Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16])C>ClC(Cl)C>[CH3:1][NH:2][CH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16]
Reactant: CN(C)CCCOCc1cc(Br)ccc1F
Solvent: CC(Cl)Cl
Product: CNCCCOCc1cc(Br)ccc1F
Temperature: 25 °C

Procedure:
In a 15 m flask, under a nitrogen atmosphere, N,N-dimethyl-3-[2-fluoro-5-bromobenzyloxy]propylamine (351 mg, 1.21 mmol) was dissolved in dichloroethane (3.5 ml). To this solution ACE•Cl (0.78 ml, 7.26 mmol) was added and the resulting mixture was heated to reflux and maintained at this temperature for 18 hours. The reaction mixture was cooled to ambient temperature, and the solvents were removed in vacuo. The residue was taken up in methanol and refluxed for 1.5 hours. The methanol solution was then partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.[CH3:15][C:16]1[C:20](B2OC(C)(C)C(C)(C)O2)=[C:19]([CH3:30])[NH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:15][C:16]1[C:20]([C:2]2[S:10][C:9]3[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=3[CH:3]=2)=[C:19]([CH3:30])[NH:18][N:17]=1
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1n[nH]c(C)c1-c1cc2c(s1)C(=O)NC(C)(C)N2C
Yield: 36 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (333 mg, 1.50 mmol), sodium carbonate (265 mg, 2.50 mmol), 1,2-dimethoxyethane (5 mL) and water (2 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. This mixture was refluxed for 18 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and EtOAc (100 mL), and the mixture was shaken well. The insoluble materials were filtered off. From the filtrate, the organic layer was collected, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc, then EtOAc to 90:10 EtOAc/MeOH). The obtained yellow solid was triturated with EtOAc/hexane and collected by filtration to afford the title compound (52.2 mg, 36%) as a pale yellow solid:
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:39])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:21]=[C:22]([C:35]([O:37][CH3:38])=[O:36])[N:23]([Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:24]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>CO.[Pd]>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:39])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([C:35]([O:37][CH3:38])=[O:36])[N:23]([Si:25]([CH:29]([CH3:30])[CH3:31])([CH:26]([CH3:27])[CH3:28])[CH:32]([CH3:34])[CH3:33])[CH:24]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: COC(=O)c1cc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cn1[Si](C(C)C)(C(C)C)C(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cn1[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A mixture of methyl 4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethynyl]-1-triisopropylsilylpyrrole-2-carboxylate (550 mg, 1.0 mmol) and 10% palladium-on-carbon (220 mg) in methanol (45 mL) was stirred overnight under hydrogen (50 psi). The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo. The residue was dissolved in methylene chloride and filtered through a short silica gel column. The eluate was evaporated to give methyl 4-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]-1-triisopropylsilylpyrrole-2-carboxylate (524 mg, 94%). The analytical sample, mp 202-204° C., was obtained by column chromatography using chloroform:methanol (19:1): 1H NMR (CDCl3) δ 11.34 (br s, 1H), 7.85 (br s, 1H), 6.98 (s, 1H), 6.90 (s, 1H), 4.69 (s, 1H), 3.79 (s, 3H), 3.36 (br d, 1H, J=10.0 Hz), 2.99 (m, 1H), 2.83 (m, 1H), 2.59 (m, 2H), 2.12 (dd, 1H, J=15.6, 9.0 Hz), 1.90-1.50 (m, 6H), 1.30 (s, 9H), 1.11 (d, 18H, J=7.6 Hz).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Li+].CC([N-]C(C)C)C.[CH:17]1([C:22](=[O:36])[CH2:23][CH2:24][C:25]2[C:30]([O:31][CH2:32][CH3:33])=[CH:29][N:28]=[C:27]([CH2:34][CH3:35])[CH:26]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH:17]1([C:22]2([CH2:23][CH2:24][C:25]3[C:30]([O:31][CH2:32][CH3:33])=[CH:29][N:28]=[C:27]([CH2:34][CH3:35])[CH:26]=3)[O:36][C:1](=[O:6])[CH2:2][C:3](=[O:4])[CH2:5]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOc1cnc(CC)cc1CCC(=O)C1CCCC1
