Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]3[C:35](=[CH:36][C:6]=2[N:5]=1)[CH:34]=[CH:33][CH:32]=[CH:31]3)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]3[C:35](=[CH:36][C:6]=2[N:5]=1)[CH:34]=[CH:33][CH:32]=[CH:31]3)[CH2:2][CH3:3]
Reactant: CCCc1nc2cc3ccccc3cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc3ccccc3cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-propyl-naphtho[2,3-d]imidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:11][CH2:10][CH2:9][C:7](=O)[C:5]=2[CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[O:11]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:9][CH2:10]1
Reactant: O=C1CCOc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C1=Cc2ccccc2OC1
Reaction time: 0.25 h

Procedure:
The chromanone was dissolved in 400 ml. of dry ethyl ether, and 2.5 gm of lithium aluminum hydride was added in portions. The reaction was refluxed for 2 hours and then allowed to come to room temperature. The excess lithium aluminum hydride was destroyed by dropwise addition of water and 150 ml. of 4N HCl was added slowly to the reaction mixture. Stirring was continued for 15 minutes. The reaction mixture was extracted with ether and washed successively with 100 ml. of water, 100 ml. 5% sodium carbonate solution and 100 ml. saturated NaCl solution. The ethereal extract was dried over anhydrous sodium sulfate. Removal of the ether in vacuo gave 15.6 g of crude chromene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1Cl.[CH2:11]([O:18][NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][NH:19][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:9][CH3:10])[C:2]=1[Cl:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NOCc1ccccc1
Reactant: CCc1nccc(Cl)c1Cl
Product: CCc1nccc(NOCc2ccccc2)c1Cl
Yield: 99 %

Procedure:
Preparation was carried out analogously to Example 1 from 3,4-dichloro-2-ethylpyridine and O-benzylhydroxylamine. Yield: 99%
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:42])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[C:18]([O:26][CH2:27][C:28]([N:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[C:35]([O:37]C(C)(C)C)=[O:36])=[O:29])[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:35]([C@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[C:28](=[O:29])[CH2:27][O:26][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:42])([OH:37])=[O:36]
Reactant: COC(=O)c1cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(OCC(=O)N2CCC[C@@H]2C(=O)O)cc(OCC(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 8 h

Procedure:
A solution of 710 mg (1.2 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-methoxycarbonyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 10 ml trifluoroacetic acid was stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue suspended in 20 ml ether. The resulting suspension was stirred overnight.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C@@H:22](/[CH:24]=[CH:25]/[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:23])[CH2:20][OH:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:41](=[O:42])C1.CN(C1C=CC=CN=1)C>C1COCC1>[O:42]=[C:41]1[O:23][CH:22]([CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:19]([NH:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:20][O:21]1
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO)NC(=O)CCCCCCCCCCCCCCC
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC=CC1OC(=O)OCC1NC(=O)CCCCCCCCCCCCCCC

