Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[Sn](CCCC)(CCCC)CCCC.[OH-].[Na+]>CN(C)C=O>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:12]2[N:11]([CH3:10])[CH:15]=[CH:14][N:13]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nccn2C)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
A mixture of 3-iodoanisole (0.6 mL, 5 mmol), 1-methyl-2-(tributylstannyl)-1H-imidazole (Bull. Chem. Soc. Jpn. 1986, 59, 677, 2.5 g, 6 mmol), and dichlorobis(triphenylphosphine)palladoim(II) (421 mg, 0.6 mmol) in N,N-dimethylformamide (10 mL) was stirred at 60° C. for 8 h under nitrogen atmosphere. The reaction mixture was poured into 2 N sodium hydroxide aqueous solution (10 mL) and the basic mixture was extracted with ethyl acetate (30 mL×6). The combined organic extracts were washed with brine (10 mL×2) and dried (sodium sulfate). After removal of solvent, the residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (20/1) to afford 724 mg (77%) of the title compound as pale orange oil: 1H-NMR (CDCl3) δ 7.39–7.33 (1H, m), 7.22–7.16 (2H, m), 7.13–7.12 (1H, m), 6.97–6.94 (2H, m), 3.86 (3H, s), 3.76 (3H, s); MS (ESI) m/z 189 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]1=2)[CH2:4][OH:5].[C:19]([OH:36])(=O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)C=O>[C:19]([O:1][CH2:2][CH:3]([O:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]1=2)[CH2:4][O:5][C:19](=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: Nc1nc2c(ncn2COC(CO)CO)c(=O)[nH]1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 50 °C
Reaction time: 50 h
Yield: 97.6 %

Procedure:
To 50 mg of 9-(1,3-dihydroxy-2-propoxymethyl)guanine in 5 ml of N,N-dimethylformamide were added 290 mg dicyclohexycarbodiimide and 300 mg of n-hexadecanoic acid and the solution was stirred at 50° C. for 50 hours. The compound was then precipitated in ice water. The water was extracted with methylene chloride (3×). The combined methylene chloride extracts were concentrated, then purified on preparative silica gel plates developed in 1:9 methanol:methylene chloride to yield 140 mg 9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)guanine, m.p. 150°-154° C.
Reaction SMILES: [NH2:1][C:2]1[NH:30][CH2:29][C:28]2[CH:31]=[C:32]([Cl:33])[C:25](=[C:26]([Cl:34])[CH:27]=2)[NH:24][C:23](=[O:35])[CH2:22][NH:21][CH2:20][CH2:19][CH2:18][CH:17]=[CH:16][CH2:15][O:14][C:13]2[CH:36]=[CH:37][C:10](=[CH:11][CH:12]=2)[C:9]2[C:5](=[C:6]([CH3:38])[S:7][N:8]=2)[C:4](=[O:39])[N:3]=1.[CH:40](=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC)(OC)OC>C(O)(=O)C>[NH2:1][C:2]1[NH:30][CH2:29][C:28]2[CH:27]=[C:26]([Cl:34])[C:25](=[C:32]([Cl:33])[CH:31]=2)[NH:24][C:23](=[O:35])[CH2:22][N:21]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16][CH2:15][O:14][C:13]2[CH:12]=[CH:11][C:10](=[CH:37][CH:36]=2)[C:9]2[C:5](=[C:6]([CH3:38])[S:7][N:8]=2)[C:4](=[O:39])[N:3]=1
Reactant: Cc1snc2c1C(=O)N=C(N)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CNCCCC=CCOc1ccc-2cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: Cc1snc2c1C(=O)N=C(N)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CN(Cc1ccccc1)CCCC=CCOc1ccc-2cc1

