Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C.FC(F)(F)S(O[CH2:44][CH:45]([F:47])[F:46])(=O)=O>ClCCl>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][N:13]([CH2:44][CH:45]([F:47])[F:46])[CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:17][CH2:16]1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: Cc1nc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CN(CC(F)F)C4)CC2)no1
Reaction time: 16 h

Procedure:
To a mixture of trans-8-chloro-1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.100 g, 0.237 mmol) and N-ethyldiisopropylamine (0.122 ml, 0.712 mmol) in dichloromethane (2.4 ml) was added 2,2-difluoroethyl trifluoromethanesulfonate (0.061 g, 0.29 mmol). After stirring for 16 h the reaction mixture was partitioned between ethyl acetate (50 ml) and 0.5 M aqueous sodium hydroxide solution (50 ml). The layers were separated. The aqueous layer was extracted with one 50 ml-portion of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.031 g, 33%) as colorless solid. MS m/e: 449 ([M+H]+).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[NH:22][CH:21]=2)=[O:19])[C:12]=1[F:30])C1C=CC=CC=1.[OH-].[Na+]>O>[NH2:10][C:11]1[C:12]([F:30])=[C:13]([C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[NH:22][CH:21]=2)=[O:19])[C:14]([F:17])=[CH:15][CH:16]=1
Reactant: O=C(Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Cl)cc23)c1F)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Cl)cc23)c1F
Yield: 80.8 %

Procedure:
[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-carbamic acid benzyl ester (7, 800 mg, 1.81 mmol) was added to 15.00 mL of 10 M sodium hydroxide and warmed to reflux overnight. The reaction mixture was diluted with 30 mL of water and extracted with ethyl acetate. The organic layer was separated, dried, filtered and the filtrate concentrated under vacuum to give the desired compound (8, 450 mg, 81%).
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][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:28].I[CH:31]([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+]>CC#N>[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][CH2:14][N:13]([CH:31]([CH3:33])[CH3:32])[CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: CC(C)I
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(C)C)C1)O2
Temperature: 75 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
A mixture of (±)-(E)-3-[4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester hydrochloride (Intermediate 2, 300 mg, 0.888 mmol), 2-iodopropane (302 mg, 1.76 mmol) and K2CO3 (491 mg, 3.55 mmol) in CH3CN (40 ml) was stirred at 75° C. for 24 h. The solvent was removed and the residue was partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude mixture was purified by column chromatography (eluent: DCM/MeOH 98:2) to give (±)-(E)-3-[1′-isopropyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (252 mg).
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1O)(=[O:33])[CH3:32]>>[C:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:1][CH:2]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(=[O:33])[CH3:32]
Reactant: COc1ccc(C(O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Reactant: CC(=O)c1ccccc1O
Product: COc1ccc(C(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)Oc2ccccc2C(C)=O)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-acetylphenol: ESMS m/e: 529.2 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8](=[CH:11][CH2:12][CH:13]1[CH2:17][CH2:16][CH:15]([CH3:18])[C:14]1([CH3:20])[CH3:19])[CH:9]=[O:10].[H][H].Cl.[OH-].[Al+3].[OH-].[OH-]>O.C(OCC)C>[CH3:7][C:8](=[CH:11][CH2:12][CH:13]1[CH2:17][CH2:16][CH:15]([CH3:18])[C:14]1([CH3:19])[CH3:20])[CH2:9][OH:10]
Reactant: [H][H]
Reactant: CC(C=O)=CCC1CCC(C)C1(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(=CCC1CCC(C)C1(C)C)CO
Temperature: 0 °C
Yield: 52.8 %

Procedure:
To a stirred suspension of 1.5 g (0.04 mole) of lithium aluminium hydride and 75 ml of dried diethyl ether are added over 1/2 hour 15 g (0.08 moles) of 2-methyl-4-(2,2,3-trimethylcyclopent-1-yl)-but-2-enal. The mixture is heated under argon to reflux for 2 hours. It is cooled with ice water and, with caution, treated first with water until hydrogen no longer evolves and then with HCl 5%, whereupon the aluminium hydroxide precipitate dissolves. The material is extracted with ether and the combined organic phases are washed with saturated common salt; it is then dried over MgSO4 and distilled. A fractional vacuum distillation leads to 8.3 g of 2-methyl-4-(2,2,3-trimethyl-cyclopent-1-yl)-but-2-en-1-ol (mixture of isomers) (55% yield);
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH:9]3[CH2:17][NH:16][CH2:15][CH2:14][N:10]3[CH2:11][C:12]=2[CH:13]=1)([O-])=O.[ClH:18].[H][H]>CO.O>[ClH:18].[ClH:18].[ClH:18].[CH2:17]1[CH:9]2[N:10]([CH2:11][C:12]3[CH:13]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=3[CH2:8]2)[CH2:14][CH2:15][NH:16]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CN1CCNCC1C2
Reactant: [H][H]
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1ccc2c(c1)CN1CCNCC1C2