Procedure:
N-palmitoylsphingosine (C16-ceramide, 1.61 g, 3 mmol) was dissolved in dry THF (100 ml) with heating. The clear solution was brought to room temperature and N,N′-disuccinimidyl carbonate (1.92 g, 7.5 mmol) was added. Dimethylaminopyridine (DMAP 0.81 g, 7.5 mmol) was added with stirring and the reaction further stirred for 16 hours. The solvent was removed under reduced pressure and the residue was re-crystallized from n-heptane yielding 1.3 g (68%) of disuccinimidylceramidyl carbonate as white powder m.p. 73-76° C.
Reaction SMILES: C(N(CC)CC)C.CS(C)=O.[C:12]([O:15][C@H:16]1[CH2:20][CH2:19][C@H:18]([CH2:21][OH:22])[C@H:17]1[CH2:23][CH2:24][S:25][C:26]1[S:27][CH:28]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:30]=1)(=[O:14])[CH3:13].Cl>C(OCC)(=O)C>[C:12]([O:15][C@H:16]1[CH2:20][CH2:19][C@H:18]([CH:21]=[O:22])[C@H:17]1[CH2:23][CH2:24][S:25][C:26]1[S:27][CH:28]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:30]=1)(=[O:14])[CH3:13]
Reactant: CCOC(=O)c1csc(SCC[C@@H]2[C@@H](CO)CC[C@@H]2OC(C)=O)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1csc(SCC[C@H]2[C@@H](OC(C)=O)CC[C@@H]2C=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Triethylamine (3.7 mL) and sulfur trioxide•pyridine complex (1.7 g) were added to a dimethyl sulfoxide(4.0 mL)/ethyl acetate(8.0 mL) solution of ethyl 2-({2-[(1R,2S,5S)-2-(acetyloxy)-5-(hydroxymethyl)cyclopentyl]ethyl}thio)-1,3-thiazole-4-carboxylate (500 mg) (see compound 7 described in the pamphlet of International Publication No. WO 2006/129788) at 10° C., followed by stirring at room temperature for 30 min. To the reaction solution, 1 N hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine; dried with anhydrous sodium sulfate; and concentrated to obtain the title compound (497 mg) having the following physical properties:
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][N:5]1[C:11](=[O:12])[C@H:10]([OH:13])[C@H:9]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[S:8][C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2.[C:29](Cl)(=[O:31])[CH3:30].C1(C)C=CC=CC=1>N1C=CC=CC=1.C(Cl)Cl>[C:29]([O:13][C@@H:10]1[C@H:9]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[S:8][C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:28])[C:11]1=[O:12])(=[O:31])[CH3:30]
Reactant: COC(=O)c1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 127 mg (0.317 mmol) of methyl 4-((2S,3S)-5-(2-(dimethylamino)ethyl)-3-hydroxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-2-yl)benzoate in 160 μL of pyridine at 0° C. was added 25 μL (0.35 mmol) of acetyl chloride. The solution was stirred at 0° C. for 2 hours. The solvent was evaporated to leave a residue which was co-evaporated with toluene (3×). The material was then dissolved in DCM, washed with 1 N NaOH, dried (Na2SO4), and evaporated. Purification was afforded by flash chromatography on silica gel, eluting first with DCM then gradually increasing to 5% methanol/DCM to give 1m. MS found M+H=443. The observed 1H NMR coupling constants between the C2 and C3 methine protons (J=7.4 Hz) confirmed retention of the cis stereochemical relationship. The hydrochloride salt of 1m was recrystallized from isopropanol/ether; mp 214-216° C.; [α]25D+98.9° (c 0.99, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)=[CH:9][N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1.[NH2:33][C@H:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][OH:36].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:36][CH2:35][C@H:34]([NH:33][C:13]1[N:12]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:9]=2)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1)[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)[C@@H](N)CO
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@@H](CO)C(C)C)ncc3C#N)c3cc(C)cnc32)cc1
Yield: 76.9 %

Procedure:
A mixture of 4-(5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (120 mg, 0.257 mmol), (R)-(−)-2-amino-3-methyl-1-butanol (57 μl, 0.515 mmol) and diisopropylethylamine (90 μl, 0.515 mmol) in THF (4 mL) was heated at reflux for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified on silica gel by flash column chromatography to give the title compound as a colourless glassy solid (97 mg, 77% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([CH2:16][NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH:13]=[CH:12][C:11]=2[N:26]2[CH2:31][CH2:30][CH:29]([C:32](OC)=[O:33])[CH2:28][CH2:27]2)=[O:8])[CH:3]=1.[NH3:36]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([CH2:16][NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH:13]=[CH:12][C:11]=2[N:26]2[CH2:31][CH2:30][CH:29]([C:32]([NH2:36])=[O:33])[CH2:28][CH2:27]2)=[O:8])[CH:3]=1
Reactant: COC(=O)C1CCN(c2ccc(CN[C@H](C)c3ccccc3)cc2NC(=O)c2cc(C)on2)CC1
Reactant: N
Product: Cc1cc(C(=O)Nc2cc(CN[C@H](C)c3ccccc3)ccc2N2CCC(C(N)=O)CC2)no1
Temperature: 75 °C
Yield: 23 %

