Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([OH:23])[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:37]([CH:39]1[O:41][CH2:40]1)Cl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:37][CH:39]1[O:41][CH2:40]1)[CH:15]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2cc(O)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2cc(OCC3CO3)ccc12

Procedure:
Reaction of 3′,4′-dibenzyloxy-7-hydroxy-flavone, 23 (10 g, 22.2 mmol), 50% sodium hydride (3 g, 125 mmol) and epichlorohydrin (6.9 mL, 88 mmol) in dry dimethyl formamide (160 mL) using identical procedure as described for 28 furnished 29. Yield 9.7 g (86%); mp 168-170° C.; MS (FAB) 507 (M++1); IR (KBr) 1639; 1H NMR (200 MHz, CDCl3) δ 8.12 (d, J=8.7 Hz, 1H), 7.50-7.32 (m, 12H), 7.04-6.93 (m, 3H), 6.61 (s, 1H), 5.24 (s, 4H), 4.38 (dd, J=11.1 Hz, 2.9 Hz, 1H), 4.05 (dd, J=11.1 Hz, 5.8 Hz, 1H), 3.42-3.40 (m, 1H), 2.96 (t, J=4.5 Hz, 4.5 Hz, 1H), 2.80 (dd, J=4.8 Hz, 2.6 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][C:13]([F:25])([F:24])[C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:7]=[CH:6][C:5]=2[S:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:24][C:13]([F:25])([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)[CH2:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)=[CH:3][S:4][C:5]=2[CH:6]=[N:7]1
Reactant: O=c1c2c(Br)csc2cnn1CC(F)(F)c1ccc2ccccc2n1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: O=c1c2c(-c3ccncc3)csc2cnn1CC(F)(F)c1ccc2ccccc2n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
A mixture of 3-bromo-5-(2,2-difluoro-2-(quinolin-2-yl)ethyl)thieno[2,3-d]pyridazin-4(5H)-one (0.118 mmol), pyridin-4-yl boronic acid (0.118 mmol), Na2CO3 (31.4 mg, 0.296 mmol) and PdCl2(dppf)-CH2Cl2 adduct (9.67 mg, 0.012 mmol) in dioxane (1.5 mL) and water (0.5 mL) was stirred at 100° C. for 2 h. The solvent was evaporated and the residue was purified by Pre-TLC (PE/EA=1/1) to give a crude yellow solid. The solid was dissolved in DCM (1.5 mL) and filtered. The white solid obtained was the title compound (40 mg, yield 80%).
Reaction SMILES: [Cl:1][CH:2]1[CH2:9][CH2:8]C[NH:6][C:4](=[O:5])[CH2:3]1.C1(=O)NCCCC1.[C:17]([N:25]1[CH2:31][CH2:30]C[CH:28]([Cl:32])[CH2:27][C:26]1=[O:33])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ClC1CCNC(=O)C1>>[Cl:1][CH:2]1[CH2:9][CH2:8][NH:6][C:4](=[O:5])[CH2:3]1.[C:17]([N:25]1[CH2:31][CH2:30][CH:28]([Cl:32])[CH2:27][C:26]1=[O:33])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CC(Cl)CCCN1C(=O)c1ccccc1
Reactant: O=C1CC(Cl)CCCN1
Agent: O=C1CC(Cl)CCN1
Agent: O=C1CCCCN1
Product: O=C1CC(Cl)CCN1C(=O)c1ccccc1