Procedure:
To 8-nitro-2,3,4,6,11,11a-hexahydro-1H-pyrazino[1,2-b]isoquinoline (2.98 g) in methanol (150 ml) and water (10 ml) was added concentrated hydrochloric acid (3.26 ml) and 5% Pd--C (300 mg). The mixture was treated with hydrogen at 50 psi on a Parr Hydrogenator. Hydrogen uptake was complete in 1.0 hour. The catalyst was filtered off and the solvent removed under reduced pressure to yield the title product as a solid (3.69 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH:15]=O)=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH2:29]([NH2:31])[CH3:30]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:31][CH2:29][CH3:30])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reactant: CCN
Product: CCNCc1c(C(=O)OCC)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
5-Fluoro-3-formyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 76.1.) was reacted with ethyl amine as described in Example 86.1. to give 3-ethylaminomethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was reacted with methyl chloroformate as described in Example 77.1. to give 3-[(ethyl-methoxycarbonyl-amino)-methyl]-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give 3-[(ethyl-methoxycarbonyl-amino)-methyl]-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid as an off-white solid. MS: 433.5 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][C:12](=O)[C:13](F)(F)F)[CH:3]=1.Br.BrCC1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:3]=1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Reactant: BrCc1ccncc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1sc(Br)cc1NCc1ccncc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (500 mg, 1.51 mmol), 4-(bromomethyl)pyridine hydrobromide (457 mg, 1.81 mmol), cesium carbonate (1.72 g, 5.29 mmol) and DMA (15 mL) was stirred at 80° C. for 2 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was dissolved in MeOH (5 mL). To the solution were added potassium carbonate (500 mg) and water (2.5 mL). The mixture was stirred at room temperature for 2 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 50:50 hexane/EtOAc) to give the title compound (238 mg, 48%) as a yellow solid:
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[N:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.C([O-])(O)=O.[Na+]>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[N:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CO)cn2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)cn2)cc1
Reaction time: 3 h

Procedure:
To a solution of [1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-methanol (5.20 g, 20.61 mmol) in THF was added Dess-Martin periodinane (15.00 g, 35.37 mmol). After 3 hours, the mixture was diluted with saturated aqueous NaHCO3 and filtered through diatomaceous earth. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 20-50% ethyl acetate in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford 1-(toluene-4-sulfonyl)-1H-pyrazole-4-carbaldehyde.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[C:31]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([N:18]2[C:19]3[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:16]([CH2:15][CH2:14][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]3[CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:17]2[CH3:27])=[O:40])=[CH:42][CH:43]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
1-(4-t-Butylbenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 4-t-butylbenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccccc1OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccccc2F)CC1
Temperature: 25 °C

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (2.79 g, 15 mmol) and 1-(2-bromoethoxy)-2-fluoro-benzene (3.28 g, 15 mmol) in DMF (6 mL) was added cesium carbonate (Cs2CO3, 9.75 g, 30 mmol). The mixture was stirred at room temperature for a day and then treated with water. The aqueous solution was extracted with ethyl acetate and the extract was washed with water and brine. The organic layer was concentrated and the residue was dried under the vacuum to yield the title compound quantitatively as an oil (5.1 g). 1H NMR (400 MHz, DMSO-d6): δ 1.39 (s, 9H), 2.44 (t, 4H), 2.73 (t, 2H), 3.29 (t, 4H), 4.45 (t, 2H), 6.93 (m, 1H), 7.11 (t, 1H), 7.18 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:20])[C:7]=3[C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:8]1[C:7]2[C:13](=[O:20])[C:14]3[C:19]([C:6]=2[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c3c(c(=O)[nH]c2c1)C(=O)c1ccccc1-3
Product: Cc1ccc2c3c(c(Cl)nc2c1)C(=O)c1ccccc1-3
Yield: 73.4 %