Procedure:
The cis/trans mixture of the title compound of 9-amino-14,32-dichloro-5-methyl-26-oxa-4-thia-3,8,10,16,19-pentaazatetracyclo[25.2.2.212,15.02,6]tritriaconta-1(29),2,5,8,12,14,23,27,30,32-decaene-7,17-dione (Example 4) (60 mg), benzaldehyde (24 mg), sodium triacetoxyborohydride (30 mg), trimethyl orthoformate (0.2 mL) and acetic acid (0.1 mL), in 2 mL of DMF was stirred at room temperature for 16 hrs. Ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL) were added. Layers were separated after the mixture was well shaken. The organic layer was dried over anhydrous magnesium sulfate and solvent was evaporated in vacuo to give a crude product, which was purified by preparative HPLC to give 27 mg of the title compound as an inseparable mixture of cis/trans isomers.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:6]=[CH:5]2.[N+:20]([CH2:23][CH3:24])([O-:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C>[CH2:13]([O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:23]([N+:20]([O-:22])=[O:21])[CH3:24])[CH:3]=2)[N:8]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC[N+](=O)[O-]
Reactant: CCCCCCCOc1ccc2cc(Br)ccc2n1
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CCCCCCCOc1ccc2cc(C(C)[N+](=O)[O-])ccc2n1
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
6-bromo-2-(heptyloxy)quinoline (2.014 g, 6.27 mmol) and Pd2(dba)3 (172 mg, 0.188 mmol, 0.03 eq.) were dissolved in DME (5 mL) and stirred under nitrogen atmosphere for 10 min. 2-di-tert-butylphosphino-2′-methylbiphenyl (117 mg, 0.36 mmol, 0.06 eq.) was added and the mixture was stirred at r.t. for 10 min. Then nitroethane (0.9 mL, 12.54 mmol, 2.0 eq.) and cesium carbonate (2.5 g, 7.5 mmol, 1.2 eq.) were added. The mixture was stirred at 50° C. under nitrogen atmosphere for 15 h. The mixture was extracted with ethyl acetate and the organic layer was purified by silica gel column chromatography using petroleum/ethyl acetate (5/1) as eluent to give product as a slight red oil (1.5 g, 78%). ESI-MS: 317.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, 1H), 7.86 (d, 1H), 7.79 (s, 1H), 7.69 (q, 1H), 6.93 (d, 1H), 5.77-5.74 is (m, 1H), 4.46 (t, 2H), 1.98 (d, 3H), 1.84-1.80 (m, 2H), 1.48-1.29 (m, 8H), 0.89 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][C:14](OCC)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].C[O-].[Na+].[Na]>CO>[OH:28][NH:27][C:14](=[O:15])[CH2:13][N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(CC(=O)NO)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-[[4-methoxybenzenesulfonyl](benzyl)amino]acetate (11.20 g, 30.9 mmol) is dissolved in methanol (100 mL). To this solution is added hydroxylamine hydrochloride (4.31 g, 62.0 mmol), followed by the addition of sodium methoxide, freshly prepared from sodium (2.14 g, 93.0 mmol) dissolved in methanol (55 mL). The reaction is stirred overnight at room temperature. The reaction is worked up by partitioning between dilute hydrochloric acid (pH=~3) and ethyl acetate. The aqueous phase is extracted well with ethyl acetate, the combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (75% ethyl acetate/hexane) to give N-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]acetamide, m.p. 112°-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[C:26]([F:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])(O)=O.[Na+].Cl>C(Cl)Cl.C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([NH:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]([OH:32])[C:26]=1[F:33])=[O:6]
Reactant: Nc1c(F)ccc(O)c1F
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1c(F)ccc(O)c1F)c1cc(-c2cccc(F)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
To a solution of 2-chloro-5-(3-fluorophenyl)benzoic acid (500 mg, 2.0 mmol, 1.0 eq) in DCM (20 mL) was added oxalyl chloride (761.6 mg, 6.0 mmol, 3.0 eq) and DMF (0.1 mL). The solution was stirred at room temperature for 1 h, then the solvent removed in vacuo. The resultant residue was dissolved in dry THF (30 mL) and added dropwise to a suspension of 3-amino-2,4-difluorophenol (intermediate X(a)) (290.2 mg, 2.0 mmol, 1.0 eq) and NaHCO3 (504 mg, 6.0 mmol, 3.0 eq) in THF (30 mL). The mixture was warmed to room temperature and stirred for 30 min. The pH of the reaction was adjusted to pH 3 by addition of 1M HCl and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) filtered and evaporated in vacuo. The residue was purified by chromatography to give the title compound as a white solid (200 mg, 27%).
Reaction SMILES: C([O:8][C:9]1[N:14]2[N:15]=[C:16]([CH3:23])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[CH:12]=[C:11]([CH3:24])[CH:10]=1)C1C=CC=CC=1.C1CCCCC=1>C(O)C.[Pd]>[OH:8][C:9]1[N:14]2[N:15]=[C:16]([CH3:23])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[CH:12]=[C:11]([CH3:24])[CH:10]=1
Reactant: CCOC(=O)c1c(C)nn2c(OCc3ccccc3)cc(C)cc12
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOC(=O)c1c(C)nn2c(O)cc(C)cc12
Yield: 85.7 %