Procedure:
3-Chlorovalerolactam is synthesized as for 3-chlorocaprolactam (prepared from caprolactam according to J. Am. Chem. Soc. 1958, 80, 6238) using valerolactam in place of caprolactam. Thereafter, the title compound is synthesized as for N-benzoyl-3-chlorocaprolactam (Example VI) using 3-chlorovalerolactam in place of 3-chlorocaprolactam.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[CH:16]1[CH2:20][CH2:19][N:18]([CH3:21])[C:17]1=[O:22]>ClCCCl>[C:1](=[N:14][CH:16]1[CH2:20][CH2:19][N:18]([CH3:21])[C:17]1=[O:22])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CN1CCC(N)C1=O
Solvent: ClCCCl
Product: CN1CCC(N=C(c2ccccc2)c2ccccc2)C1=O
Temperature: 95 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Benzophenone imine (200.04 g, 1103.8 mmol) was added dropwise over 20 minutes to a stirred solution of 3 amino-1-methylpyrrolid-2-one (120 g, 1051.2 mmol) in DCE (1000 mL) at ambient temp under nitrogen in a 2 L flask fitted with a magnetic stirrer bar. The reagent was washed with further DCE (100 mL). The stirred solution was heated at reflux on a heat-on block at a block temp of 95° C. for 7 h, using a N2 bubbler with exhaled gas passing through a safety trap then into 2 L of water via an upturned funnel (for scrubbing NH3 gas, estimated to be approx 23 L). The reaction was left to stand at ambient temp overnight under N2. The mixture was evaporated to a thick, off-white oil. To this was added Et2O (700 ml) and to this stirred solution, as it began to crystallize, was added iso-hexane (700 ml) over 2 minutes. The mixture was stirred for 1 h then filtered under suction and washed with Et2O/iso-hexane (1:1) (500 ml). The white solid was dried at 35° C. under vacuum for 3 h to afford 3-(benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (D5) (259.4 g, 88.6%);
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6]P(=O)(OCC)OCC)=[CH:4][CH:3]=1.[CH:17]([C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:17]/[C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:16]=1
Reactant: CCOP(=O)(Cc1ccc(Cl)cc1)OCC
Reactant: CCOC(=O)c1ccc(OC)c(C=O)c1
Product: CCOC(=O)c1ccc(OC)c(/C=C/c2ccc(Cl)cc2)c1

Procedure:
The captioned compound was synthesized from diethyl (4-chlorobenzyl)phosphonate and ethyl 3-formyl-4-methoxybenzoate obtained in step C of Example 1-2-1 in accordance with the same procedure as in the methods described in step A of Example 2-2-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(CCl)Nc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: O=C(CN1CCCC1)Nc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
N-(4-Bromo-phenyl)-2-chloro-acetamide (0.3 g, 1.21 mmol) was dissolved in anhydrous toluene (10 ml). Pyrrolidine (0.3 ml, 3.63 mmol) was added dropwise to the mixture, which was then heated to reflux and stirred overnight. The toluene was removed under reduced pressure and the residue was dissolved in ethyl acetate. Saturated ammonium chloride was added and the aqueous layer was extracted twice with ethyl acetate. The organics were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Yield 0.22 g, 65%. LCMS method: 2, RT: 2.62 min; MI: 283-285 [M+1].
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([N:41]=[C:42]=[O:43])[C:15]([O:17][C@@H:18]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:19][C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:41][C:42]([N:45]([CH3:44])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)=[O:43])[C:15]([O:17][C@@H:18]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:19][C:20]([O:22][CH2:23][C:24]([Cl:26])([Cl:25])[Cl:27])=[O:21])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCC[C@@H](CC(=O)OCC(Cl)(Cl)Cl)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)N=C=O
Reactant: CNc1ccccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCC[C@@H](CC(=O)OCC(Cl)(Cl)Cl)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)N(C)c1ccccn1
Yield: 65.1 %

Procedure:
A solution of (3S)-(2,2,2-trichloroethyl) 3-[(2S)-5-benzyloxycarbonyl-2-isocyanatopentanoyl]oxyhexadecanoate (0.33 g) and 2-(methylamino)pyridine (113 mg) in dichloromethane (5 ml) was stirred at room temperature overnight. The mixture was poured into ethyl acetate (20 ml), and washed with aqueous 1 N-hydrochloric acid (20 ml×2), saturated sodium bicarbonate (20 ml), and brine (20 ml). Then, the solution was dried over magnesium sulfate, and evaporated to dryness. The residue was chromatographed on a silica gel to give (3S)-(2,2,2-trichloroethyl) 3-[(2S)-5-benzyloxycarbonyl-2-{3-methyl-3-(2-pyridyl)ureido}pentanoyl]oxyhexadecanoate (0.25 g).
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH:13][C:14](=[O:17])[O:15][CH3:16])[CH:11]=[CH2:12].C(N(CC)CC)C>C(OCC)C>[CH3:16][O:15][C:14]([NH:13][CH2:10][CH:11]1[O:9][N:8]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12]1)=[O:17]
Reactant: ON=Cc1ccccc1
Reactant: C=CCNC(=O)OC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)NCC1CC(c2ccccc2)=NO1
Temperature: 15 °C
Reaction time: 3 h