Procedure:
To (R)-methyl 1-(2-(5-methylisoxazole-3-carboxamido)-4-((1-phenylethylamino)methyl)phenyl)piperidine-4-carboxylate 61 (0.220 g, 0.46 mmol) was added ammonia (2 M in MeOH, 50 mL). The reaction mixture was heated to 75° C. in a sealed tube for 7 d, and concentrated in vacuo. Purification by flash column chromatography on silica gel (1% to 10% MeOH (2 M NH3) in DCM) gave (R)-1-(2-(5-methylisoxazole-3-carboxamido)-4-((1-phenylethylamino)methyl)phenyl)piperidine-4-carboxamide 62 (0.048 g, 23% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.26 (d, J=6.7 Hz, 3H), 1.76-1.84 (m, 4H), 2.24 (m, 1H), 2.52 (s, 3H), 2.67 (t, J=8.8 Hz, 2H), 2.95 (d, J=11.5 Hz, 2H), 3.43 (d, J=13.3 Hz, 1H), 3.48 (d, J=13.7 Hz, 1H), 3.71 (q, J=6.5 Hz, 1H), 6.71 (s, 1H), 7.19 (s, 1H), 7.05 (d, J=8.1 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.22 (d, J=3.9 Hz, 1H), 7.31-7.38 (m, 6H), 8.22 (s, 1H), 9.73 (s, 1H). Mass spectrum: calculated for C26H31N5O3 461.2. found 462.3 (M++1).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH2:7][C:8](=[O:10])[NH2:9])=[O:4]>CO.[Pd]>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH2:7][C:8](=[O:10])[NH2:9])=[O:4]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)CN
Temperature: 25 °C
Yield: 83.2 %

Procedure:
1.3 g of Z-Gly-Asn-Leu-OMe are dissolved in 100 ml of methanol with warming and the solution, after having cooled to room temperature, is hydrogenated in the presence of 0.3 g of palladium on charcoal (10 % Pd). After completion of the hydrogen uptake the catalyst is filtered off and the filtrate evaporated to dryness. 760 mg of H-Gly-Asn-Leu-OMe are hereby obtained in an amorphous form.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:16][C:6]2=[CH:7][C:8]3[C:9]([CH3:15])=[CH:10][CH:11]=[N:12][C:13]=3[CH:14]=[C:5]2[C@@H:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:3]1[OH:26].C(O)(=O)/C=C\C(O)=O.CCCCCC>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:27])[O:16][C:6]2=[CH:7][C:8]3[C:9]([CH3:15])=[CH:10][CH:11]=[N:12][C:13]=3[CH:14]=[C:5]2[CH:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:3]1[OH:26]
Reactant: Cc1ccnc2cc3c(cc12)OC(C)(C)[C@@H](O)[C@@H]3NCCc1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccnc2cc3c(cc12)OC(C)(C)C(O)C3NCCc1ccccc1
Temperature: 0 °C
Yield: 72 %

Procedure:
To a solution of (±)-trans-2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol (219 mg, 0.60 mmol) in ethyl acetate (3 mL), a solution of maleic acid (77 mg, 0.66 mmol) in ethyl acetate (1 mL) was added dropwise, the resulting reaction solution was cooled to 0° C., hexane (10 mL) was added thereto, and precipitated solid was filtered off to obtain 2,2,9-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol 3/2 maleate (yield: 72%).
Reaction SMILES: BrC1C=C[C:5]([N:8]2[CH2:13][C@H:12](C)[NH:11][C@H:10]([CH3:15])[CH2:9]2)=CC=1.I[C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1.CN(C)[C@H]1CCNC1>>[I:23][C:20]1[CH:21]=[CH:22][C:17]([N:11]2[CH2:10][CH2:15][C@H:13]([N:8]([CH3:5])[CH3:9])[CH2:12]2)=[CH:18][CH:19]=1
Reactant: Ic1ccc(I)cc1
Reactant: C[C@@H]1CN(c2ccc(Br)cc2)C[C@H](C)N1
Agent: CN(C)[C@H]1CCNC1
Product: CN(C)[C@H]1CCN(c2ccc(I)cc2)C1

