Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=1.CCN(CC)CC>CCO>[C:22]([NH:21][C:17]1[CH:16]=[C:15]([NH:14][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])[CH:20]=[CH:19][CH:18]=1)(=[O:24])[CH3:23]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(=O)Nc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)Nc1cccc(Nc2ccc(C(=O)O)cc2[N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
A mixture of 4-fluoro-3-nitrobenzoic acid (10.2 g, 54.9 mmol), N-(3-aminophenyl)-acetamide (9.21 g, 66.6 mmol), and Et3N (1.4 mL, 10.1 mmol.) in anhydrous EtOH (160 mL) was heated at reflux under N2 atmosphere. After 16 h, the reaction mixture was cooled and the resultant precipitate filtered. The orange solid was washed with 2 M aq HCl and dried to yield 4-{[3-(acetylamino)phenyl]amino}-3-nitrobenzoic acid. 1H NMR (400 MHz, DMSO-d6): δ 2.03 (s, 3H), 7.02 (d, J=7.9 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.68 (s, 1H), 7.93 (dd, J=9.0, 1.9 Hz, 1H), 8.62 (s, 1H), 9.76 (s, 1H), 10.08 (s, 1H), 13.02 (brs, 1H). MS (ES+): m/z 316 [MH+].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (2S)-2-amino-N,3,3-trimethyl-butanamide (CAN 89226-12-0) as starting materials, MS (D): m/e=411.4 [M+H]+.
Reaction SMILES: [O:1]1[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:19])[CH2:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=1>>[OH:19][CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][CH2:2][C:3]2([OH:1])[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:10]=1)[CH2:16][C:17]#[N:18]
Reactant: C1CCC2(C1)CO2
Reactant: N#CCC(O)c1cccc(N)c1
Product: N#CCC(O)c1cccc(NCC2(O)CCCC2)c1

Procedure:
Reaction between 1-oxaspiro[2.4]heptane and aniline 12 gives 3-hydroxy-3-(3-((1-hydroxycyclopentyl)methylamino)phenyl)propanenitrile.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C:8]([OH:10])=[O:9])[C:5]2[CH:11]=[C:12]([O:19]CC3C=CC=CC=3)[C:13]3[NH:14][CH:15]=[C:16]([CH3:18])[C:17]=3[C:4]1=2.C(O)C>C1COCC1.[Pd]>[OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C:8]([OH:10])=[O:9])[C:5]2[CH:11]=[C:12]([OH:19])[C:13]3[NH:14][CH:15]=[C:16]([CH3:18])[C:17]=3[C:4]1=2
Reactant: Cc1c[nH]c2c(OCc3ccccc3)cc3c(c12)C(CO)CN3C(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c[nH]c2c(O)cc3c(c12)C(CO)CN3C(=O)O

Procedure:
242 mg (0.59 mM) of the product of step 2, 1,1-dimethylethyl ester of 1-(hydroxymethyl)-1,6-dihydro-8-methyl-5-(phenylmethoxy)-benzo[1,2-b:4,3-b']dipyrrole-3(2H)-carboxylic acid, is dissolved in distilled THF (2.4 ml) and absolute ethanol (25 ml). The compound is hydrogenalized over 10% palladium on carbon (192 mg) at 42 PSI for 50 minutes. The reaction is filtered through diatomaceous earth, washing with absolute ethanol. Evaporation yields compound 4, 1,1-dimethylethyl ester of 1-(hydroxymethyl)-1,6-dihydro-8-methyl-5-hydroxy-benzo[1,2-b:4,3-b']dipyrrole-3(2H)-carboxylic acid.
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH2:5][CH2:6][CH2:7][CH3:8])#[N:2].[C:12]([C:14]1[CH:27]=[CH:26][C:17]2[O:18][C:19]([CH3:25])([CH3:24])[C@@H:20]([OH:23])[C@H:21]([NH2:22])[C:16]=2[CH:15]=1)#[N:13]>C(OCC)(=O)C>[C:12]([C:14]1[CH:27]=[CH:26][C:17]2[O:18][C:19]([CH3:25])([CH3:24])[C@@H:20]([OH:23])[C@H:21]([NH:22][C:4](=[N:3][C:1]#[N:2])[CH2:5][CH2:6][CH2:7][CH3:8])[C:16]=2[CH:15]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: CCCCC(=NC#N)OCC
Solvent: CCOC(C)=O
Product: CCCCC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reaction time: 2 h