Reactant: COC(=O)CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1cnc(CC)cc1CCC1(C2CCCC2)CC(=O)CC(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
Methyl acetoacetate (1.2 mL, 10.9 mmol) was added to a cooled −50° C. suspension of LDA [prepared from diisopropylamine (3.0 mL, 21.8 mmol), and n-BuLi (8.7 mL, 21.8 mmol) dissolved in THF (30 mL)]. The reaction was stirred for 30 mins and then a solution of 1-cyclopentyl-3-(5-ethoxy-2-ethyl-pyridin-4-yl)-propan-1-one (1.0 g, 3.6 mmol) dissolved in THF (30 mL) was added. The reaction was warmed to room temperature and stirred for 2 hours. The reaction was poured into 1 N NaOH and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. The residue was dissolved in methanol (100 mL), treated with potassium carbonate (1.5 g, 10.9 mmol), and refluxed under N2 for 120 mins. The reaction mixture was partitioned between H2O and IPE. The aqueous layer was made neutral with 1N HCl and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated to give the product (1.3 g, 99% yield). 1H NMR (400 MHz, CDCl3): δ 1.26 (t, J=7.6 Hz, 3 H), 1.43 (t, J=6.8 Hz, 3 H), 1.50-2.05 (br m, 9 H), 2.34 (m, 2 H), 2.62-2.77 (m, 6 H), 3.44 (m, 2 H), 4.11 (q, J=6.8 Hz, 2 H), 6.90 (s, 1 H), 8.08 (s, 1 H).
Reaction SMILES: O1[C:5]2([CH2:14][CH2:13][C:8]3([CH2:12][CH2:11][NH:10][CH2:9]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>CO>[CH2:9]1[C:8]2([CH2:13][CH2:14][C:5](=[O:4])[CH2:6][CH2:7]2)[CH2:12][CH2:11][NH:10]1
Reactant: C1CC2(CCC3(CC2)OCCO3)CN1
Agent: Cl
Solvent: CO
Product: O=C1CCC2(CCNC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.8 %

Procedure:
To a solution of 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecane (10 g, 50.69 mmol) in MeOH (100 mL) was added HCl aqueous solution (2 M, 30 mL, 60 mmol). The reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was dissolved in water (100 mL) and adjusted to pH=8 with a saturated Na2CO3 aqueous solution, then extracted with DCM (200 mL×3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/7) to give the title compound as a yellow solid (10 g, 100%).
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-:36].[K+]>C(O)(C)(C)C.ClCCl>[CH2:34]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)[C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]([NH2:17])=[O:36])=[CH:10][CH:11]=1)=[O:5])[CH3:35]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(C#N)c2)N2CCN(Cc3ccccc3)CC2)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(C(N)=O)c2)N2CCN(Cc3ccccc3)CC2)cc1
Yield: 84.2 %

Procedure:
To a solution of INTERMEDIATE 4a (428 mg) in tert-butanol (10 mL) was added crushed potassium hydroxide (129 mg, 2.5 eq) and the reaction was heated to reflux. After 90 minutes the reaction was cooled and diluted with dichloromethane (40 mL). The reaction was washed with water (30 mL) and the organic layer separated. The aqueous layer was neutralized with 2 N hydrochloric acid and washed with dichloromethane (2×25 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography, eluting 3% methanol in dichloromethane to yield COMPOUND 1 as a colorless foam (374.5 mg, 84%). 1H NMR (CD3OD) δ 1.06 (t, J=6.9 Hz, 3H), 1.20 (t, J=6.8 Hz, 3H), 3.15-3.40 (m, 6H), 3.545-3.54 (m, 2H), 3.57-3.67 (m, 4H), 4.44 (s, 2H), 5.39 (br s, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.43-7.59 m, 6H), 7.82 (d, J=7.8 Hz, 3H), 7.93 (d, J=7.0 Hz, 1H), 8.22 (s, 1H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[O:28]=[S:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:31][CH2:30]1>>[O:28]=[S:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH:40]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:38][CH:37]=2)[CH2:31][CH2:30]1