Procedure:
A 24 g. portion of benzaldoxime was chlorinated, isolated and dissolved in diethyl ether. The solution was cooled to 15° C., and 46 g. of methyl allylcarbamate was added. Sixty ml. of triethylamine was then added dropwise, keeping the temperature below 20° C. The mixture was stirred for 3 hours, and filtered. The filtrate was evaporated to dryness, and the residue was washed with water and filtered again. The solids were identified as 32 g. of product, m.p. 102°-103° C., NMR singlets at 3.63 and 5.48 ppm., multiplets at 2.82-3.80, 4.57-5.08, 7.13-7.50 and 7.45-7.77 ppm.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2O)[NH:4][N:3]=1.CCN(C1C=CC=CC=1)CC.O(Cl)[Cl:24]>>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[Cl:24])[NH:4][N:3]=1
Reactant: ClOCl
Reactant: Oc1ncnc2[nH]nc(Br)c12
Solvent: CCN(CC)c1ccccc1
Product: Clc1ncnc2[nH]nc(Br)c12
Temperature: 106 °C

Procedure:
3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate A) (15.08 g, 70.5 mmol) was suspended in 189 ml of phosphous oxychloride. Diethylaniline (19 ml, 119.4 mmol) was added and the resulting reaction mixture was heated to 106° C. for 2 hours. After cooling to room temperature, the solvent was removed and the resulting amber syrup was poured to 300 ml of ice-water. 20 minutes later, the aqueous layer was extracted with diethyl ether (500 ml×4). The combined organic layer was washed, dried and evaporated to give 6.87 g of 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine as light yellow solid. 1H NMR (DMSO) 8.857 (s 1H), 14.84 (bs, 1H); LC/MS (MH+=233).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CN(C)C=O.[Cu]I>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[NH:19][C:14]2[C:13]([CH:12]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCC#Cc1ccccc1N
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1cc2ccccc2[nH]1

Procedure:
2-[4-(tert-Butyldimethylsilanyloxy)but-1-ynyl]phenylamine (8 mmol) was heated at reflux in N,N-dimethylformamide (30 mL) with copper(I) iodide (5 mg, 0.026 mol) for 3 hours. The solvent was evaporated, and the residue was diluted with ether and filtered through Celite. The filtrate was concentrated, and the residue was purified by SiO2 chromatography (5-20% ethyl acetate/hexanes) to give the desired product, 0.88 g. 1H NMR (300 MHz, CDCl3) δ8.62 (br, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.13-7.03 (m, 2H), 6.22 (s, 1H), 3.92 (t, J=5.7 Hz, 2H), 2.95 (t, J=5.7 Hz, 2H), 0.95 (s, 9H), 0.08 (s, 6H).
Reaction SMILES: N#N.[C:3]1([CH3:11])[C:4]([CH:9]=O)=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:13]>C(O)(C)C.N1CCOCC1>[C:12]([C:14](=[CH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:11])[C:15]([O:17][CH3:18])=[O:16])#[N:13]
Reactant: Cc1ccccc1C=O
Reactant: COC(=O)CC#N
Agent: N#N
Solvent: C1COCCN1
Solvent: CC(C)O
Product: COC(=O)C(C#N)=Cc1ccccc1C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A 100-mL, 1-necked round bottom flask (with magnetic stir-bar and dry N2 adaptor) was charged with 11.6 mL (12.0 g, 100 mmol) of o-tolualdehyde, 8.8 mL (9.9 g, 100 mmol) of methyl cyanoacetate, and 50 mL of isopropanol. Morpholine (0.50 mL, 0.55 g, 6.3 mmol, 6.3 mol %) was added and the mixture was stirred at 20–33° C. for 60 minutes. This mixture was diluted with 25 mL of isopropanol. The precipitate was filtered, washed with 10 mL of isopropanol, and dried to afford 17.37 g (86.3%) of methyl 2-cyano-3-(2-mehtylphenyl)-2-propenoate as a colorless solid.
Reaction SMILES: ClC1C=CN=C(C(Cl)=O)C=1.C(N)C.Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])[CH:16]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[CH2:24]([NH:23][C:21]([C:17]1[CH:16]=[C:15]([O:33][C:30]2[CH:31]=[CH:32][C:27]([NH2:26])=[CH:28][CH:29]=2)[CH:20]=[CH:19][N:18]=1)=[O:22])[CH3:25]
Reactant: Nc1ccc(O)cc1
Reactant: CCNC(=O)c1cc(Cl)ccn1
Agent: CCN
Agent: O=C(Cl)c1cc(Cl)ccn1
Product: CCNC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline according to Method C1a to afford the urea.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C1(O)C=CC=CC=1.Cl.Br[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>>[N:20]1[CH:21]=[CH:22][C:17]([NH:1][N:2]2[CH2:6][CH2:5][CH2:4][C:3]2=[O:7])=[CH:18][CH:19]=1
Reactant: NN1CCCC1=O
Reactant: Brc1ccncc1
Agent: Cl
Solvent: Oc1ccccc1
Product: O=C1CCCN1Nc1ccncc1
Temperature: 140 °C
Yield: 16 %