Procedure:
2 g (5.98 mmol) of ethyl 7-(benzyloxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate from Example 7A were initially charged in 80 ml of ethanol under argon, and 636 mg (0.59 mmol, 10%) of palladium on activated carbon and 18 ml (179.42 mmol) of cyclohexene were added. The reaction mixture was stirred under reflux for 2.5 hours. Then the reaction mixture was filtered through kieselguhr and washed with ethanol, and the filtrate was concentrated. The residue was taken up in DMSO and acetonitrile and purified by means of preparative HPLC (RP 18 column, eluent:acetonitrile/water gradient with addition of 0.1% TFA). The product fractions were combined, concentrated and lyophilized. 1.2 g of the target compound were obtained (86% of theory).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:33][CH2:34][O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=O)=O.C(OCC)(=O)C>CN(C=O)C>[C:36]([O:35][CH2:34][CH2:33][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CC(C)(C)OCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 70 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 2-tert-butoxyethyl methanesulfonate (0.218 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 384.2 (M+H)+, HRMS calcd for C22H30N3O3 384.2287 (M+H)+, found 384.2276, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=10.5 min, 97.7% purity.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[N:11]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])[C:10]1=[O:34])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[N:11]1[C:12]2[C:17](=[CH:16][C:15]([F:20])=[C:14]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[CH:13]=2)[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:34]
Reactant: [H][H]
Reactant: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(F)cc2F)c(=O)n1O
Yield: 100.7 %

Procedure:
Twenty percent Pd/C (50 mg) was added to a solution of 3-benzyloxy-1-(2,4-difluorophenyl)-6-fluoro-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione (Example K-4, 0.22 g, 0.5 mmol) in 40 mL of THF, and this was shaken under 50 PSI of hydrogen for 16 hours. The mixture was filtered and concentrated to afford 0.19 g of a solid. This solid was triturated with ether and filtered to give 0.08 g of the title compound as a solid, mp 232-234° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Na].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>>[O:16]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Product: Nc1cc(Oc2ccccc2)ncn1
Temperature: 140 °C
Reaction time: 20 h
Yield: 13.9 %