Reactant: Nc1ccc(CN2CCS(=O)CC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCS(=O)CC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(1-oxo-thiomorpholin-4-yl-methyl)-aniline Rf value: 0.7 (silica gel, methylene chloride/methanol=10:1) C28H27N3O4S
Reaction SMILES: BrC1C=CN=CC=1.[Li].C(=O)CCC.S(Cl)(Cl)=O.Cl[CH:19]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[H-].[Na+].Cl>CN(C)C=O>[N:29]1([CH:19]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21][CH3:22])[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: c1c[nH]cn1
Reactant: CCCC(Cl)c1ccncc1
Agent: Brc1ccncc1
Agent: Cl
Agent: [H-]
Solvent: O=S(Cl)Cl
Solvent: CCCC=O
Solvent: CN(C)C=O
Product: CCCC(c1ccncc1)n1ccnc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The initial material, 4-(1-chlorobutyl)-pyridine, necessary for this reaction is obtained by the following reaction sequence. Commercial 4-bromo-pyridine is converted, by halometal exchange, into the corresponding 4-lithium-pyridine compound. This lithium compound is converted, with butyraldehyde, into the corresponding secondary alcohol. The alcohol is then converted by reaction with thionyl chloride into 4-(1-chlorobutyl)pyridine. 0.68 g of imidazole is dissolved in 5 ml of dimethylformamide, 0.3 g of sodium hydride (80%) is added and stirred for 10 minutes at room temperature. A solution of 3.87 g of 4-(1-chlorobutyl)-pyridine in 4 ml of dimethylformamide is added to this solution and stirred for 24 hours at room temperature. Then it is poured into 100 ml of 10% hydrochloric acid and extracted with ethyl acetate. The aqueous phase is made alkaline with sodium hydroxide solution (pH 13) and extracted with methylene chloride. The methylene chloride solution is concentrated by evaporation in a vacuum and the residue is distilled on a bulb tube, boiling point: 170°-190° C./0.04 mbar. 0.3 g of 4-[1-(1-imidazolyl)-butyl]-pyridine is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].BrC[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: Clc1ccc(CCBr)cc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(Cl)cc3)CC1)O2
Yield: 92.7 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (169 mg, 0.500 mmol, Intermediate 1, hydrochloride salt) was alkylated using 1-(2-bromo-ethyl)-4-chloro-benzene (0.15 ml, 1.5 mmol) as described in Example 56, Step A, giving (E)-3-{1′-[2-(4-chloro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (204 mg) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12].C([O-])(=O)C.[K+]>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:15]([O:14][C:10](=[O:13])[CH:11]=[CH:12][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Clc1cc(Cl)cc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C=Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3,5-dichloro-iodobenzene (5 g, 18 mmol), tert butyl acrylate (6.5 mL, 2.5 eq), tetrabutyl ammonium chloride hydrate (5.1 g, 1 eq), potassium acetate (5.4 g, 3 eq) and palladium (II) acetate (˜200 mg, 30 mol %) in DMF (50 mL) was stirred at ambient temperature for 5 h. The reaction mixture was reduced in vacuo and partitioned between water and ethyl acetate. The ethyl acetate fractions were dried over magnesium sulphate and filtered through a small plug of silica gel using 10% ethyl aceate/n-heptanes as eluent to afford 3-(3,5-dichlorophenyl)-acrylic acid tert butyl ester as a white solid. 1H-NMR (DMSO-d6, 400 MHz): δ 7.81 (d, J=1.77 Hz, 2H), 7.59 (t, J=1.89 Hz, 1H), 7.49 (d, J=16.04 Hz, 1H), 6.69 (d, J=16.04 Hz, 1H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3](=[O:28])[NH:4][C:5]1[C:13]([CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[C:12]([CH2:24][CH3:25])[C:11]([CH3:26])=[C:10]2[C:6]=1[C:7](=[O:27])[O:8][CH2:9]2.O.O.[OH-].[Li+]>CO>[CH3:29][N:2]([CH3:1])[C:3](=[O:28])[NH:4][C:5]1[C:13]([CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:12]([CH2:24][CH3:25])[C:11]([CH3:26])=[C:10]2[C:6]=1[C:7](=[O:27])[O:8][CH2:9]2