Procedure:
The title compound was synthesized according to the synthesis of 1-(4-bromophenyl)-cis-3,5-dimethylpiperazine, except reacting 1,4-diiodobenzene (2.41 g, 7.30 mmol) with (S)—N,N-dimethylpyrrolidin-3-amine (1.0 g, 8.8 mmol). The title compound was purified by silica gel chromatography (MeOH/CH2Cl2, 2:98 to 1:9) as a yellow solid (1.27 g, 55%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.7 Hz, 2H), 6.33 (d, J=8.0 Hz, 2H), 3.47-3.38 (m, 2H), 3.32-3.26 (m, 1H), 3.16-3.12 (m, 1H), 2.89-2.83 (m, 1H), 2.33 (s, 6H), 2.26-2.21 (m, 1H), 1.99-1.89 (m, 1H); MS ESI 317.0 [M+H]+, calcd for [C12H17IN2+H]+ 317.04.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:36])=[C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Li+]>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:36])=[C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Cl)nc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(5-chloro-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (332 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N lithium hydroxide aqueous solution (3.00 mL), and the mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (3.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (278 mg, 89%) as a pale-yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][CH:2]=1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Pd].C(O)(C)C.O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccc(-c2ccncc2)c1
Agent: [Pd]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)c1cccc(C2CCNCC2)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
Ethyl 3-(pyridin-4-yl)benzoate (1.46 g, 6.42 mmol), 5% palladium on carbon (50% wet) (0.301 g, 0.07 mmol) and citric acid monohydrate (0.601 g, 2.86 mmol) in a mixture of isopropanol (50 mL) and water (5 mL) were stirred under an atmosphere of hydrogen at 20 atmosphere and 70° C. for 15 hours. The reaction was cooled to room temperature, the catalyst removed by filtration and the solvent evaporated to give the crude product, which was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M ammonia in methanol to give ethyl 3-(piperidin-4-yl)benzoate (1.190 g, 79%) as a liquid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].C(N(CC)CC)C.[CH3:16][OH:17]>>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([O:17][CH3:16])=[O:5]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CCl
Temperature: 25 °C

Procedure:
219 g of chloropivaloyl chloride was added drop-by-drop to a chilled (0°-5° C.), stirred solution of 141.4 g of triethylamine in 320 g of anhydrous methanol. The resulting mixture was warmed to room temperature in one hour, and most of the methanol was evaporated under reduced pressure. The residue was drowned in water and extracted with ether. The extract was dried (MgSO4) and the solvent was evaporated. The residue was distilled to give methyl 3-chloro-2,2-dimethylpropionate (2A), b.p.: 40°-50° C. (14 Torr.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:29]([O:28][C:26](=[O:27])[CH2:25][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:3][C:2]=1[F:1])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(O)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(OCc2cccc(OCC(=O)OC(C)(C)C)c2)c(F)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 105.8 %

Procedure:
To a solution of ethyl 3-{3-fluoro-4-[(3-hydroxybenzyl)oxy]phenyl}propanoate (0.30 g, 0.94 mmol) and tert-butyl bromoacetate (0.92 g, 4.70 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.52 g, 3.76 mmol), and the mixture was stirred at 60° C. for 12 hours. The reaction mixture was diluted with ethyl acetate, filtered, washed with water, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=6:4) to give the title compound (0.43 g, yield 99%) as an oily matter.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>C(O)(=O)C.C(O)(C)C>[C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([OH:10])[C:9]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:18][CH:17]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(=O)Oc1ccc(C(O)(c2ccccc2)C(O)(c2ccccc2)c2ccc(OC(C)=O)cc2)cc1
Yield: 99.1 %