Procedure:
To 3.35 g of ethyl N-cyanovalerimidate, 4.37 g of 6-cyano-3,4-dihydro-2,2-dimethly-trans-4-amino-2H-benzo[b]pyran-3-ol was added, and the mixture was reacted under stirring at a temperature of from 100° to 120° C. for 2 hours. The reaction mixture was cooled, then dissolved in 100 ml of ethyl acetate, washed twice with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residual oily substance was purified by silica gel column chromatography to obtain 1.25 g of the above identified compound as an oily substance.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[N:16][N:15]([CH3:18])[C:14](=[O:19])[CH:13]=2)=[CH:8][CH:7]=1.[NH:20]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=[CH:21]1>>[N:20]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[N:16][N:15]([CH3:18])[C:14](=[O:19])[CH:13]=3)=[CH:8][CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cn1ncc(-c2ccc(OCCCCl)cc2)cc1=O
Reactant: C1=CC=CNC=C1
Product: Cn1ncc(-c2ccc(OCCCN3CCCCCC3)cc2)cc1=O

Procedure:
This compound was prepared as the hydrochloride salt using 5-[4-(3-chloropropoxy)-phenyl]-2-methyl-2H-pyridazin-3-one and azepine using the procedure described in Example 91 Step 5; Mp 247-8° C.; MS m/z 342 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:24]=[CH:23][C:10]([CH2:11][N:12]3[CH2:16][C:15]4([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[O:14][C:13]3=[O:22])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)C.[Pd]>[CH:1]1([C:7]2[CH:24]=[CH:23][C:10]([CH2:11][N:12]3[CH2:16][C:15]4([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]4)[O:14][C:13]3=[O:22])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1OC2(CCCCC2)CN1Cc1ccc(C2=CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C1OC2(CCCCC2)CN1Cc1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
3-(4-Cyclohex-1-enyl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one (Example 1.31, 15 mg, 0.046 mmol) was dissolved in ethanol (3 mL) in a round bottom flask. Pd/C (5 mg) was added and the flask was flushed with hydrogen and stirred at room temperature overnight. The reaction mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated in vacuo to give the title product as a white powder (15 mg, quantitative yield). 1H NMR (300 MHz, CDCl3): δ (ppm)=7.19 (s, 4H), 4.4 (s, 2H), 3.11 (s, 2H), 1.82 (m, 10H), 1.45 (m, 11H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:19][CH2:18][CH2:17][CH2:16][Br:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(OCCCCBr)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
To a solution of 10 g (49.7 mmol) 4-Hydroxy-piperidine-1-carboxylic-acid tert-butyl ester and 18 ml (149 mmol) of 1,4-dibromobutane in 100 ml DMF was added under ice-cooling at 0° C., 3.25 g (74.53 mmol) NaH (57% in oil). After 2 h stirring at r.t., 140 ml of sat. NH4Cl-solution was added carefully. The reaction-mixture was diluted with Et2O and washed with water. The organic layer was concentrated in vacuo and the crude product was purified by chromatography on silica gel with Et2O/Hexane 1:2 to yield 2.47 g (15%) of clean 4-(4-Bromo-butoxy)-piperidin-1-carboxylic acid tert-butyl ester, MS: 336 (M+).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH2:36][OH:37])[CH2:35][O:34][CH2:33]1>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([O:22][CH2:31][C:32]2([CH2:36][OH:37])[CH2:35][O:34][CH2:33]2)=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: OCC1(CBr)COC1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CO)COC2)c1OC(F)F
Temperature: 80 °C
Yield: 19 %