Reactant: CCc1c(C)c2c(c(NC(=O)N(C)C)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1c(C)c2c(c(NC(=O)N(C)C)c1C/C=C(\C)CCC(=O)O)C(=O)OC2

Procedure:
To a solution of 0.3 g (0.74 mmol) of methyl (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate in 7.4 ml of 4:1 methanol:water is added 0.13 g (2.96 mmol) of lithium hydroxide monohydrate. The solution is heated at 50°-60° C. for 4 hours. Upon cooling, the reaction is partitioned between aqueous sodium hydrogen sulfate and ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, and concentrated to give (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:20][CH2:21][CH2:22]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+]>ClCCl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:9][N:10]([CH2:11][CH2:12]2)[CH2:22][CH2:21][O:20]3)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2(c3ccc(Br)cc3)CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Brc1ccc(C23CCN(CCO2)C3)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To an ambient solution of Example 54D (0.100 g, 0.186 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.5 ml). The reaction was stirred for 0.5 h, and the solution was then carefully added to a slurry of K2CO3 (3.0 g, 21.7 mmol) 1 h dichloromethane (10 mL). After the evolution of gas ceased, the mixture was heated to 40° C. for 1 h. The mixture was cooled to room temperature and was diluted with water (10 mL). The layers were separated, and the aqueous was extracted with additional dichloromethane (2×10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title product, which was used in the subsequent step without further purification. MS (ESI) m/z 268 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH:7]([C:11]([OH:13])=O)[CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:29]1([C:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[O:4]1[C:5]2([CH2:10][CH2:9][CH2:8][CH:7]([C:11]([N:38]3[CH2:37][CH:36]=[C:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:40][CH2:39]3)=[O:13])[CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)C1CCCC2(C1)OCCO2
Reactant: C1=C(c2ccccc2)CCNC1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCCC2(C1)OCCO2)N1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
A solution of 1,4-dioxaspiro[4.5]decane-7-carboxylic acid (Step A) (99.3 g) and triethylamine (80.8 g) in 1000 mL of dichloromethane is cooled in an ice bath, and treated dropwise with isobutyl chloroformate (80.1 g), dropwise, under nitrogen. After 30 minutes, a solution of 4-phenyl-1,2,3,6-tetrahydropyridine (84.7 g) in 500 mL of dichloromethane is added dropwise over a 2-hour period. The mixture is stirred at room temperature for 2 additional hours. The solvent is removed in vacuo. The residue is suspended in 1000 mL of ethyl acetate, cooled to 0° C., and sequentially washed with ice-cold 1N aqueous hydrochloric acid solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The crude product is purified by flash chromatography (silica; hexane:ethyl acetate, 3:1) to give 107.1 g of the title compound as a yellow oil (silica; Rf =0.4; 1% methanol, 99% chloroform); Mass Spectrum (Electron Ionization) (MS (EI)) 327 (M, 26.1%), 141 (100%).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 214 mg portion of ethyl 4-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}amino)benzoate was dissolved in 5.0 ml of ethanol, mixed with 1.0 ml of 1 M sodium hydroxide aqueous solution and stirred overnight at room temperature. The reaction solution was poured into 1 M hydrochloric acid, and the thus formed precipitate was collected by filtration. The thus obtained solid matter was purified by a silica gel column chromatography (chloroform-methanol) to obtain 131 mg of 4-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}amino)benzoic acid as a colorless amorphous substance.
