Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH3:23])[C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24](=O)[CH2:25][CH3:26].C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH3:23])[C:15]2[C:20]([NH:21][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC=O
Reactant: CCN(c1ncccc1N)C1CCN(Cc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCNc1cccnc1N(CC)C1CCN(Cc2ccccc2)CC1
Reaction time: 16 h

Procedure:
1-Benzyl-4-[N-ethyl-N-(3-amino-2-pyridinyl)amino]piperidine (EXAMPLE 204B, 6.37 g, 20.56 mmol) and propionaldehyde (1.63 ml, 22.6 mmol) are dissolved in 50 ml methanol and cooled to 0°. Sodium cyanoborohydride (1.42 g, 22.6 mmol) is added and the mixture is warmed to 20°-25°. Twice more propionaldehyde (22.6 mmol) and sodium cyanoborohydride (22.6 mmol) are added, cooling the mixture to 0° before and warming to 20°-25° after each addition. The mixture is stirred 16 hr, then poured into 1N sodium hydroxide and extracted with dichloromethane. The extract is dried over sodium sulfate, filtered and concentrated. Chromatography (silica gel, 300 g; ethyl acetate/hexane (25/75)), gives the title compound, NMR (400 MHz, CDCl3) 7.72, 7.30, 6.91, 6.78, 4.79, 3.49, 3.14, 3.04, 2.87, 1.98, 1.73, 1.63, 1.01 and 0.86δ.
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:32](Cl)(=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]2[O:2][C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:12][C:4]=2[CH:5]=1)([O-:11])=[O:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Product: O=[N+]([O-])c1ccc2oc(-c3ccccc3)cc2c1
Yield: 80.4 %

Procedure:
39 g (78 mmol) of (2-hydroxy-5-nitrophenyl) methyltriphenylphosphonium bromide and 18 ml (156 mmol) of benzoyl chloride are treated under conditions analogous to those of step 1 of Example 1. 15 g of product are obtained. Melting point: 159° C.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:43])[CH:24]([NH:25][C:26](=[O:42])[CH:27]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[NH:28]C(OC(C)(C)C)=O)[C@H:21]3[S:20][CH2:19][C:18]=2[CH:44]=[N:45][O:46][CH3:47])=[O:16])C2C=CC=CC=2)C=CC=CC=1.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].C1(OC)C=CC=CC=1>CCOCC>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[CH3:47][O:46][N:45]=[CH:44][C:18]1[CH2:19][S:20][C@@H:21]2[CH:24]([NH:25][C:26](=[O:42])[CH:27]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH2:28])[C:23](=[O:43])[N:22]2[C:17]=1[C:15]([OH:16])=[O:14]
Reactant: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c3ccccc3)[C@H]2SC1
Solvent: CCOCC
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CON=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccccc3)[C@H]2SC1
Reaction time: 0.42 h
Yield: 93.3 %

Procedure:
A solution of diphenylmethyl-3-methoxyiminomethyl-7-(N-tertiary butoxycarbonyl-α-phenylglycyl)amino-3-cephem-4-carboxylate (64 mg) in ice-cooled trifluoroacetic acid (0.6 ml) and anisole (0.3 ml) is kept at room temperature for 25 minutes, and diluted with ether (5 ml) and petroleum ether (15 ml). The resulting crystals are collected by filtration and dried to give 3-methoxyiminomethyl-7-(α-phenylglycyl)amino-3-cephem-4-carboxylic acid trifluoroacetate (46 mg; 93.3%). m.p. about 270° C.
Reaction SMILES: [CH:1]([N:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:5](=[O:21])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].[C:30]1([NH:36][N:37]=[C:38]([C:42](Cl)=[O:43])[C:39](Cl)=[O:40])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[O:43]=[C:42]1[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:39](=[O:40])[C:38]1=[N:37][NH:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)C(=NNc1ccccc1)C(=O)Cl
Reactant: COc1ccc(N(C(=O)CNc2ccccc2Nc2ccccc2)C(C)C)cc1
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)Cn2c(=O)c(=NNc3ccccc3)c(=O)n(-c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Solutions of N-isopropyl-N-(4-methoxy-phenyl)-2-(2-phenylamino-phenylamino)-acetamide(3.00 g) in THF (30 mL) and 2-(phenyl-hydrazono) propandioyl dichloride (1.89 g) in THF (30 mL) were added concomitantly dropwise with stirring in an ice/methanol bath over a 30 minute period. After complete addition, the solution was allowed to warm to room temperature and stirred over night. The solvent was evaporated under reduced pressure and the resultant oil taken into ethyl acetate (250 mL), washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.28 g) as a yellow foam.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]([NH:22][CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[O:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:9][CH:10]=1)(=O)C>Cl>[NH2:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]([NH:22][CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[O:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1
Agent: Cl
Product: Nc1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1