Procedure:
To a stirring solution of 4-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.75 mmol) and (3-bromomethyl-oxetan-3-yl)-methanol (68 mg, 0.375 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 19%).
Reaction SMILES: CO[C:3](=[O:20])[C@@H:4]([N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:7][CH:8]=O)[CH3:5].[NH2:21][CH2:22][C:23]1([CH2:27][OH:28])[CH2:26][O:25][CH2:24]1.[B-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][N:21]([CH2:22][C:23]2([CH2:27][OH:28])[CH2:26][O:25][CH2:24]2)[C:3](=[O:20])[C@@H:4]1[CH3:5])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCC1(CO)COC1
Reactant: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Agent: CC(=O)O[B-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H]1C(=O)N(CC2(CO)COC2)CCN1C(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
A solution of (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (intermediate 27C; 258 mg, 0.92 mmol) in dichloromethane (1 mL) was added at room temperature to a suspension of (3-(aminomethyl)oxetan-3-yl)methanol (108 mg, 0.92 mmol), sodium triacetoxyborohyride (222 mg, 1.01 mmol) and acetic acid (111 mg, 1.85 mmol) in dichloromethane (1 mL). The reaction mixture was heated at 40° C. for 16 h, then partitioned between 1 M aq. sodium carbonate solution and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. The residue was taken up in methanol (2 mL), then after addition of potassium carbonate (255 mg, 1.85 mmol) the suspension was stirred for 2 h. The reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) afforded the title compound (45 mg, 14%). Light yellow oil, MS (ISP)=349.3 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[N:10]=[N:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[O:18]=[N+:19]=[O:20].O>C(#N)C>[N+:19]([C:4]1[CH:3]=[CH:2][C:1]([N:7]2[C:11](=[O:12])[N:10]=[N:9][NH:8]2)=[CH:6][CH:5]=1)([O-:20])=[O:18]
Reactant: O=c1nn[nH]n1-c1ccccc1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: O=c1nn[nH]n1-c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
A solution of 1-phenyl-5-tetrazolone (30 g) in acetonitrile (300 mL) was stirred under argon at 0° C. and nitronium tetrafluoroborate (36.9 g) was added over 30 minutes. After stirring at 0° C. for an additional 30 minutes the mixture was poured into water (900 mL). The precipitate was collected by filtration and dried under vacuum to give 23.1 g of the title compound as cream-colored solids. The filtrate was extracted with ethyl acetate, dried (MgSO4), filtered, and concentrated to give an additional 8.6 g of solids which was a 1:1 mixture of ortho- and para-substituted isomers. 1H NMR (acetone-d6) δ 13.62 (br s, 1H), 8.36 (ABq, JAB=9.2 Hz, 4H); MS (EI) m/z 207 (M+); Rf=0.2 (10% methanol/dichloromethane).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][C:3]=1[N+:12]([O-])=O>CO.[Pd]>[NH2:12][C:3]1[CH:4]=[C:5]([C:8](=[O:11])[CH2:9][CH3:10])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CCC(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCC(=O)c1ccc(N)c(N)c1
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of 1-(4-amino-3-nitrophenyl)propan-1-one (1.94 g, 10 mmol) in 50 mL of methanol was added 0.5 g 10% Pd/C and the mixture was hydrogenated under H2 (1 atm) at rt for 1 h. The mixture was filtered and the filtrated was concentrated to give the desired product (1.48 g, 90%).
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([CH:7]1[CH2:11][C:10](=[O:12])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:8]1)=O.O>C(O)C>[OH:4][CH2:5][CH:7]1[CH2:8][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:10](=[O:12])[CH2:11]1
Reactant: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(CN2CC(CO)CC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaBH4 (15 g, 0.081 mol) was added in portions to ester 79 in ethanol (600 mL) at room temperature. After 4.5 hours water (˜200 mL) was carefully added to the reaction and the solution stirred at room temperature overnight. The resultant solid was removed by filtration and the filtrate concentrated to give alcohol 80 as an oil. 15.33 g, 81%. MS, m/z (relative intensity): 235 [M+H, 100%].
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=O)[CH2:8][CH:7]2[CH3:16]>O.C1(C)C=CC=CC=1.[Zn]>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:6](=[CH:5][C:4]=1[O:3][CH3:2])[CH:7]([CH3:16])[CH2:8][CH2:9]2
Reactant: COc1cc2c(cc1OC)C(C)CC2=O
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(cc1OC)C(C)CC2
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a suspension of 53.3 g (815 mmol) of zinc dust in 74 ml of water were added 4 ml of concentrated hydrochloric acid. The supernatant was decanted off after stirring for 30 min, and to the residue were added, with ice cooling, 42 ml of water and then, dropwise, 55 ml of concentrated hydrochloric acid. 28.0 g (136 mmol) of 5,6-dimethoxy-3-methylindan-1-one dissolved in 53 ml of toluene were added and the mixture was refluxed for 3 days (d), in the course of which, after 48 h, a further 55 ml of concentrated hydrochloric acid were added. After cooling, the reaction mixture was poured into 200 ml of water and the product was extracted twice in 300 ml of ether. The combined extracts were washed with 100 ml of water and 25 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. After flash chromatography (pentane/ether, 9:1, Rf=0.23) on silica gel, 19.6 g (75%) of 5,6-dimethoxy-1-methylindane were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:28])[CH2:24][C:25]([OH:27])=[O:26])[CH:5]=[C:6]([CH3:21])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]([CH3:20])[CH3:19].[OH-].[K+:30]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:28])[CH2:24][C:25]([O-:27])=[O:26])[CH:5]=[C:6]([CH3:21])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]([CH3:19])[CH3:20].[K+:30]
Reactant: Cc1cc(NC(=O)CC(=O)O)cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)CC(=O)[O-])cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Reaction time: 1 h
Yield: 99 %