Procedure:
A mixture of 3-methyl-5H-indeno[2,1-c]quinoline-6,7-dion obtained in reference example 5 (700 mg, 2.7 mmol) and phosphorous oxychloride (10 ml, 107 mmol) was refluxed with heat for 1.5 hours. The reaction mixture was distilled to dryness. To the residue was added water to obtain a crystal precipitated by filtration. The crystal obtained was washed with water and dissolved in chloroform to filter off undissolved substances. Recrystallization from benzene to give 550 mg (yield 73.4%) of the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:11][N:12]1C(=O)O[C:15](=[O:16])[C:14]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:13]12>>[CH3:11][NH:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:16]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: NOCc1ccccc1
Agent: Cl
Product: CNc1ccccc1C(=O)NOCc1ccccc1
Yield: 29.3 %

Procedure:
In the same manner as Example 35(a), O-benzylhydroxylamine hydrochloride (1.92 g, 12 mmol) reacted with N-methylisatoic anhydride (2.0 g, 10 mmol) to give 2-methylamino-N-benzyloxylbenzamide as a yellow solid (0.75 g).
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+]([O-])=O)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].[CH3:16][OH:17]>>[CH3:16][O:17][C:9]1[CH:10]=[CH:11][CH:12]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=1[C:7]#[N:8]
Reactant: CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Na]
Product: COc1cccc([N+](=O)[O-])c1C#N
Yield: 94 %

Procedure:
A solution of sodium methoxide, obtained by adding sodium (1.68 g, 73.1 mmol) to anhydrous MeOH (73 mL), was added to 2,6-dinitrobenzonitrile (13.20 g, 68.4 mmol) in dry MeOH (284 mL) under nitrogen at room temperature over 10 min. The reaction was refluxed for 1 hour, and then MeOH was removed under vacuum. Dichloromethane (400 mL) was added, and the insoluble solids were filtered out. The organic layer was washed with brine (100 mL), dried with MgSO4, and removed under vacuum to give 11.45 g (94%) of 2-methoxy-6-nitrobenzonitrile, which was used without further purification. 1H-NMR (400 MHz, DMSO-d6) δ 7.87-7.94 (m, 2H), 7.68-7.75 (m, 1H), 4.01 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:14][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(-c2cccc(C)c2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(-c2cccc(CBr)c2)c1
Yield: 15.7 %

Procedure:
3-Bromomethyl-3'-methyl[1,1'-biphenyl] was prepared by treating 3,3'-dimethyl[1,1'-biphenyl] (20.0 g, 0.11 mole) with N-bromosuccinimide (18.9 g, 0.11 mole) in the presence of 0.1 g of benzoyl peroxide in 130 ml of carbon tetrachloride. Irradiation of the reaction mixture with white light afforded 3-bromomethyl-3'-methyl-[1,1'-biphenyl] (4.5 g). The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([CH3:12])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:4].[F:13][C:14]1[CH:15]=[C:16]([N:33]2[CH2:37][C@H:36]([CH2:38][N:39]3[CH:43]=[CH:42][N:41]=[N:40]3)[O:35][C:34]2=[O:44])[CH:17]=[CH:18][C:19]=1[C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH2:30][C@@H:29]([CH2:31]O)[O:28][N:27]=2)=[CH:24][CH:25]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([N:5]([CH3:12])[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:31][C@H:29]1[O:28][N:27]=[C:26]([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[CH:18]=[CH:17][C:16]([N:33]4[CH2:37][C@H:36]([CH2:38][N:39]5[CH:43]=[CH:42][N:41]=[N:40]5)[O:35][C:34]4=[O:44])=[CH:15][C:14]=3[F:13])=[CH:21][N:22]=2)[CH2:30]1)=[O:10])=[O:4]
Reactant: COC(=O)N(C)CCCC(=O)O
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)N(C)CCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The carbamate prepared as above (0.32 g, 1.83 mmol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 0.2 g, 0.46 mmol), 4-dimethylaminopyridine (0.01 g, 0.08 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.19 g, 0.99 mmol) were combined in DMF (2 ml). The suspension was allowed to stir for 2 hours at room temperature. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0.5 to 10% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as an off-white solid (0.23 g), melting point: 135° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:10]=[CH:9]2)C=CC=CC=1.Cl>C(O)C>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[N:10]=[CH:9]1
Reactant: C(=C\CCC1CCCCC1)\CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: CCO
Product: C(=C\CCC1CCCCC1)\CCc1c[nH]cn1
Temperature: 90 °C
Yield: 96.4 %