Procedure:
6-Chloropyrimidin-4-amine (3.00 g, 23.14 mmol) was added to a solution of sodium (0.197 g, 8.57 mmol) in phenol (11.29 g, 120 mmol) at 55° C. The mixture was heated at 140° C. for 2 h, then held at room temperature for 20 h. The reaction mixture was poured into 32% aqueous NaOH on ice/water keeping the mixture temperature below 20° C. The mixture was extracted with chloroform and the organic extract dried over calcium chloride and concentrated. The residue was purified by silica gel chromatography (2-20% ethyl acetate in hexanes) to afford 6-phenoxypyrimidin-4-amine (0.6 g, 3.21 mmol, 75% yield) as a white solid. LCMS R.T.=1.37; [M+H]+=197.95.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[CH:15]=1)[C:5]([O:7]CC)=O.[NH:18]([C:20]1[CH:25]=[C:24]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:23]=[CH:22][N:21]=1)N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:43]>C(O)C.O1CCOCC1>[ClH:43].[Br:16][C:14]1[CH:15]=[C:10]([C:4]2[C:5](=[O:7])[N:18]([C:20]3[CH:25]=[C:24]([N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)[N:23]=[CH:22][N:21]=3)[NH:2][CH:3]=2)[CH:11]=[N:12][CH:13]=1
Reactant: CCOC(=O)C(=CN(C)C)c1cncc(Br)c1
Reactant: NNc1cc(N2CCCCC2)ncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=c1c(-c2cncc(Br)c2)c[nH]n1-c1cc(N2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 100° C., 500 mg (1.7 mmol) of the compound from Example 11A, 323 mg (1.7 mmol) of the compound from Example 8A and 58 mg (0.3 mmol) of p-toluenesulfonic acid are stirred in 2 ml of ethanol for 16 h. After cooling to RT, 0.5 ml of a 4 N solution of hydrogen chloride in dioxane is added, and the mixture is stirred at RT for 30 min. The precipitate is filtered off, washed first with ethanol and then with diethyl ether and dried under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH3:32][O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1.C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:41][C:38]2[CH:37]=[CH:36][C:35]([C:34]([O:33][CH3:32])=[O:43])=[CH:40][CH:39]=2)([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2(C(=O)OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (30.12 mmol; 9.62 g) in dry THF (100 mL) under argon at −78° C. was added, dropwise, a 2M solution of lithium diisopropylamide (2M solution in heptanes/THF/ethylbenzene; 39.16 mmol; 19.58 mL). The resulting solution was stirred at −78° C. for 2 hours. 4-Bromomethylbenzoic acid methyl ester (30.12 mmol; 6.90 g) was added and the resulting solution was stirred at −78° C. for 2 hours and allowed to warm to room temperature overnight. Ethyl acetate (150 ml) was added. The resulting solution was washed with a 1M aqueous hydrochloric acid solution (2×50 mL) and brine (50 mL) and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient: 0 to 50% EtOAc in heptane) to yield 4-(4-methoxycarbonyl-benzyl)-piperidine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester. MS (ESI) m/z 468.20 [M+H]+.
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4](OCC)=[O:5].[CH2:13]([S:15][CH:16]([CH3:23])[CH2:17][CH:18]=[CH:19][C:20](=[O:22])[CH3:21])[CH3:14].[OH-].[Na+].Cl>O.C(O)C>[CH2:13]([S:15][CH:16]([CH3:23])[CH2:17][CH:18]1[CH2:3][C:4](=[O:5])[CH2:21][C:20](=[O:22])[CH2:19]1)[CH3:14]
Reactant: CCSC(C)CC=CC(C)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCSC(C)CC1CC(=O)CC(=O)C1
Temperature: 50 °C

Procedure:
2.53 g of metallic sodium were added to 100 ml of ethanol at room temperature. To this was then added 17.6 g of diethyl malonate, with stirring, and then 17.2 g of 6-ethylthio-3-hepten-2-one was added. The resulting mixture was then refluxed for four hours and then an aqueous sodium hydroxide solution, containing 9.5 g of sodium hydroxide in 75 ml of water, was added and the mixture refluxed for another two hours. The mixture was cooled to 50° C. and then acidified by the addition of concentrated hydrochloric acid. The mixture was then warm until decarboxylation was complete and then evaporated to a liquid residue. The residue was mixed with ethyl ether, washed with water, and evaporated to a brown liquid. The liquid was base, acid extracted affording 5-(2-ethylthiopropyl) cyclohexane-1,3-dione.
Reaction SMILES: [CH3:1][C@@H:2]([O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>CO>[CH2:16]([NH:18][C:19](=[O:20])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([O:5][C@H:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)[CH3:17]
Reactant: CC[C@@H](C)Oc1ccc(OCCO)cc1
Reactant: CCN=C=O
Solvent: CO
Product: CCNC(=O)OCCOc1ccc(O[C@H](C)CC)cc1