Procedure:
A solution of 1-[3-(acetylamino)phenyl]-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide (0.47 g) in 2M HCl(aq) (5 mL) was heated at reflux until complete consumption of the starting material as judged by LC-MS (approximately 40 min). The crude reaction mixture was concentrated in vacuo and the residue dried in vacuo to afford 1-(3-aminophenyl)-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide that was used without further purification. 1H-NMR (DMSO-d6, 400 MHz): δ 3.5-5.5 (br), 4.72 (d, J=5.2 Hz, 2H), 7.24 (d, J=7.6 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.44 (s, 1H), 7.56 (t, J=8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 8.10-8.50 (m, 2H), 8.47 (s, 1H), 8.59 (d, J=8.0 Hz, 1H), 8.85 (1H, J=5.6 Hz, 1H), 8.96 (s, 1H), 9.25 (s, 1H), 9.64 (t, J=5.6 Hz, 1H). MS (ES+): m/z 344 [MH+]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@H:12]3[CH2:15][C@@H:16]([OH:18])[CH2:17][N:11]3[C:10]2=[O:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@H:12]3[CH2:15][C:16](=[O:18])[CH2:17][N:11]3[C:10]2=[O:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1[C@@H]2C[C@@H](O)CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1C[C@H]2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)N2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (7aS,6R)-2-(3,5-dichloro-phenyl)-6-hydroxy-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione (11.3 g) (0.038 mol) (Preparation 2), in 185 mL of DCM was added molecular sieves 3A (18 g) then PDC (33.5 g) (0.093 mol). The reaction mixture was stirred for 72 h at RT, then the insoluble material eliminated. After evaporating the solvent, the residue was purified by SiO2 chromatography (eluent: DCM/EtOAc 95/5) to afford the titled compound as a white solid (7.3). NMR (CDCl3, 200 MHz): 7.45-7.35 (3H, m), 4.65 (1H, dd), 4.25 (1H, dd), 3.12 (1H, dd), 2.97 (1H, dd), 2.65 (1H, dd).
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]([O-])(=[O:23])[CH2:14]CCC=CCCCC>>[C:13]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:23])[CH3:14]
Reactant: CCCCC=CCCCC(=O)O
Reactant: CCCCC=CCCCC(=O)[O-]
Product: CCCCC=CCCCCOC(C)=O

Procedure:
For example, 5-hexenoic acid or an ester of 5-hexenoic acid (e.g. methyl 5-hexenoate, ethyl 5-hexenoate, etc . . . ) could be used instead of 1-hexene, but the synthesis would entail a reduction of a carboxylic acid or an ester to an alcohol followed by acetylation. These syntheses are respectively shown in FIGS. 12 and 13. With reference to FIGS. 12 and 13, the 5-hexenoic acid or 5-hexenoate is reacted with 5-decene to form 5-decenoic acid or 5-decenoate, respectively, in the presence of Catalyst 823 and under vacuum. The resulting 5-decenoic acid or 5-decenoate is reduced and acetylated to form 5-decenyl acetate. In addition, synthesizing 5-decenoic acid has advantages because the salt of 5-decenoic acid can be recrystallized to increase the trans-isomer to greater than 90 percent trans-5-decenoic acid, which is then reduced and acetylated to greater than 90 percent trans-5-decenyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:19][C:20]1[C:21]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:22]=2[S:23][CH:24]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:21]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:22]=3[S:23][CH:24]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(F)cc2c1C=O
Reactant: Fc1ccc2scc(CBr)c2c1
Product: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1csc2ccc(F)cc12

