Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH2:19]1[O:27][C:26]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=2[O:20]1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:23]=[CH:22][C:21]5[O:20][CH2:19][O:27][C:26]=5[CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(c4)OCO5)cc3CC[C@@H]12
Yield: 57.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3,4-methylenedioxyphenyl boronic acid (131 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 130 mg (57%) of the title compound as an amorphous solid. mp 146°-152°. FDMS: m/e=349. α[D]589 =+67.92 (c=1.06, chloroform).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2CO[CH:15]3[N:12]([C:13](=[O:23])[CH:14]3[C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:11]=2[NH:24][C:25](=[O:43])[CH2:26][C:27]([O:29]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:28])=[CH:8][N:9]=1)(=[O:3])[CH3:2].[CH2:44]([OH:46])[CH3:45]>C(O)=O>[C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:45][C:44](=[O:46])[CH:15]3[N:12]([C:13](=[O:23])[CH:14]3[C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:11]=2[NH:24][C:25](=[O:43])[CH2:26][C:27]([OH:29])=[O:28])=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)Nc1ncc(C2=C(NC(=O)CC(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(c4cccs4)C3OC2)s1
Solvent: O=CO
Product: CC(=O)Nc1ncc(C2=C(NC(=O)CC(=O)O)N3C(=O)C(c4cccs4)C3C(=O)C2)s1

Procedure:
A solution of 3-(2-acetylaminothiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-(thien-2-yl)-acetamido-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (0.1 g) in formic acid (5 cc) is heated at 50° C. for 30 minutes, with stirring. The mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. and the residue is dissolved in ethanol (5 cc). The suspension obtained is stirred at 50° C. for 5 minutes and the solvent is evaporated off under reduced pressure (30 mm Hg; 4 kPa) at 50° C.; this operation is repeated once and the residue thus obtained is taken up in ethanol (2 cc). After filtration, the suspended solid gives 3-(2-acetylaminothiazol-5-yl)-2-carboxy-8-oxo-7-(thien-2-yl)-acetamido-5-oxo-1-azabicyclo[4.2.0]oct-2-ene (12 mg) in the form of a beige powder.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([OH:11])[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)C.[OH-].[Na+]>CO.C1COCC1>[CH:12]1([C:5]([OH:11])([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:18])=[O:3])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)C(O)(c1cccs1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(O)(c1cccs1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of cyclohexyl-hydroxy-thiophen-2-yl-acetic acid ethyl ester (361.8 g, 1.35 mol) in MeOH (1.5 litres) and THF (1.5 litres) is treated portionwise with 2M NaOH (1.1 litres) over 30 minutes. The reaction mixture is stirred at room temperature overnight and then concentrated in vacuo to remove the organic solvents. The remaining aqueous portion is partitioned between EtOAc (2 litres) and 20% citric acid in water (1 litre). The organic layer is separated, washed with brine and concentrated in vacuo to afford the titled compound which is used crude in the next step.
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([F:9])[CH2:7][NH:6][CH2:5]1)=[N+:2]=[N-:3].CCN(C(C)C)C(C)C.[C:19](Cl)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl>[N:1]([C@H:4]1[C@H:8]([F:9])[CH2:7][N:6]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1CNC[C@H]1F
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a stirred mixture of (trans)-3-azido-4-fluoropyrrolidine (18 g) in CH2Cl2 (120 mL) was added DIPEA (35 g, 0.27 mol, 2.5 eq), then CBZ-Cl (22 g, 0.13 mol) was added dropwise at 0-5° C. After addition, the resulting mixture was stirred at rt overnight. The mixture was washed with sat. aq. NH4Cl (150 mL), sat. aq. NaHCO3 (3×40 mL) and brine (40 mL). The organic layer was concentrated and purified by column (petroleum ether/EtOAc=10:1˜5:1) to give the title compound (30 g, ˜100% yield in two steps, containing residual EtOAc and DCM) as a light yellow oil.