Reaction SMILES: [CH3:1][C:2]([C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([N+:16]([O-])=O)=[CH:8][N:7]=1)([CH3:5])[CH:3]=[O:4].CC(=O)OCC>[Ni].CO>[NH2:16][C:9]1[CH:10]=[C:11]([C:12]([F:15])([F:13])[F:14])[C:6]([C:2]([CH3:5])([CH3:1])[CH2:3][OH:4])=[N:7][CH:8]=1
Reactant: CC(C)(C=O)c1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(CO)c1ncc(N)cc1C(F)(F)F
Yield: 67.2 %

Procedure:
A solution of 2-methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanal (100 mg, 0.381 mmol) and Raney nickel (22.39 mg, 0.381 mmol) in MeOH (30 mL) was stirred at 25° C. under H2 overnight. After TLC analysis (PE/EA=5/1) showed the starting material was consumed, the mixture was filtered. The filtrate was concentrated to give 2-(5-amino-3-(trifluoro methyl)pyridin-2-yl)-2-methylpropan-1-ol (60 mg, 0.256 mmol, 67% yield): 1H NMR (400 MHz, CD3OD) δ 8.08 (br. s., 1H), 7.36 (d, J=2.8 Hz, 1H), 1.31 (s, 6H); ES-LCMS m/z: 235.1 (M+H).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH:10]([CH3:14])[CH2:11][CH:12]=[O:13])[CH2:5]1)([CH3:3])[CH3:2].C=O.[C:17](O)(=O)CC.N1CCCC1>C(O)(C)C.CC(OC)(C)C>[CH:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH:10]([CH3:14])[C:11](=[CH2:17])[CH:12]=[O:13])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1CCCC(C(C)CC=O)C1
Reactant: CCC(=O)O
Agent: C=O
Solvent: CC(C)O
Solvent: COC(C)(C)C
Solvent: C1CCNC1
Product: C=C(C=O)C(C)C1CCCC(C(C)C)C1
Temperature: 45 °C
Reaction time: 3 h
Yield: 800 %

Procedure:
A solution of 3-(3-isopropylcyclohexyl)butanal (6 g, 30.5 mmol) in isopropanol (3.5 mL) followed by formaldehyde (37% wt in water, 30.5 mmol, 1 eq) was charged into a 50 mL three-necked round-bottom flask equipped with a reflux condenser and a mechanical stirrer. Propionic acid (228 L, 3.0 mmol, 0.1 eq) and pyrrolidine (255 L, 3.0 mmol, 0.1 eq) were added at ambient temperature. The reaction mixture was then stirred at 45° C. for 3 h. The crude mixture was cooled to ambient temperature dissolved in MTBE (100 mL) and washed with saturated aqueous NaHCO3 (100 mL), brine (100 mL), dried over magnesium sulphate and concentrated. The crude product was chromatographed on a silica gel column with 3% EtOAc in hexane as elution agent giving 3-(3-isopropylcyclohexyl)-2-methylenebutanal (5 g, gc purity>99%; yield 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:13])[CH:10]=NO.S(=O)(=O)(O)[OH:15]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:9](=[O:13])[C:10]2=[O:15]
Reactant: O=C(C=NO)Nc1ccccc1F
Reactant: O=S(=O)(O)O
Product: O=C1Nc2c(F)cccc2C1=O
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
31.3 g of the product of Step A were added at 75°-77° C. over 65 minutes to 155 ml of concentrated sulfuric acid and the mixture was heated over 10 minutes to 90° C. and held there for 10 minutes and then cooled to 20° C. The mixture was poured into 750 g of ice and the mixture was stirred until the ice melted and was filtered. The filtrate was saturated with sodium chloride and was extracted several times with ethyl acetate. The combined organic phases were washed with aqueous saturated sodium chloride solution until the wash water was neutral, dried, filtered and evaporated to dryness under reduced pressure. The residue was dissolved in 350 ml of xylene at reflux and the hot solution was filtered and the filter was washed with 20 ml of boiling xylene. The filtrate was iced and vacuum filtered. The product was washed with xylene and dried under reduced pressure at 80° C. to obtain 12.85 g of 7-fluoro-1 H-indole-2,3-dione melting at 198° C.