/z=420: [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16]CCCCC.[Si](C=[N+]=[N-])(C)(C)C>CO.C1C=CC=CC=1>[CH3:16][O:11][C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of the N-tert-butoxycarbonylproline (6.00 g, 0.0279 mol) in MeOH:benzene (1:4, v/v) was added dropwise 2.0 M-n-hexane solution of TMSCHN2 (16.7 mL, 0.0334 mol) at room temp. After the resulting solution was stirred for 1 hr at room temp, the mixture was evaporated off in vacuo to afford 6.39 g (100%) N-tert-butoxycarbonylproline methyl ester as a yellow syrup. 1H-NMR (CDCl3) δ1.41 (s, 9H), 1.85-1.98 (m, 4H), 2.21-2.28 (m, 2H), 3.72 (s, 3H), 4.29 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[C-:32]#[N:33].[Na+]>CS(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([S:19][C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([C:32]#[N:33])=[N:3][N:4]=4)=[CH:14][CH:15]=3)=[CH:21][CH:22]=[N:23]2)=[N:28][CH:27]=1
Reactant: [C-]#N
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cnc2c(Sc3ccc(Nc4nnc(C#N)c5ccccc45)cc3)ccnc2c1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
In a 15 ml sealed pressure tube, was dissolved 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (150 mg, 490 μmol) in 0.8 ml of DMSO. Sodium cyanide (72 mg, 1469 μmol) was added and the reaction was capped and stirred at 130° C. for 3 hours. The reaction was cooled to RT and purified via Gilson Reverse Phase HPLC eluting with a 12-75% gradient of ACN in water with 0.1% TFA. The product fractions were basified with saturated sodium bicarbonate and extracted into DCM. The DCM layers were dried over Na2SO4, filtered and concentrated in vacuo to afford 4-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenylamino)phthalazine-1-carbonitrile. MS: [M+H]=437.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:12])[CH3:11])\[C:6]([O:8][CH3:9])=[O:7].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[C:47]([O:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:49])[CH3:48].C(N(CC)CC)C>ClCCl.O.CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:23])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:54]2[CH2:55][CH2:56][CH:51]([O:50][C:47](=[O:49])[CH3:48])[CH2:52][CH2:53]2)=[O:21])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:11])[CH3:12])\[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C(Cc1ccc(C(=O)O)cc1)=C(\C(=O)OC)C(C)C
Reactant: CC(=O)OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)/C(Cc1ccc(C(=O)N2CCC(OC(C)=O)CC2)cc1)=C(\C(=O)OC)C(C)C
Yield: 77.4 %

Procedure:
To a solution of 2-(4-carboxybenzyl)-3-isopropylmaleic acid dimethyl ester (10.3 mg, 0.0322 mmol) in dichloromethane (500 μL) were added 1-hydroxybenzotriazole (13.3 mg, 0.0965 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (20.8 mg, 0.109 mol), piperidin-4-yl acetate hydrochloride (28.8 mg, 0.161 mmol) and triethylamine (14.6 mg, 0.145 mmol) with stirring under ice cooling. After stirring at room temperature for 1 h, the reaction mixture was diluted with water to separate the phases. The aqueous layer was extracted again with ethyl acetate, and the combined organic layer was concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 1:2) to give 11.1 mg of the title compound as a solid (yield: 78%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=O)(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([N:26]3[CH2:27][CH2:28][CH2:29][C:30]3=[O:32])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCNS(=O)(=O)c1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(S(=O)(=O)N3CCCC3=O)cc2)CC1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
8.2 g of product obtained in Stage A, 8.2. g of sodium acetate and 123 cm3 of acetic anhydride are heated to reflux for 30 minutes. The mixture is cooled to ambient temperature, evaporated to dryness, the residue is taken up with 100 cm3 of water, filtered and dried. 5.6 g of 1-[4-(4-benzyloxycarbonylpiperazin-1-yl)phenylsulphonyl]-2-pyrrolidinone is obtained. m.p.=153°-155° C. After recrystallization from an ethanol-acetone mixture (10-1), 3.7 g of product is obtained, melting at 158°-160° C. 7 g of product prepared as above and 1 g of palladium are put in suspension in 105 cm3 of dimethylacetamide, a few drops of triethylamine are added, then the whole is hydrogenated under ambient pressure (with 280 cm3 of hydrogen). The catalyst is filtered off, evaporated to dryness and 2 g of product is obtained which is dissolved in acetic acid and evaporated to dryness. The residue is taken up in isopropyl alcohol and 1.5 g of crystallized product is obtained.
Reaction SMILES: [OH-].[Na+].C(O)C.[F:6][C:7]([F:21])([F:20])[CH2:8][O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([O:18]C)=[O:17])=[N:14][CH:15]=1.O>C1COCC1.C(OCC)(=O)C>[F:21][C:7]([F:6])([F:20])[CH2:8][O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[N:14][CH:15]=1
Reactant: COC(=O)c1cnc(OCC(F)(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(OCC(F)(F)F)cn1