Procedure:
0.04 g of acetic acid was added to 35.98 g of isopropyl alcohol, and 4.02 g of 4-acetoxybenzophenone was dissolved therein. To this solution, ultraviolet rays were irradiated by a high pressure mercury lamp (UVL-100HA, manufactured by Riko Kagaku Sangyo K.K.) to carry out the reaction for 6 hours. After the reaction, the solvent was distilled off to obtain 4.00 g of 1,2-bis(p-acetoxyphenyl)-1,2-diphenyl-1,2-ethanediol (compound (C5)).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([C:21]([NH2:23])=O)[C@@H:17]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.B.CSC>C1COCC1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH2:21][NH2:23])[C@@H:17]2[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:32])([F:1])[F:31])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H](C(N)=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: C[C@@H](O[C@H]1CC[C@@H](CN)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.6 %

Procedure:
To a solution of 0.70 gm of the amide from Step B in 10 mL of THF was added 2.25 mL of 2M borane-dimethylsulfide in THF. The reaction was stirred at room temperature for 16 hours and then warmed at 50° C. for another 6 hours. The excess borane was quenched with dropwise addition of methanol and then 20 mL of methanol and 5 mL of 2N hydrochloric acid were added and the reaction was stirred at room temperature for 24 hours. The mixture was concentrated in vacuo, diluted with water, made basic with 2N sodium hydroxide and extracted twice with methylene chloride. The organic layers were washed with brine, dried over sodium sulfate, combined and evaporated. The residue was purified by FC (methylene chloride, the 5 -10% methanol in methylene chloride) to give 350 mg of title compound. NMR (CDCl3) δ1.33 (d, 3H, J=6.5 Hz), 1.53 (br s, NH2+H2O), 1.5-1.65 (m, 1H), 1.7-1.85 (m, 1H), 1.85-2.0 (m, 2H), 2.0-2.15 (m, 1H), 2.59 (dd, 1H, J=8 and 10 Hz 2.52 and 2.67 (dABq, 2H, J=4.6 and 12.6 Hz), 3.67 (q, 1H, J=6 Hz), 4.45 (q, 1H, J=6.5 Hz), 6.85-6.95 (m, 2H), 6.95-7.05 (m, 2H), 7.38 (s, 2H), 7.64 (s, 1H). Mass spec (ESI): 450(M+1).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=O)[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2].[OH-].[K+].Cl.[CH2:20]([O:23][NH2:24])[CH:21]=[CH2:22].C(=O)(O)[O-].[Na+]>O1CCCC1.N1C=CC=CC=1>[CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=[N:24][O:23][CH2:20][CH:21]=[CH2:22])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: C=CCON
Reactant: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CCON=C(C(=O)O)c1nc(NC=O)sc1Cl
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
Ethyl (2-formamido-5-chlorothiazol-4-yl)glyoxylate (40.0 g) was added to 1N aqueous solution of potassium hydroxide (305 ml) at ambient temperature and stirred for 10 minutes. The reaction mixture was adjusted to pH 2.0 with 10% aqueous hydrochloric acid under ice cooling. A solution of allyloxyamine (14.4 g) in tetrahydrofuran (200 ml) was added to the stirred suspension of the above mixture in pyridine (54.1 g) at ambient temperature and stirred for 4 hours at the same temperature. The resultant mixture was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate, and washed with ethyl acetate. The separated aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. The residue was washed with diisopropyl ether and collected by filtration to give 2-(2-formamido-5-chlorothiazol-4-yl)-2-allyloxyiminoacetic acid (syn isomer, 24.74 g), mp. 166° to 167° C.