Procedure:
1.16 g (2.89 mmol) of 3-({3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methyl-phenyl}amino)-3-oxopropionic acid (Example 6) are dissolved in 15 ml of THF and treated dropwise at 0° C. with 5.67 ml of a 0.51 molar potassium hydroxide solution. The reaction mixture is stirred for one hour and the solvent is then removed in vacuo. By co-evaporation with toluene, 1.25 g (99% of theory) of potassium 3-({3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methylphenyl}-amino)-3-oxopropanoate are obtained
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[F:26][C:27]([F:34])([F:33])[CH:28]([OH:32])[C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[CH:28]([OH:32])[C:27]([F:34])([F:33])[F:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C(O)C(F)(F)F

Procedure:
The title compound, white solid (6.2 mg, 17%), MS (ISP) m/z=457.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and 3,3,3-trifluoro-2-hydroxypropanoic acid
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]([C@H:24]([C@@H:26]([C@@H:28]([CH2:30][O:31][C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[OH:29])[OH:27])[OH:25])[OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[H-].[Na+].[CH2:53](Br)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[C:1]([O:20][CH2:21][C@H:22]([C@H:24]([C@@H:26]([C@@H:28]([CH2:30][O:31][C:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[O:29][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:27][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:25][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[O:23][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O[C@@H]([C@H](O)[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: c1ccc(CO[C@@H]([C@H](OCc2ccccc2)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)OCc2ccccc2)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)OCc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 219 %