Procedure:
Using general procedure B, 5-fluoro-3-formyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-5-fluoro-benzo[b]thiophene (Lit. 18) to give 5-fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-formyl-1H-indole-2-carboxylic acid ethyl ester as white solid. MS: 400.1 ([M+H]+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:11]1([C@@:14]23[C@H:21]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[O:34][CH3:35])[CH2:24][CH2:23]4)[CH2:20][C:19](=O)[N:18]2[C@@H:17]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:16][O:15]3)[CH2:13][CH2:12]1.[OH-].[Na+]>C1COCC1.CCOCC.O>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH:25]1[CH2:24][CH2:23][N:22]([C@@H:21]2[CH2:20][CH2:19][N:18]([C@@H:17]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:16][OH:15])[CH:14]2[CH:11]2[CH2:13][CH2:12]2)[CH2:27][CH2:26]1
Reactant: COc1ccccc1C1CCN([C@@H]2CC(=O)N3[C@@H](c4ccccc4)CO[C@]23C2CC2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1C1CCN([C@@H]2CCN([C@H](CO)c3ccccc3)C2C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To solid aluminum chloride (0.422 g, 3.16 mmol) at 0° C. was added anhydrous THF (23 mL). The mixture was stirred until all solid went into solution. Lithium aluminum hydride (1.0 N in THF, 8.95 mL, 8.95 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature. After about 20 minutes, the reaction mixture was cooled to about −78° C. and a solution of (3S,7R,7aR)-7a-cyclopropyl-7-(4-(2-methoxyphenyl)piperidin-1-yl)-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-one (preparation #25) (1.29 g, 2.98 mmol) in THF (16 mL) was added. The reaction mixture was stirred for about 1 h then allowed to warm up to room temperature and stirred for an additional 3 h. The reaction mixture was cooled to about 0° C. and water (2.7 mL) was added dropwise followed by aqueous NaOH (2.0N, 4 mL). More water (9 mL) was added, then ether (70 mL) and the mixture was stirred for about 30 min. The ether solution was decanted, dried over MgSO4 and concentrated in vacuo to afford (2S)-2-((3R)-3-(4-(2-methoxyphenyl)piperidin-1-yl)-2-cyclopropylpyrrolidin-1-yl)-2-phenylethanol (1.25 g, 2.98 mmol) as a pair of diastereomers as a white solid. RP-HPLC (Table 1, Method a) Rt 1.79 and 1.96 min; m/z: (M+H)+ 421.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]1=[O:18].[C:19]12([CH2:29][C:30](O)=[O:31])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[C:19]12([CH2:29][C:30]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:9]4[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=4[C:3]3=[O:18])=[O:31])[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: Nn1nc(-c2ccccc2)c2c(c1=O)CCCC2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(-c2ccccc2)c2c(c1=O)CCCC2

Procedure:
The product from Example 185A and 2-(adamantan-1-yl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.16 (s, 1H), 7.39-7.52 (m, 5H), 2.51-2.56 (m, 2H), 2.37-2.41 (m, 2H), 2.01 (s, 2H), 1.90-1.96 (bs, 3H), 1.70-1.77 (m, 2H), 1.53-1.71 (m, 14H); MS (APCI+) M/Z 419 (M+H)+.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]([O:27]CC)=[O:26])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]([OH:27])=[O:26])[CH2:20]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](OC1CC2C(C1)C2C(=O)O)(c1ccccc1)c1ccccc1
Reaction time: 20 h
Yield: 81.4 %

Procedure:
To a solution of ethyl 3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxylate (70.0 g, 171 mmol) in ethanol (400 mL) was slowly added a solution of sodium hydroxide (20.56 g, 513.94 mmol) in water (100 mL). After 20 h, the reaction mixture was concentrated and the resulting residue was diluted with water (200 mL). The aqueous solution was adjusted to pH=3 by dropwise addition of 3 M aqueous hydrochloric acid. The aqueous mixture was extracted with ethyl acetate (2×200 mL). The combined organics were washed with saturated aqueous sodium chloride (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxylic acid as a yellow solid (53 g). To an ice-cooled suspension of crude acid in dichloromethane (600 mL) was added carbonyldiimidazole (25.5 g, 158 mmol). After 2 h, N, O-dimethylhydroxylamine hydrochloride (32 g, 0.33 mmol) was added. After 3 h, the reaction mixture was filtered and the filtrate was concentrated. Purified by flash column chromatography (6:1 petroleum ether/ethyl acetate) afforded 3-((tert-butyldiphenylsilyl)oxy)-N-methoxy-N-methylbicyclo[3.1.0]hexane-6-carboxamide (37 g, 60%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.63-7.61 (m, 4H), 7.42-7.33 (m, 6H), 4.33-4.31 (m, 1H), 3.74 (s, 2H), 3.57 (s, 1H), 3.21 (s, 2H), 3.10 (s, 1H), 2.21-2.18 (m, 1H), 2.00-1.80 (m, 6H), 1.06-1.01 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](O)=O.[OH-].[Na+]>O>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1O
Reactant: O=C(O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(-c2nc3ccccc3o2)nc1
Temperature: 210 °C
Yield: 78.5 %