Procedure:
A slurry consisting of 1-amino-2-pyrrolidinone (7.40 g), phenol (17.8 g), and 4-bromopyridine hydrochloride (15.8 g) was heated in a 140° C. oil bath for 70 minutes under nitrogen. The resulting solution was cooled to room temperature and purified via flash column chromatography (silica gel, 2% Et3N/0-50% MeOH/EtOAc) and preparative high performance liquid chromatography (HPLC) (silica gel, 10% MeOH/DCM). The resulting product fractions were concentrated and the product was redissolved in dichloromethane and sat. aqueous sodium bicarbonate. Exhaustive extraction of the aqueous layer afforded the pure product (free of triethyl amine salts). Recrystallization from dichloromethane/ether afforded 2.10 g (16%) of 1-(4-pyridinylamino)-2-pyrrolidinone, m.p. 177°-179.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:34])[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=[C:21]([C:23](O)=[O:24])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:67]([N:74]1[CH:78]=[C:77]([NH2:79])[CH:76]=[N:75]1)[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:34])[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=[C:21]([C:23](=[O:24])[NH:79][C:77]2[CH:76]=[N:75][N:74]([CH2:67][C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=3)[CH:78]=2)[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cnn(Cc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)O)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)Nc3cnn(Cc4ccccc4)c3)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Temperature: 90 °C

Procedure:
Intermediate (1c), 2-[5-carboxy-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester (300 mg, 0.62 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (357 mg, 1.86 mmol), 1-hydroxybenzotriazole hydrate (251 mg, 1.86 mmol), N,N-diisopropylethylamine (320 mg, 0.431 mL, 2.48 mmol), 1-benzyl-1H-pyrazol-4-ylamine (322 mg, 1.86 mmol) and tetrahydrofuran (12 mL) were combined in a 20 mL microwave vial. The contents of the vial were heated at 90° C. for 30 minutes under microwave irradiation. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and dichloromethane, and the organic layer was separated. The aqueous was extracted with a further portion of dichloromethane and the combined dichloromethane layers were dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with 20% ethyl acetate/hexane and then 2% methanol/dichloromethane to afford the desired title compound as a solid, 315 mg, 80%.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27].C(OCC)(=O)C.CCCCCC>CN(C=O)C>[C:29]1([O:28][C:26](=[O:27])[NH:11][CH2:10][C:8]2[N:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(CNC(=O)Oc2ccccc2)n(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.3 %

Procedure:
To a solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (5 g, 0.018 mol) in DMF (25 ml, 5 times), potassium carbonate (9.16 g, 0.066 mol, 3.5 eq) was added and cooled the contents to 0° C. Then phenyl chloroformate (3.28 g (2.65 ml), 0.02 mol, 1.1 eq) was added drop wise for 15 min and the overall reaction mixture was stirred for another 15 min at 0° C. Progress of the reaction was monitored by TLC (20% ethyl acetate/hexane, Rf˜0.3). On completion of the reaction, reaction contents were filtered, filtrate was diluted with cold water (100 ml) and the product extracted with ethyl acetate (3×25 ml). Combined organic layer was washed with brine solution (100 ml), dried over sodium sulfate and concentrated under reduced pressure. Crude obtained was purified by column chromatography (silica gel, 10% ethyl acetate/hexane) to yield the required product as a white solid (3.2 g, 45% yield).
Reaction SMILES: [CH2:1]([NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[S:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:29]([C:34](O)=[O:35])#[C:30][C:31]([OH:33])=[O:32]>>[CH2:17]([N:16]1[C:34](=[O:35])[C:29](=[CH:30][C:31]([OH:33])=[O:32])[S:15][C:14]1=[N:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCNC(=S)NCCCCCCCCCCCC
Reactant: O=C(O)C#CC(=O)O
Product: CCCCCCCCCCCCN=C1SC(=CC(=O)O)C(=O)N1CCCCCCCCCCCC
Yield: 79.9 %