Procedure:
10.64 g (16 mmol) of 1,6-di-O-trityl-D-mannitol and 3.07 g of NaH (60% oil dispersion) were added into a 250 mL round-bottom flask. The flask was purged with N2 and cooled in a dry ice/isopropanol bath, and then 133 mL of anhydrous DMF was added. After stirring for 5 min, 8.55 mL (72 mmol) of benzyl bromide was added slowly to the reaction mixture. The dry ice/iPrOH bath was removed and the reaction mixture stirred at RT for 3.5 hr and then concentrated under reduced pressure. 400 mL of EtOAc and 300 mL of deionized water were added to the residue. After separation, the water layer was back extracted twice with EtOAc. The combined EtOAc layers were washed three times with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 18 g of desired product (yield: 109%). The product was used directly for the next reaction without further purification. Mass spec analysis (MALDI-TOF): exact mass: 1026.49, obtained: 1050.85 [M+Na]+.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([N:10]1C(=O)C2C(=CC=CC=2)C1=O)[C@H:5]([CH3:9])[CH2:6][CH:7]=[CH2:8]>Cl.C(O)(=O)C>[NH2:10][C@@H:4]([C@H:5]([CH3:9])[CH2:6][CH:7]=[CH2:8])[C:3]([OH:21])=[O:2]
Reactant: C=CC[C@@H](C)[C@@H](C(=O)OC)N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: C=CC[C@@H](C)[C@H](N)C(=O)O
Temperature: 25 °C
Yield: 50 %

Procedure:
(2S,3R)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-methyl-hex-5-enoic acid methyl ester (2.01 g, 7.00 mmol) is dissolved in a 2:1 mixture of 6 N hydrochloric acid and glacial acetic acid (62.5 mL), and the solution is heated at reflux for 4 h. The solution is cooled to room temperature and concentrated under reduced pressure. The product is taken up in water and the solution is filtered. The filtrate is concentrated under reduced pressure and the residue is dissolved in water, then the solution is applied to a column of Amberlite™ IR 120 cation exchange resin (NH4+ form.). The column is washed with water (2.5 L), then eluted with aqueous ammonia solution (2.5 L). The eluate is boiled until no ammonia can be detected, then concentrated under reduced pressure affording the title compound (0.5 g, 3.50 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl.[NH2:14]O.C([O-])=O.[Na+].O>C(O)=O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:14])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1ccc(O)c([N+](=O)[O-])c1
Yield: 87.6 %

Procedure:
A mixture of 5.0 g of 4-hydroxy-3-nitrobenzaldehyde with 2.5 g of hydroxylamine hydrochloride and 3.6 g of sodium formate was heated under reflux in 35 ml of formic acid for 5 hours. After the reaction mixture was cooled, water was added thereto. The precipitated crystal was collected by filtration to give 4.3 g of 4-hydroxy-3-nitrobenzonitrile. 3.5 g of thioacetamide was added thereto and the mixture was heated at 80° C. for 1 hour in 12 ml of N,N-dimethylformamide saturated with hydrochloric acid. After the completion of the reaction, the reaction mixture was neutralized with 30 ml of water and 18 ml of 2N sodium hydroxide. The precipitated crystal was collected by filtration and recrystallized from ethanol to give 3.9 g of 4-hydroxy-3-nitrobenzthioamide. This product was dissolved in 30 ml of ethanol, 2.7 g of ethyl 2-chloroacetoacetate was added thereto, and the mixture was heated under reflux for 5 hours. The reaction mixture was cooled, and the precipitated crystal was collected by filtration and recrystallized from ethanol to give 3.4 g of ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate (yield: 37%).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4](=[N:20][OH:21])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: NO
Reactant: O=C(c1ccc(F)cc1)c1ccc(O)c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccc(F)cc1)c1ccc(O)c(Cl)c1Cl

Procedure:
To a solution of 35 g of 2,3-dichloro-4-hydroxy-4'-fluorobenzophenone in 250 ml pyridine, 34.6 g of hydroxylamine HCl is added. The mixture is refluxed for 4 hours. The pyridine is evaporated in vacuo. The residue is partitioned between 5% HCl and ethyl acetate. The ethyl acetate extract is washed with water, dried over Na2SO4 and evaporated to give 2,3-dichloro-4-hydroxy-4'-fluorobenzophenone oxime as a mixture of isomers, mp 150°-156° C.