Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C@H:8]([NH2:23])[C:7]=2[CH:24]=1.[C:25](=O)([O:48]C1C=CC([N+]([O-])=O)=CC=1)[O:26][CH2:27][CH2:28][O:29][P:30]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C@H:8]([NH:23][C:25](=[O:48])[O:26][CH2:27][CH2:28][O:29][P:30]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:31])[C:7]=2[CH:24]=1
Reactant: COc1ccc2c(c1)[C@@H](N)CCc1cc(OC)c(OC)c(OC)c1-2
Reactant: O=C(OCCOP(=O)(OCc1ccccc1)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: COc1ccc2c(c1)[C@@H](NC(=O)OCCOP(=O)(OCc1ccccc1)OCc1ccccc1)CCc1cc(OC)c(OC)c(OC)c1-2
Yield: 85 %

Procedure:
A solution of (5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-ylamine (0.329; 1 mmol) and 2-[di-(benzyloxy)phosphoryloxy]ethyl 4-nitrophenyl carbonate (0.633 g; 1.3 mmol) in acetonitrile (8 ml) was heated at 65° C., under argon atmosphere for 8 hours. After evaporation to dryness, the residue was purified by flash chromatography eluting with a 50-80% gradient of ethyl acetate/petroleum ether to give 2-[di(benzyloxy)phosphoryloxy]ethyl N-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]carbamate.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:25])=[O:24]
Reactant: OCCCCCCOc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCOc1ccccc1

Procedure:
To a chilled (-2° C.) mixture of 9.7 g of 6-(phenoxy)-1-hexanol in 250 ml of dichloromethane containing 11.1 g of triethylamine is added 6.95 g of methanesulfonyl chloride. The product is isolated as described in Example 2 to give the product as an oil.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[C:21]2[CH2:26][CH2:25][N:24](C)[CH2:23][CH2:22]2)[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1>ClC(Cl)Cl>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:21]2[CH2:22][CH2:23][N:24]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[CH2:25][CH2:26]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(=C(c2ccc(F)cc2)c2cccnc2)CC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(=C(c2ccc(F)cc2)c2cccnc2)CC1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a stirred solution of 180 parts of ethyl carbonochloridate in 600 parts of trichloromethane was added dropwise a solution of 110 parts of 3-[(4-fluorophenyl)(1-methyl-4-piperidinylidene)methyl]pyridine in 600 parts of trichloromethane. Upon completion, the whole was heated till reflux and stirring at reflux was continued for 16 hours. The reaction mixture was evaporated. The residue was stirred in water and the whole was alkalized with a sodium hydroxide solution. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated, yielding 100 parts (75%) of ethyl 4-[(4-fluorophenyl)(3-pyridinyl)methylene]-1-piperidinecarboxylate as a residue (intermediate 20).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[N:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=1)=C=O.[CH2:37]([N:39]1[C:51]2[CH:50]=[CH:49][C:48]([NH2:52])=[CH:47][C:46]=2[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH3:38]>>[CH2:37]([N:39]1[C:51]2[CH:50]=[CH:49][C:48]([NH:52][C:24]([C@@H:9]3[CH2:10][C:11](=[N:13][O:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[CH2:12][N:8]3[C:6]([NH:27][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)=[O:7])=[O:26])=[CH:47][C:46]=2[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH3:38]
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: Cc1cccc(N=C=O)c1
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=NOCc4ccc(OC)cc4)CN3C(=O)Nc3cccc(C)c3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 1-isocya-nato-3-methylbenzene, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 72% purity by LC/MS. MS(ESI+): m/z=590.8.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:17])=[C:13]([CH:16]=1)[C:14]#[N:15].C1(C)C=CC=CC=1.O>CCOC(C)=O>[Cl:17][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1cc(N)ccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(Cl)c(C#N)c1
Yield: 91.8 %

Procedure:
Acetic anhydride (2.79 mL, 29.5 mmol), 5-amino-2-chloro-benzonitrile (3.00 g, 19.7 mmol), N,N-dimethylaminopyridine (0.241 g, 1.97 mmol), and toluene (50 mL) were combined and heated to reflux for 1.5 h. The reaction mixture was cooled, and water and EtOAc (150 mL) were added. The solid remaining in the mixture was collected and set aside. The aqueous layer was extracted once more with EtOAc, and the combined layers were washed with brine. The reserved precipitate was then dissolved in EtOAc, which was washed with brine. All organic layers were combined, dried, filtered, and concentrated. The residue was triturated with DCM/hexanes to yield the titled compound (3.52 g, 92% yield). This compound did not yield MS data. 1H NMR (400 MHz, CDCl3): 7.92 (d, J=1.0 Hz, 1H), 7.57 (dd, J=2.1, 1.2 Hz, 2H), 2.17 (s, 3H).