Procedure:
Following the procedure of Example 9, the above alcohol (0.42 g, 2.0 mmol) is reacted with ethyl isocyanate (0.18 ml, 2.2 mmol) to give O-2-[(R)-4-(1-methylpropoxy)phenoxy]ethyl N-ethylcarbamate, specific rotation [αD20 =-19.103° (c=10% in methanol).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([NH:6][C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:28][CH3:29])=[C:22]([C:25](O)=[O:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:4][CH:3]=1.Cl.C(N=C=N[CH2:40][CH2:41][CH2:42][N:43](CC)CC)C.O.ON1C2C=CC=CC=2N=N1.C1(N)CC1>CN(C)C=O.O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:42]1([NH:43][C:25]([C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][C:21]=2[O:28][CH3:29])[N:18]=[CH:17][CH:16]=[C:15]3[O:14][C:13]2[CH:30]=[CH:31][C:10]([NH:9][C:7]([NH:6][C:5]3[CH:32]=[CH:33][C:2]([F:1])=[CH:3][CH:4]=3)=[O:8])=[CH:11][CH:12]=2)=[O:26])[CH2:40][CH2:41]1
Reactant: CCN=C=NCCCN(CC)CC
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C(=O)O
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
After dissolving the N-[4-(6-carboxy-7-methoxy-4-quinolyl)oxyphenyl]-N′-(4-fluorophenyl)urea (60 mg) synthesized in Example 341 in dimethylformamide (1.5 ml), there were added 1-ethyl-3-(3-diethylaminopropyl)-carbodiimide hydrochloride (39 mg), 1-hydroxy-1H-benzotriazole monohydrate (31 mg), triethylamine (30 μl) and cyclopropylamine (0.05 ml) and the mixture was stirred overnight at room temperature. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and then dried over anhydrous sodium sulfate. After distilling off the solvent, crystals were precipitated with ethyl acetate, filtered out and dried under reduced pressure to obtain the title compound (29 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(C=C(C(=O)O)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(CC(C(=O)O)c2ccccc2)cc1

Procedure:
13 g of 3-(4-methoxyphenyl)-2-phenylacrylic acid was dissolved to 600 ml of ethyl acetate and 2.6 g of 10% palladium on charcoal was added under inert atmosphere. Starting material was hydrogenated at room temperature to give quantitative yield of 3-(4-methoxyphenyl)-2-phenylpropionic acid. 1H-NMR (400 MHz, d6-DMSO): 12.3 (bs, 1H), 7.32-7.20 (m, 5H), 7.1-7.0 (m, 2H), 6.8-6.7 (m, 2H), 3.79 (dd, 1H, J 6.9, 8.7 Hz), 3.70 (s, 3H), 3.22 (dd, 1H, J 8.7, 13.7 Hz), 2.87 (dd, 1H, J 6.9, 13.7 Hz).
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([O:14][C:15]([NH:17][NH2:18])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([NH:17][N:18]=[C:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C1CCCCCCC1
Reactant: CC(C)(C)OC(=O)NN
Product: CC(C)(C)OC(=O)NN=C1CCCCCCC1

Procedure:
According to a published procedure, cyclooctanone Compound 21a was reacted with hydrazinecarboxylic acid tert-butyl ester to produce an intermediate N′-cyclooctylidene-hydrazinecarboxylic acid tert-butyl ester Compound 21b (as described in Ghali N K and Venton D L, J. Org. Chem., 1981, 46, 5413). According to the published procedure, Compound 21b was carried forward to provide cyclooctyl-hydrazine hydrochloride Compound 21c.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2([C:51]3[C:42](=[CH:43][C:44]4[O:49][CH2:48][CH2:47][O:46][C:45]=4[CH:50]=3)[O:41][CH2:40]2)[C:32]1=[O:52].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[CH3:19][C:15]1([CH3:18])[O:14][C@@H:13]([CH2:12][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]3([C:51]4[C:42](=[CH:43][C:44]5[O:49][CH2:48][CH2:47][O:46][C:45]=5[CH:50]=4)[O:41][CH2:40]3)[C:32]2=[O:52])[CH2:17][O:16]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CC1(C)OC[C@H](CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)O1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 1′-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (98%): mp 55-57° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.30-6.99 (m, 4H), 6.47-6.20 (m, 2H), 4.88-4.84 (m, 1H), 4.63-4.59 (m, 1H), 4.48-4.40 (m, 1H), 4.17-3.77 (m, 8H), 1.35-1.28 (m, 6H); MS (ES+) m/z 410.1 (M+1).