Reaction SMILES: C1([CH2:7][C:8]([O:10]CC)=[O:9])C=CC=CC=1.[CH3:13][C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH2:17][NH:16][C:15]1=[O:20].CC(C)([O-])C.[K+].BrCC(OCC)=O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:13][C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH2:17][NH:16][C:15]1=[O:20].[CH3:13][C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH2:17][N:16]([CH2:7][C:8]([OH:10])=[O:9])[C:15]1=[O:20]
Reactant: CCOC(=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC1(c2ccccc2)CCCNC1=O
Agent: CCOC(=O)CBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccccc2)CCCN(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Methyl-3-phenylpiperidin-2-one is prepared using the procedures described in Examples 91A and 91B substituting ethyl 2-phenylpropionate for ethyl 2-phenylacetate. To 3-methyl-3-phenylpiperidin-2-one (1.01 g, 5.34 mmol) in tetrahydrofuran (3 mL) was added potassium t-butoxide (1.0 Min tetrahydrofuran, 6.40 mL, 6.40 mmol), and the mixture was allowed to stir at room temperature for 30 minutes. To the mixture was added ethyl 2-bromoacetate (0.591 mL, 5.34 mmol). The reaction was heated to 60° C. and stirred for 2 hours. The reaction was cooled, diluted with ethyl acetate (50 mL), washed with 1 N HCl (25 mL) and brine (25 mL), dried over magnesium sulfate and concentrated. The residue was loaded directly onto a SF25-40 silica gel column (Analogix®, Burlington, Wis.), and the intermediate ethyl ester was eluted using a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate over 30 minutes (flow=30 mL/minute). The ethyl ester was dissolved in ethanol (10 mL) and sodium hydroxide (2.0 M, 5.34 mL, 10.67 mmol) was added. After stirring for 30 minutes, thin layer chromatography (100% ethyl acetate) showed complete consumption of the starting material. The reaction was diluted with ethyl acetate (50 mL), washed with 1 N HCl (50 mL) and brine (50 mL), dried over magnesium sulfate, and concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.42-7.11 (m, 5H), 4.28 (d, J=16.7, 1H), 4.12 (d, J=16.7, 1H), 3.59-3.33 (m, 2H), 2.23 (dt, J=4.5, 13.5, 1H), 2.07-1.89 (m, 1H), 1.85-1.66 (m, 2H), 1.61 (s, 3H); MS (APCI+) m/z 248 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:14]1([C:12]2[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]3[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]5[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=5)[CH:27]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C4CC4)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(C5CC5)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-cyclopropyl-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M270) (349 mg, 0.63 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (91 mg, 33%).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([CH:8]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH:23]([C:28](=O)[CH2:29][CH3:30])[C:24](=O)[CH2:25][CH3:26])=[CH:15][CH:14]=1)(=[O:7])[CH2:5][CH3:6]>C(O)C>[C:4]([CH:8]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]2[C:28]([CH2:29][CH3:30])=[N:2][NH:3][C:24]=2[CH2:25][CH3:26])=[CH:15][CH:14]=1)(=[O:7])[CH2:5][CH3:6]
Reactant: NN
Reactant: CCC(=O)C(CCCOc1ccc(OCCCC(C(=O)CC)C(=O)CC)cc1)C(=O)CC
Solvent: O
Solvent: CCO
Product: CCC(=O)C(CCCOc1ccc(OCCCc2c(CC)n[nH]c2CC)cc1)C(=O)CC
Reaction time: 8 h

Procedure:
A solution of 0.36 ml (0.00815 m) of hydrazine hydrate in 350 ml of ethanol was added dropwise during a 90 minute period to a solution of 3.3 g (0.0074 m) of 1,4-bis(4,4-dipropionylbutyloxy)benzene in 700 ml of ethanol held at 0°-5° C. and with vigorous stirring. The reaction mixture was then heated at reflux for 2.5 hours and allowed to stand at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was treated with ethereal hydrogen chloride. The solid product which formed was collected and stirred for two hours with 250 ml boiling isopropyl acetate, then filtered and concentrated. The solid residue was recrystallized from isopropyl acetate to give 1.6 g of 4-{3-[4-(4,4-dipropionylbutyloxy)phenoxy]propyl}-3,5-diethyl-1H-pyrazole, m.p. 135°-136° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](OCC)=[O:21].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: CCOC(=O)CCCCCCCCCCCCCCCOCOC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COCOCCCCCCCCCCCCCCCCO
Reaction time: 1 h

Procedure:
To a solution of 3.0 g of ethyl 16-methoxymethoxyhexadecanoate in 50 ml of tetrahydrofuran was added under ice-cooling 1.5 g of lithium aluminum hydride and the mixture was stirred for one hour. After a saturated aqueous solution of sodium sulfate was added, the insolubles precipitated out were filtered off and distilled under reduced pressure. The residue was chromatographed over a silica gel column to afford the title compound as a colorless oily substance.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[N:12](C(OC(C)(C)C)=O)[CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N>>[N:1]1([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[NH:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCCC[C@@H]1N1CCCC1
Agent: Cl
Agent: N
Product: CN[C@@H]1CCCC[C@@H]1N1CCCC1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
(±)-cis-2-Pyrrolidinyl-N-t-butyloxycarbonyl-N-methylcyclohexylamine (247 gm) was slowly added to 6 M hydrochloric acid at 60° C. with vigorous stirring. The solution was stirred an additional 5 minutes at 60° C. and poured onto ice (200 gm). Excess concentrated aqueous ammonia was added and the mixture was extracted with methylene chloride. The combined extracts were dried (Na2SO4) and the solvent removed on a rotary evaporator. The residue was distilled (78° C. at 0.3 mm Hg) to give the product as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([S:14]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])=[O:15])[CH:5]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH3:33])=[O:31].O>ClCCl>[C:18]([NH:17][S:14]([C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:30]([O:32][CH3:33])=[O:31])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:16])=[O:15])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1ccc(CCN)cc1S(=O)(=O)NC(C)(C)C
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)NCCc1ccc(C(=O)OC)c(S(=O)(=O)NC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1.45 g (4.6 mmol) of methyl 4-(2-aminoethyl)-2-tert-butylaminosulfonylbenzoate and 0.71 ml (5.1 mmol) of triethylamine in 10 ml of dichloromethane was added dropwise to an ice-cooled solution of 1.31 g (13.8 mmol) of methyl chloroformate in 20 ml of dichloromethane. After 2 h at room temperature, water was added, the phases were separated, and the aqueous phase was re-extracted twice with dichloromethane. The combined organic extracts were washed with water, dried over Na2SO4 and concentrated in vacuo. This gave 1.4 g (81%) of methyl 2-tert-butylaminosulfonyl-4-[2-(methoxycarbonylamino)ethyl]benzoate as a viscous oil.