Procedure:
A 5 N sodium hydroxide solution (3 mL) and ethanol (3 mL) were added to a solution of methyl 5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylate obtained in Preparation Example 50-(1) (197 mg) in THF (5 mL), and the mixture was heated under reflux for 15 minutes. After returning to room temperature, water and ethyl acetate were added and the aqueous layer was separated. The aqueous layer was adjusted to pH 1 with hydrochloric acid, and ethyl acetate was added to the aqueous layer. The organic layer was separated and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound (87 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[SH:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[S:22][C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Sc1ccc2ccccc2c1
Product: O=[N+]([O-])c1ccc(Sc2ccc3ccccc3c2)c(Cl)c1

Procedure:
2-(2-Chloro-4-nitro-phenylsulfanyl)-napthalene was synthesized (100%) from 3-chloro-4-fluoro-nitrobenzene (Aldrich) and napthalene-2-thiol (Avocado) in a similar manner as described in example 89.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][NH:10][C:11]=3[CH:12]=[C:4]2[CH2:3][CH2:2]1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN(C=O)C>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][N:15]=[C:14]2[N:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][NH:10][C:11]=3[CH:12]=[C:4]2[CH2:3][CH2:2]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: c1c2c(cc3c1NCC3)NCC2
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCc4cc5c(cc43)CCN5)c2cc1OC
Yield: 65 %

Procedure:
Utilizing a procedure analogous to that described in Example 24, this product was prepared in 65% yield from 1,2,3,5,6,7-hexahydro-pyrrolo[2,3-f]indole (1.7 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in DMF. (LC-MS: 349 (MH+); RP18-HPLC RT: 3.51 min)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[S:12]([NH:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[C:17]=1[CH3:22])(=[O:14])=[O:13].[CH3:23][C:24]([CH3:26])=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:23][CH:24]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[S:12]([NH:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[C:17]=1[CH3:22])(=[O:14])=[O:13])[CH3:26]
Reactant: Cc1noc(NS(=O)(=O)c2cccc3c(N)cccc23)c1C
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2cccc3c(NC(C)C)cccc23)c1C
Reaction time: 0.75 h
Yield: 123.5 %

Procedure:
To a solution of Example 3 (0.150 g, 0.473 mmol) in 10 mL of methanol, was added acetone (0.035 g, 0.473 mmol). The resulting clear yellow solution was stirred for 45 minutes. Sodium cyanoborohydride (0.058 g, 0.95 mmol) and acetic acid (0.172 g, 2.85 mmol) were added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, taken up in 20 mL of water and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (1×35 mL), dried (magnesium sulfate) and concentrated in vacuo to give 0.21 g of a yellow solid. This material was chromatographed (50 g Merck silica gel) using ethyl acetate:hexanes (1:1) as the eluant to give 0.101 g (60%) of Example 18 as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:34][CH2:35][C:36]1[CH:37]=[C:38]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)[CH:43]=2)[CH:39]=[CH:40][CH:41]=1>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:26]([NH:34][CH2:35][C:36]4[CH:37]=[C:38]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]6[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:53][CH2:54]6)[CH:43]=5)[CH:39]=[CH:40][CH:41]=4)=[O:27])[CH:29]=[CH:30][CH:31]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (0.072 g, 0.16 mmol) in DMF (1 mL) was added 1,1-dimethylethyl 4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.061 g, 0.16 mmol), (1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinylphosphorus hexafluorophosphate (0.100 g, 0.192 mmol), and TEA (0.045 mL, 0.320 mmol) and this mixture was stirred at room temperature for 16 h. The resultant mixture was purified using a Gilson HPLC (with 0.1% TFA) and concentrated by GeneVav EZ-2 evaporator to afford the title compound. It was used in the next reaction step without further purification. LC-MS m/z 815 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH2:58])[S:55][C:45]=2[C:46]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[N:47][CH:48]=1>C1COCC1>[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH:58][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])[S:55][C:45]=2[C:46]([N:49]2[CH2:50][CH2:51][O:52][CH2:53][CH2:54]2)=[N:47][CH:48]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)C3CCCCC3)nc12