Procedure:
Prepared by the method described in Example 16 from N,N'-didodecylthiourea (25.0 g, 61 mmoles) and acetylenedicarboxylic acid (7.3 g, 61 mmoles). Recrystallization from 2-propanol, then ethyl acetate gave the product (24.8 g), mp 71°-72° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]([C:11]([OH:13])=[O:12])[CH2:2]1>CO.[Pd]>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH:3]([C:11]([OH:13])=[O:12])[CH2:2]1
Reactant: O=C(O)C1=Cc2ccccc2OC1
Agent: [Pd]
Solvent: CO
Product: O=C(O)C1COc2ccccc2C1

Procedure:
A solution of 10.4 g of the methyl ester of 2H-1-benzopyran-3-carboxylic acid (Taylor et al., supra) in 50 ml of methanol containing 300 mg of 10% palladium-on-carbon catalyst was hydrogenated in a Parr apparatus for 1.5 hours, at an initial pressure of 44 psig. The mixture then was filtered through a Celite pad, the filtrate was stripped of solvent, and the product was vacuum distilled to give the methyl ester of 3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (2A), as a colorless liquid, bp: 86°-88° C. (0.01 Torr.).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[C:14]([OH:21])[C:13]=2[CH2:22][CH2:23][CH3:24])[CH:5]=1.[OH-].[Na+]>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:25])=[O:2])=[C:13]([CH2:22][CH2:23][CH3:24])[C:14]=1[OH:21])(=[O:20])[CH3:19]
Reactant: CCCc1c(OCc2cccc(C(=O)OC)c2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Product: CCCc1c(OCc2cccc(C(=O)O)c2)ccc(C(C)=O)c1O

Procedure:
3-[(4-Acetyl-3-hydroxy-2-propylphenoxy)methyl]benzoic acid methyl ester was allowed to react with 1.0N sodium hydroxide according to the procedure of Example 70 and the product was purified by recrystallization from acetone to give 3-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]benzoic acid, the title compound, m.p. 221°-224°, in 92% yield. Analysis Calculated for C19H20O5 : C, 69.50; H, 6.14. Found: C, 69.64; H, 6.35.
Reaction SMILES: [OH:1][C@:2]1([C@@H:15]2[CH2:19][S:18][C:17](=[O:20])[N:16]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:7][C@@H:6]([OH:8])[CH2:5][C@@H:4]([CH2:9][CH2:10][C@H:11]([CH3:14])[CH:12]=[CH2:13])[O:3]1.O[C@:31]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@@H](O)C[C@@H](CCCC=C)O1>>[OH:8][C@H:6]1[CH2:5][C@@H:4]([CH2:9][CH2:10][C@H:11]([CH3:14])[CH:12]=[CH2:13])[O:3][C@:2]([C@@H:15]2[CH2:19][S:18][C:17](=[O:20])[N:16]2[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)([O:1][CH3:31])[CH2:7]1
Reactant: C=C[C@@H](C)CC[C@@H]1C[C@H](O)C[C@](O)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Reactant: C=CCCC[C@@H]1C[C@H](O)C[C@](O)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Product: C=C[C@@H](C)CC[C@@H]1C[C@H](O)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1

Procedure:
Application of the method shown in Example 13, with the modification that (R)-4-((2R,4S,6R)-2,4-dihydroxy-6-((S)-3-methylpent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one was substituted for (R)-4-((2R,4S,6R)-2,4-dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:7]=1[C:8]#N)([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:27])C>C1(C)C=CC=CC=1>[CH3:1][C:2]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:7]=1[CH:8]=[O:27])([CH3:4])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)Oc1cccc(Cl)c1C#N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1cccc(Cl)c1C=O
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 2-[(1,1-dimethylethyl)oxy]-6-chlorobenzonitrile (9.22 g, 44.0 mmol) in toluene (100 mL) cooled in an ice-bath was added diisobutylaluminum hydride (1M in hexane, 48.4 mL, 48.4 mmol) keeping the temperature less than 10° C. The reaction was stirred for 1 h and was poured into a mixture of 10% aqueous acetic acid (100 mL) and ice. The mixture was filtered through Celite, the layers separated and the aqueous layer extracted with ether (2 times). The combined organic layers were washed with saturated sodium bicarbonate, brine, dried (MgSO4) and concentrated to afford 9.07 g (97%) of 2-[(1,1-dimethylethyl)oxy]-6-chlorobenzaldehyde as a yellow oil.