Reaction SMILES: FC(F)(F)C(O)=O.[N+:8]([C:11]1[CH:30]=[CH:29][C:14]([CH2:15][NH:16][C:17]([N:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:20][CH2:21][CH3:22])=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH:31]([C@@H:33]1[C@@H:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:36][N:35]([C@H:44]([CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]2)[C:45]([O:47]CC2C=CC(OC)=CC=2)=[O:46])[CH2:34]1)=O>>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17]([N:19]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:31][C@@H:33]3[C@@H:37]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:36][N:35]([C@H:44]([CH:57]4[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]4)[C:45]([OH:47])=[O:46])[CH2:34]3)[CH2:25][CH2:24]2)[CH2:20][CH2:21][CH3:22])=[O:18])=[CH:29][CH:30]=1)([O-:10])=[O:9]
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: CCCN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1
Yield: 63.4 %

Procedure:
The title compound was prepared from 4-(N-(N-(4-nitrobenzyl)carbamoyl)-N-(prop-1-yl)amino)-piperidine trifluoroacetate (21 mg, 0.048 mmol, from Step A) and 2-(R)-(3-(R)-formyl-4-(S)-phenyl-pyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (14 mg, 0.028 mmol, Aldehyde 5) according to the method described in Example 1, Step C to give 11 mg (63%) of the title compound. ESI-MS: 620.4 (M+H); HPLC A: 2.33 min.
Reaction SMILES: OS(O)(=O)=O.C([NH:9][C:10]1[C:11]([N+:20]([O-:22])=[O:21])=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=[O:14])(=O)C>>[NH2:9][C:10]1[C:11]([N+:20]([O-:22])=[O:21])=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=[O:14]
Reactant: CC(=O)Nc1c(C)ccc(C(=O)O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1N
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
To a 70% aqueous solution of H2SO4 (100 mL) is added 3-(Acetylamino)-4-methyl-2-nitrobenzoic Acid (15) (14.30 g, 60.00 mmol), and the reaction mixture heated to about 115° C. for about 30 minutes. The mixture is then cooled to ambient temperature, added to ice water (250 mL) and held at about 0° C. for about 30 minutes. The resulting solid is filtered, washed with water (100 mL), and dried to provide 3-amino-4-methyl-2-nitrobenzoic acid (16) as a rust colored solid (7.17 g, 61% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=[N:13]2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:14]=[N:13]2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-n2cc(CCCc3ccccc3)nn2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-n2cc(CCCc3ccccc3)nn2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a solution of ethyl 4-methyl-2-(4-(3-phenylpropyl)-1H-1,2,3-triazol-1-yl)thiazole-5-carboxylate (7.04 g, 19.78 mmol) in a mixture of tetrahydrofuran (25 mL) and water (25 mL) was added lithium hydroxide (4.15 g, 98.90 mmol). The reaction mixture was stirred at ambient temperature 18 hours, acidified with 10% hydrochloric acid solution, and extracted with dichloromethane (2×100 μL). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to afford the title compound in 89% yield (5.82 g): 1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.31-7.15 (m, 5H), 2.75-2.49 (m, 7H), 2.00-1.95 (m, 2H); MS (ES+) m/z 329.2 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.[N:25]1([C:30]([O-:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:7]([O:31][C:30]([N:25]1[CH2:29][CH2:28][C@H:27]([O:14][C:11]2[CH:10]=[CH:9][C:8]([CH:7]3[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[CH2:3][CH:2]3[OH:1])=[CH:13][CH:12]=2)[CH2:26]1)=[O:32])([CH3:8])([CH3:2])[CH3:6]
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: O=C([O-])N1CCCC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3O)cc2)C1

Procedure:
Analogously to Method I, 0.665 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.822 g of tert-butyl 3(R)-toluene-4-sulphonyloxy)pyrrolidine-1-carboxylate are reacted. The title compound is obtained as a white foam. Rf=0.14 (1:1 EtOAc-heptane). Rt=4.91.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[NH:11][C:10](=[O:13])[C:9]3=[CH:14][N:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[N:8]3[C:7]=2[N:6]=[C:5]([N:22]2[CH:26]=[CH:25][N:24]=[C:23]2C(CC)CC)[N:4]=1)[CH3:2].N1C=CN=C1>>[CH2:1]([C:3]1[C:12]2[NH:11][C:10](=[O:13])[C:9]3=[CH:14][N:15]=[C:16]([CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[N:8]3[C:7]=2[N:6]=[C:5]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[N:4]=1)[CH3:2]