Procedure:
From cyclohexanecarboxylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 377 (M+H+, 100).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[NH:16][N:15]=[CH:14][C:12]=2[N:13]=1.IC>O1CCCC1>[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[N:16]([CH3:1])[N:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Clc1ncc2[nH]ncc2n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1ncc2nc(Cl)ncc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.8 %

Procedure:
Potassium t-butoxide (1.68 g, 14.67 mmol, 1.14 equiv) was added to a solution of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine (2.1 g, 12.91 mmol, 1.00 equiv, 95%) in tetrahydrofuran (50 mL) at 0° C. After the reaction mixture was stirred at 0° C. for 30 min, iodomethane (3 g, 20.71 mmol, 1.60 equiv, 98%) was added dropwise at 0° C. The resulting solution was stirred for 4.5 h at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/ethyl acetate (10/1) to give 300 mg (14%) of 5-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine as a white solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].C([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[N:13][C:14]1[C:15](Cl)=[N:16][C:17]([CH3:21])=[N:18][C:19]=1[Cl:20])(=O)C>CO>[Cl:20][C:19]1[C:14]([N:13]=[C:9]2[NH:8][CH2:12][CH2:11][NH:10]2)=[C:15]([O:2][CH3:1])[N:16]=[C:17]([CH3:21])[N:18]=1
Reactant: CC(=O)N1CCNC1=Nc1c(Cl)nc(C)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1nc(C)nc(Cl)c1N=C1NCCN1

Procedure:
The final product, 4-chloro-N-(imidazolin-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine is synthesized by first preparing sodium methoxide in situ from anhydrous methanol and sodium. The fifth intermediate, N-(1-acetylimidazolin-2-ylidene)-4,6-dichloro-2-methyl-5-pyrimidinamine, is added and the reaction mixture brought to a boil. From 15 minutes to 1 hour after the reaction mixture is brought to a boil, further sodium methoxide is added and the reaction mixture is maintained at a boil for from 15 minutes to 1 hour to afford 4-chloro-N-(imidazolin-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine.
Reaction SMILES: [CH3:1][C:2]1[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15].C([O-])(=O)C.[K+].C(O)(=O)C.C(OC(=O)C)(=O)C.O1CCOCCOCCOCCOCCOCC1.[N:50](OCCC(C)C)=O>C(Cl)(Cl)Cl>[C:12]([N:11]1[C:10]2[CH:9]=[CH:8][C:7]3[C:6](=[O:15])[CH2:5][CH2:4][C:3]=3[C:2]=2[CH:1]=[N:50]1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc2c(c1C)CCC2=O
Reactant: CC(C)CCON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)n1ncc2c3c(ccc21)C(=O)CC3
Temperature: 65 °C
Reaction time: 23 h

Procedure:
A stirred mixture of N-(4-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)acetamide (20.00 g, 98.40 mmol), potassium acetate (19.32 g, 197 mmol), acetic acid (11.3 mL, 197 mmol), acetic anhydride (18.6 mL, 197 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (5.20 g, 19.7 mmol) in 600 mL of chloroform was heated at 65° C. and isopentyl nitrite (33.0 mL, 246 mmol) was added during 10 minutes. The mixture was stirred at 65° C. for 23 hours and was then allowed to cool to room temperature. The reaction mixture was diluted with chloroform and washed successively with saturated NaHCO3 (2×), water and brine. After drying over Na2SO4, the solution was concentrated to low volume under vacuum and flash chromatographed on silica gel eluting with EtOAc/dichloroethane (0:100 to 10:90) to give 3-acetyl-7,8-dihydrocyclopenta[e]indazol-6(3H)-one as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:3]=1[C:22](=[O:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:31]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:3]=1[C:22](=[O:24])[CH3:23])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: COCCOCOc1cc(O)c(C(C)=O)c(OCOCCOC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCOc1cc(OCOCCOC)c(C(C)=O)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 73 %