Procedure:
1-[1-Triphenylmethyl-1H-imidazol-4-yl]-6-cyclohexyl-cis-3-hexene (1 gram, 2.12 mmol) was dissolved in ethanol (20 ml). 2N HCl (60 ml) was added and the mixture heated at 90° C. for 1 hour. The reaction mixture was cooled, filtered and the filtrate neutralized with 10% NaOH solution and then partitioned between CHCl3 and water. The chloroform layer was separated, dried over Na2SO4, filtered and evaporated in vacuo to obtain the crude oil. The crude product was purified by silica gel column chromatography using MeOH/CHCl3, (10:90) to afford 475 mgs of 1-[1H-imidazol-4-yl]-6-cyclohexyl-cis-3-hexene (24).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:16]=[C:15]([C:17]([F:24])([F:23])[C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Na+].Cl>CO>[F:24][C:17]([F:23])([C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)[C:15]1[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=[C:4]([CH:16]=1)[C:3]([OH:25])=[O:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(F)(F)c2ccco2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(F)(F)c2ccco2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
Dissolve 5-(difluorofuran-2-yl-methyl)-N-methyl-N-propyl-isophthalamic acid methyl ester (30 mg, 0.08 mmol) in methanol (2 mL). Add dropwise 2 N NaOH (0.06 mL) and stir overnight at room temperature. Acidify the mixture to about pH=6 with 5 N HCl and concentrate to near dryness. Dilute the residue with ethyl acetate, wash with saturated aqueous sodium chloride solution, dry (magnesium sulfate) and concentrate to give the title compound (66%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36])[C:8]([C:10]1[N:18]2[C:13]([CH:14]=[C:15]([NH:19][CH3:20])[CH:16]=[CH:17]2)=[C:12]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:11]=1[CH3:31])=[O:9].[CH3:38]I.Cl>CN(C)C=O.ClCCl>[CH3:20][N:19]([CH3:38])[C:15]1[CH:16]=[CH:17][N:18]2[C:13]([CH:14]=1)=[C:12]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C:11]([CH3:31])=[C:10]2[C:8](=[O:9])[C:7]1[CH:32]=[CH:33][C:34]([N+:35]([O-:37])=[O:36])=[C:5]([O:4][CH3:3])[CH:6]=1
Reactant: CNc1ccn2c(C(=O)c3ccc([N+](=O)[O-])c(OC)c3)c(C)c(C(=O)OCc3ccccc3)c2c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)c2c(C)c(C(=O)OCc3ccccc3)c3cc(N(C)C)ccn23)ccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
80 mg (1.67 mmol) of sodium hydride (60% as a dispersion in oil) at room temperature are added in portions to 525 mg (1.11 mmol) of benzyl [3-(3-methoxy-4-nitrobenzoyl)-2-methyl-7-methylaminoindolizin-1-yl]carboxylate in solution in 10 mL of dimethylformamide. After 10 minutes, 138 μL (2.22 mmol) of methyl iodide are added to the reaction mixture. The medium is stirred at 40° C. for 2 hours, poured into a molar solution of hydrochloric acid and then extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The solid obtained is taken up in dichloromethane and filtered. 439 mg of a light orange-coloured solid are obtained.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:6]([CH:26]([CH3:28])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:6]([CH:26]([CH3:27])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-(4-fluorophenyl)-5-(1-heptenyl)pyridine (Example 32) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.13 (m, 4 H), 4.33 (s, 2 H), 3.41 (sept, J=6.6 Hz, 1 H), 3.22 (sept, J=6.6 Hz, 1 H), 2.26 (m, 2 H), 1.33 (d, J=6.6 Hz, 6 H), 1.30 (d, J=6.6 Hz, 6 H), 1.22 (m, 3 H), 1.11 (m, 8 H), 0.85 (t, J=7 Hz, 3 H). FAB-MS: calculated for (C25H36FNO) 385, found 386 (M+H). Anal. Calcd for C25H36FNO: C, 77.88; H, 9.41; N, 3.63. Found: C, 77.86; H, 9.66; N, 3.59. mp 73-75° C. Rf=0.3 (20% ethyl acetate/hexane).