Reactant: CCc1nc(-n2ccnc2C(CC)CC)nc2c1[nH]c(=O)c1cnc(C(CC)CC)n12
Agent: c1c[nH]cn1
Product: CCc1nc(-n2ccnc2)nc2c1[nH]c(=O)c1cnc(C(CC)CC)n12

Procedure:
Prepared by treatment of the product of Example 9a with excess imidazole at 200° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].CC(C)([O-])C.[Na+].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][C:17]=1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:18][C:17]=1[O:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1.[O:24]1[CH2:25][CH2:30][CH2:29][CH2:28]1
Reactant: CCOP([O-])OCC
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(F)c(Oc2ccccc2)c1)OCC
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
A mixture of diethylphosphite (6.9 g, 0.05 mol) in tetrahydrofuran is cooled to 10° C., treated portionwise with sodium t-butoxide (4.9 g, 0.05 mol) while maintaining the reaction mixture temperature below about 20° C., stirred at room temperature for 5 minutes, cooled, and treated dropwise with 4-fluoro-3-phenoxybenzyl bromide (14.05 g, 0.05 mol) at about 10-15° C. to give a solution of the title product in tetrahydrofuran (98% yield by gas chromatography).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:3]=1.O.[OH-].[Na+]>C(O)(=O)C.[Fe]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([S:12][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1ccc(F)cc1Sc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Sc2cc(F)ccc2CC(=O)O)cc1
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A solution of 19 g [4-fluoro-2-(4-nitrophenylthio)phenyl] acetic acid in 60 ml of acetic acid was slowly added dropwise into a boiling mixture of 300 ml water and 30 g iron powder. The mixture was then stirred and refluxed for 6 hours. After cooling, 200 ml of a 20% sodium hydroxide solution were added, the solution filtered and the filtrate acidified with acetic acid. After standing overnight, the separated product was filtered, washed with a small quantity of water and dried in vacuo. There were obtained 9.5 g of crude [2-(4-aminophenylthio)-4-fluorophenyl]acetic acid melting at 151°-155° C. After a single crystallization from a mixture of benzene and petroleum ether, the product was pure and melted at 154°-156° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([NH:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]=O.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:16][CH2:17][C@H:18]([N:21]([CH3:31])[CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: c1ccc(CCCN[C@H]2CC[C@H](c3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-[4-(4-benzyloxy-phenyl)-cyclohexyl]-(3-phenyl-propyl)-amine (0.4 g, 1.0 mmol), 36.5% aq. formaldehyde (0.12 ml) and MeOH (7 ml) was stirred overnight at RT. Excess sodium borohydride was then added, and stirring was continued for 2 h. Evaporation of the solvent, addition of H2O, extraction with CH2Cl2, drying of the organic layer with Na2SO4, evaporation of the solvent and purification of the residue by chromatography over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2—MeOH—25% aq. NH3 140:10:1 trans-[4-(4-benzyloxy-phenyl)-cyclohexyl]-methyl-(3-phenyl-propyl)-amine (0.41 g, 99%) as a colorless oil. MS: m/e=413 (M+).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:35])(=O)=O)=CC=1.O>C1COCC1>[F:35][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Brc1c(COC2CCCCO2)ccc2c1CCCC2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Fc1c(COC2CCCCO2)ccc2c1CCCC2
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To stirring solution of bromide 47.5 (1.0 g, 3.1 mmol) in THF at −78° C. is added n-BuLi (1.6 M, 2.11 mL, 3.4 mmol), and stirring is continued for 1 hour. N-Fluorobenzene sulfonimide (3.7 mmol) is added and the mixture is allowed to warm to 23° C. Water is added to quench the reaction. The aqueous layer is extracted with EtOAc (3×100 mL), and the organic layer is dried over MgSO4 and concentrated in vacuo. The residue is purified by column chromatography (silica, EtOAc/Hexane), to afford fluoride 47.6.