Reaction SMILES: C1COCC1.[C:6]([O:10][C:11]([N:13]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([N:24]=[N+]=[N-])=[CH:20][CH:19]=2)=[CH:16][N:15]=[C:14]1[NH2:27])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.[C:35](Cl)(=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>ClCCl.[Pd]>[C:6]([O:10][C:11]([N:13]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:35](=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:20][CH:19]=2)=[CH:16][N:15]=[C:14]1[NH2:27])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCCCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(N=[N+]=[N-])cc2)cnc1N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(=O)Nc1ccc(-c2cnc(N)n2C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a solution of anhydrous THF (5 mL) and 10% Pd/C (0.010 g) was charged 2-amino-5-(4-azidophenyl)imidazole-1-carboxylic acid tert-butyl ester (0.100 g, 0.332 mmol). Air was removed from the system and the reaction was back flushed with hydrogen. This process was repeated three times before setting the reaction under a hydrogen balloon at atmospheric pressure and temperature for 12 h. After that time, the reaction was filtered to remove the catalyst. The filtrate was cooled to −78° C. and triethylamine (0.046 mL, 0.332 mmol) was added prior to the drop-wise addition of heptanoyl chloride (0.049 g, 0.332 mmol) diluted in anhydrous dichloromethane (0.50 mL). The reaction was stirred at −78° C. for 30 mins and then quenched with methanol (1 mL) before being concentrated under reduced pressure and purified by flash column chromatography (10-60% EtOAc/Hexanes) to obtain the title compound 2-amino-5-(4-heptanoylaminophenyl)imidazole-1-carboxylic acid tert-butyl ester (0.124 g, 97%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.14 (br s, 2H), 7.67 (m, 4H), 7.56 (s, 1H), 2.32 (t, 2H, J=7.5 Hz), 1.49 (m, 11H), 1.28 (br s, 6H), 0.87 (t, 2H, J=6.0 Hz); 13C NMR (75 MHz, DMSO-d6) δ 171.4, 147.5, 139.1, 126.4, 124.7, 122.2, 119.2, 119.0, 111.4, 108.4, 36.4, 31.0, 28.3, 27.4, 25.0, 21.9, 13.9; HRMS (ESI) calcd for C21H30N4O3 (M+) 386.2318. found
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=O)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:32]([NH:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35]>C1(C)C=CC=CC=1.O>[CH2:32]([N:36]([CH2:37][CH2:38][CH2:39][CH3:40])[C:16]([C:10]1[C:11](=[O:15])[CH:12]=[C:13]([CH3:14])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:18])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCNCCCC
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(Cl)cc2)c(C)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.2 %

Procedure:
To an ice cooled suspension of 5.29 g (0.02 mol) 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methyl pyridazine-3-carboxylic Acid (see Example 12) and 2.02 g (0.02 mol) of triethylamine in 100 ml of toluene there is added dropwise 2.17 g (0.02 mol) of ethyl chloroformate. The suspension formed is stirred at room temperature for 15 min. and is cooled to 5° C. To the suspension is added 2.59 g (0.02 mol) di-n-butylamine and the mixture is stirred at room temperature for 18 hrs. To the mixture is added 100 ml of water and the suspension formed is stirred at room temperature for 1 hr. The toluene layer is isolated, dried over magnesium sulfate and concentrated in vacuo. The residue oil is dissolved in 25 ml of ether and to it there is added 25 ml of hexane. The mixture is allowed to stand at room temperature for 30 minutes and is vacuum filtered. The filter cake is washed with hexane and air dried to afford 5.5 g (73% yield) of product, mp 101°-105° C.