Procedure:
To a stirred suspension of 1-{2-hydroxy-4,6-bis[(2-methoxyethoxy)methoxy]phenyl}ethanone (3.53 g, 10 mmol), potassium carbonate (1.7 g, 14 mmol) in DMF (15 mL) was added benzylbromide (2.1 g, 12 mmol). After stirring overnight, the reaction mixture was diluted with ethyl acetate (100 mL) and thoroughly washed with brine. The organic phase was dried and evaporated to dryness. The crude was chromatographed on a small pad of silica gel eluting with hexane/ethyl acetate 7/1, to provide the title compound (g 3.25, yield 73%).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([CH2:8][O:9][C:10]2[C:11]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[F:28])=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15](OC)=[O:16])[CH2:5][CH2:4][O:3]1.[BH4-].[Na+]>CO>[CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([CH2:8][O:9][C:10]2[CH:19]=[C:14]([CH2:15][OH:16])[CH:13]=[N:12][C:11]=2[C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[F:28])[CH2:5][CH2:4][O:3]1
Reactant: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(OCC2CCOC(C)(C)C2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(-c2ncc(CO)cc2OCC2CCOC(C)(C)C2)c1
Yield: 105.2 %

Procedure:
To a solution of methyl 5-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy)-6-(2-fluoro-5-methoxyphenyl)nicotinate (950 mg) in methanol (20 mL) was added, at 0° C., sodium tetrahydroborate (1.16 g) by small portions, and the mixture was stirred at 60° C. for 4 hr. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (930 mg) as a pale-yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:33])[C:20]=2[CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-:36].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:33])[C:20]=2[CH2:21][F:36])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCc2c(SCc3ccc(C(C)(C)C)cc3)oc3ccccc3c2=O)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(C)(C)c1ccc(CSc2oc3ccccc3c(=O)c2CF)cc1

Procedure:
2-(4-Tert-butylbenzyl)thio-3-tosyloxymethyl chromen-4-one (3 g, 5.9 mmol) is introduced into a 15 mL round bottom flask and tetrabutylammonium fluoride solution (5.9 mmol; 1M in THF) is added to it. The solution is heated to reflux for 3 hours after which all volatiles are removed and the residue obtained is purified by silica gel flash chromatography (ethyl acetate:hexanes).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:22]([O:24]CC)=[O:23].[CH3:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]=1[OH:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Li+].[OH-].Cl>C1COCC1.O.CO>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][C:6]([C:22]([OH:24])=[O:23])=[C:5]2[CH2:4][CH2:3][CH2:2][O:38][C:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[CH:37][C:28]=1[CH3:27]
Reactant: Cc1ccc2ccccc2c1O
Reactant: CCOC(=O)c1[nH]c2c(-c3ccccc3OC)cccc2c1CCCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1-c1cccc2c(CCCOc3c(C)ccc4ccccc34)c(C(=O)O)[nH]c12

Procedure:
To a mixture of EXAMPLE 47A (71 mg), 2-methyl-1-naphthol (35 mg), triphenylphosphine (58 mg) in THF (2 mL) and di-tert-butyl azodicarboxylate (55 mg) was stirred at ambient temperature overnight and partitioned between ethyl acetate (150 mL) and water (50 mL). The organic layer was washed with brine and a dried (Na2SO4), filtered and concentrated. The concentrate was purified by flash chromatography on silica gel with 5% ethyl acetate in hexanes to provide an intermediate which was dissolved in THF (2 mL), methanol (1 mL) and water (1 mL) and hydrolyzed with LiOH (100 mg) overnight. The mixture was acidified with 5% HCl and extracted with ethyl acetate. The extract was washed with water and brine and dried (Na2SO4), filtered and concentrated. The concentrate was purified by reverse phase HPLC (C-18, 30 to 100% acetonitrile/water/0.1% TFA). 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.12 (dd, 1H), 7.82 (d, 1H), 7.77 (d, 1H), 7.52 (d, 1H), 7.36-7.47 (m, 5H), 7.27 (d, 1H), 7.09 (t, 2H), 4.10 (t, 2H), 3.83 (s, 3H), 3.48 (t, 2H), 2.46 (s, 3H), 2.38 (m, 2H).