Reaction SMILES: [OH:1][CH:2]([C:17]1[N:18]=[CH:19][N:20]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([NH:15][CH3:16])=[O:14])[CH:7]=[CH:6]2.CN(C)C(=O)C.C(OC(C)C)(C)C>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[CH3:16][NH:15][C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([C:17]3[N:18]=[CH:19][N:20]([C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:21]=3)=[O:1])[CH:4]=2)[CH:9]=1)=[O:14]
Reactant: CNC(=O)c1ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)OC(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
6-[Hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide (10.0 g, 19.1 mmol) and manganese dioxide (10.0 g, 115.0 mmol) were added to a mixed solvent of N,N-dimethylacetamide (25 mL) and ethyl acetate (63 mL), and the mixture was stirred at 60° C. for 3 hr. The insoluble material was filtered off at the same temperature, and washed with ethyl acetate (60 mL). The filtrate and washing were combined and concentrated to the volume of 30 mL under reduced pressure. To the residue was added dropwise diisopropyl ether (100 mL), and the mixture was stirred at room temperature. The obtained crystals were collected by filtration, and washed with diisopropyl ether (30 mL) to give crude wet crystals (26.4 g). The crude wet crystals (10.8 g) were added to ethyl acetate (54 mL), and the mixture was warmed to 60° C., and stirred for 0.5 hr. The obtained mixture was allowed to cool to room temperature, and diisopropyl ether (108 mL) was added dropwise thereto. The mixture was stirred with cooling to 5° C. The obtained crystals were collected by filtration, and washed with a mixed solvent (27 mL) of diisopropyl ether/ethyl acetate (2:1, volume ratio). The obtained wet crystals were dried under reduced pressure to give N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (8.2 g, 15.7 mmol). yield 82%.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH:20]([OH:23])[CH2:21]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:23][CH:20]([C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])[CH2:21][O:4]1
Reactant: OCC(O)c1ccc(Cl)cc1Cl
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Solvent: c1ccccc1
Product: Clc1ccc(C2(CBr)OCC(c3ccc(Cl)cc3Cl)O2)cc1

Procedure:
A mixture of 11.6 parts of 2-bromo-4'-chloroacetophenone, 12.4 parts of 1-(2,4-dichlorophenyl)-1,2-ethanediol, 0.1 parts of p-toluenesulfonic acid, 80 parts of n-butanol and 160 parts of benzene is stirred and refluxed for 24 hours with water-separator. The solvent is removed in vacuo and the residue is triturated in methanol. The precipitated product is filtered off and crystallized from petroleum ether, yielding 2-(bromomethyl)-2-(p-chlorophenyl)-4-(2,4-dichlorophenyl)-1,3-dioxolane; m.p. 82.7° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[CH2:21][CH:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>ClCCl>[CH3:52][S:53]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[CH2:21][CH:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])[CH2:10][CH2:9]1)(=[O:55])=[O:54]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CC1CN(C(=O)NC2CCNCC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1CN(C(=O)NC2CCN(S(C)(=O)=O)CC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a solution of rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid piperidin-4-ylamide trifluoroacetic acid prepared in Example 24 (50 mg, 0.08 mmol) in dichlormethane (10 mL) at 0° C. was added triethylamine (0.026 mL, 0.19 mmol) and methanesulfonyl chloride (10 mg, 0.08 mmol). The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (70% EtOAc in hexanes) to give as rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (1-methanesulfonyl-piperidin-4-yl)-amide as a white solid (30 mg, 63%)
Reaction SMILES: ClC1C=CC(C(C2C=CC(Cl)=CC=2)[N:9]2[CH2:12][CH:11]([C:13]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10]2)=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:9]1[CH2:12][CH:11]([C:13]([C:19]2[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=2)([OH:18])[C:14]([CH3:15])([CH3:16])[CH3:17])[CH2:10]1
Reactant: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 210 mg (0.59 mmol) of tert-butyl 3-[1-(3,5-difluorophenyl)-1-hydroxy-2,2-dimethylpropyl]azetidine-1-carboxylate (2) in 1 mL of CH2Cl2, 1.5 mL of TFA was added and the solution was stirred for 1 h at rt. It was concentrated and washed with ether to afford the title compound as white solid; Mass Spectrum: m/e=256 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH3:13])[CH3:12])=[C:6]([N+:14]([O-])=O)[CH:5]=1>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH3:13])[CH3:12])=[C:6]([NH2:14])[CH:5]=1
Reactant: COC(=O)c1ccc(NC(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(NC(C)C)c(N)c1
Yield: 89 %

Procedure:
3-Amino-4-isopropylamino-benzoic acid methyl ester (700.0 mg) was prepared by following General Procedure B starting from 4-isopropylamino-3-nitro-benzoic acid methyl ester (900.0 mg) and Pd/C (20% by weight, 180.0 mg) in MeOH:EtOAc (1:1, 10.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:11][CH2:10][CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1.[CH3:12]O.S(Cl)(Cl)=O>>[CH3:2][N:3]1[CH2:11][CH2:10][CH:6]([C:7]([O:9][CH3:12])=[O:8])[CH2:5][CH2:4]1
Reactant: CO
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCN(C)CC1
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred solution of 1-methylisonipecotic acid hydrochloride (178.64 g, 1 mol) in 350 mL of methanol (8 equivalents) was added, dropwise with stirring and cooling (ice-salt bath) to -10° C., 112.8 mL (1.55 equivalents) of thionyl chloride. After completion of the addition (1 hour), the ice-salt bath was removed and the temperature allowed to rise to 40° C. and held at this point for 2 hours. The solution was brought to about pH 8 with sodium carbonate and extracted with methylene chloride. The methylene chloride solution was dried and evaporated to give 136.88 g (87%) of methyl 1-methylpiperidine-4-carboxylate as a clear liquid. The IR spectrum confirmed that the product was the methyl ester.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][N:6]1[NH:10][CH:9]=[C:8]([C:11]2[N:12]([CH3:19])[C:13]([N+:16]([O-:18])=[O:17])=[CH:14][N:15]=2)[O:7]1.N1C=CC=CC=1.C1C=CC=CC=1>O>[C:1]([NH:5][N:6]1[NH:10][CH:9]=[C:8]([C:11]2[N:12]([CH3:19])[C:13]([N+:16]([O-:18])=[O:17])=[CH:14][N:15]=2)[O:7]1)(=[O:3])[CH3:2]
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N)O1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)NN1NC=C(c2ncc([N+](=O)[O-])n2C)O1
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
Four grams of acetyl chloride are slowly added to 3.6 grams (0.017 mole) of 2-(2-amino-5-oxadiazolyl)-1-methyl-5-nitroimidazole suspended in a mixture of 44 ml. of pyridine and 35 ml. of benzene. The addition is completed in 30 minutes, the mixture heated at 60°-70° C. for 10 minutes, and then poured into 500 ml. of ice and water. After the resulting mixture is stirred for 1 1/2 hours, the product separates. Recrystallization from 150 ml. of acetone containing some N,N-dimethylformamide affords 2.4 grams (56%) of pale yellow product. A second recrystallization from acetone gives 2.1 g. of product, melting point 224°-225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5]([OH:7])=O.[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][N:34]([C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:14])([F:16])[F:15])=[C:2]([Cl:1])[CH:3]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCOC(=O)C1CCN(C(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)CC1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid, Example 26, step 3, was reacted with piperidine-4-carboxylic acid ethylester and HBTU at 80° C. 1.5 h to give the title compound as a white solid. MS (m/e)=532.8 [M+H+].
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[C:15]([F:16])=[C:14](I)[CH:13]=[CH:12][N:11]=1.[CH3:18][I:19]>O1CCCC1>[Cl:9][C:10]1[C:15]([F:16])=[C:14]([CH3:13])[C:18]([I:19])=[CH:12][N:11]=1
Reactant: Fc1c(I)ccnc1Cl
Reactant: CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(I)cnc(Cl)c1F
Temperature: -78 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of 2.0 M of lithium diisopropylamide in tetrahydrofuran (5.5 mL) in tetrahydrofuran (20 mL, 200 mmol) at −78° C. was slowly added 2-chloro-3-fluoro-4-iodopyridine (2.589 g, 10.06 mmol) as a solution in tetrahydrofuran (8 mL). The reaction mixture was then stirred at −78° C. for 4 hours. Methyl iodide (0.70 mL, 11 mmol) was then added. After an additional 1 hour, the reaction was then quenched with saturated aqueous NH4Cl and warmed to room temp. The reaction mixture was poured into ethyl acetate and washed sequentially with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (80 g silica, solvent gradient: 0-30% ethyl acetate in heptanes) to yield 2.212 g (57%) of 2-chloro-3-fluoro-5-iodo-4-methylpyridine. LCMS (ESI): M+H=272.0; 1H NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 2.44 (d, J=1.2 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]2[OH:27])=[CH:10][CH:9]=1.Br[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH:15]2[O:27][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC3OCCO3)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC3OCCO3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In analogy to the procedure described in Example 3(c), by alkylating tert-butyl (3RS,4RS)-4-[4-([1,3]dioxolan-2-ylmethoxy)-phenyl]-3-hydroxy-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-[4-([1,3]dioxolan-2-ylmethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 520 (M+H)+.