Procedure:
A mixture of o-aminophenol (10.9 g, 0.1 mole), picolinic acid (12.3 g, 0.1 mole) and polyphosphoric acid (275 g) is heated under a nitrogen atmosphere at 210° C for 3 hours. The mixture is then cooled to 160° C and slowly poured into 1 liter of water. The mixture is neutralized with 50% sodium hydroxide solution yielding 15.4 g of the title compound as a crystalline solid, melting point 105°-107° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][N:3]1[C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15].IC.[H-].[Na+].[C:26](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:26][C@:5]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][C:2](=[O:1])[N:3]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[CH2:4]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C[C@H](c1ccccc1)N1CC(C(=O)OC(C)(C)C)CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: C[C@H](c1ccccc1)N1C[C@@](C)(C(=O)OC(C)(C)C)CC1=O
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-4-carboxylate (30.05 g, 0.104 mol) in N,N-dimethylformamide (210 mL), iodomethane (26.0 mL, 59.28 g, 0.418 mol), and then, sodium hydride (55%, in oil, 11.35 g, 0.260 mol) was added at room temperature in nitrogen atmosphere while stirring the mixture. When inner temperature increased to about 50° C., the reaction mixture was cooled to 30° C. by adding ice water to the outer bath. After changing the bath to a water bath at an outer temperature of 17° C., the mixture was stirred for 23 hours. The reaction mixture was poured into cold aqueous solution of citric acid (1 L of 10% citric acid and 500 g of ice), and after stirring the mixture for 30 minutes, the mixture was extracted with ethyl acetate (800 mL, 500 mL). The organic layers were combined, and washed with saturated aqueous solution of sodium chloride. After drying with anhydrous sodium sulfate, the mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. The concentrate was purified by flash silica gel column chromatography (elution was started at hexane:ethyl acetate of 5:1, and after elution of the low polarity isomer, hexane:ethyl acetate was changed to 4:1) to obtain 10.63 g (33.7%) of high polarity isomer of tertbutyl (3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate as a white solid. 14.91 g (47.3%) of low polarity isomer of tert-butyl (3R)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate was also obtained.
Reaction SMILES: [C:1]([N:20]1[C:24]([C:25](OC)=[O:26])=[CH:23][C:22]([C:29](OC)=[O:30])=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[C:1]([N:20]1[C:24]([CH2:25][OH:26])=[CH:23][C:22]([CH2:29][OH:30])=[N:21]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(C(=O)OC)n(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1cc(CO)n(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of dimethyl 1-trityl-3,5-pyrazoledicarboxylate (3.200 g, 7.50 mmol) in dry THF (50 mL) were added 30 mL of 1.0 M LiAlH4 in Et2O. The resulting solution was stirred for about 16 h at room temperature (20-25° C.). After this time, the reaction was quenched by the slow addition of 1 mL of distilled water, followed by addition of 1 mL of 10% NaOH and 2.4 mL of water. The solids formed were removed by filtration, and 50 mL of dichloromethane was added to the filtrate. The organic phase was separated, washed with distilled water and a white microcrystalline solid was obtained after evaporation of the solvent under vacuum. Yield: 90% (2.843 g, 6.71 mmol).
Reaction SMILES: [C:1]1(=[CH:7][C:8]#[N:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:10]([CH3:13])([O-:12])=[O:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[N+:10]([CH2:13][C:1]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:12])=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: N#CC=C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCC1(C[N+](=O)[O-])CCCCC1
Yield: 70.7 %

Procedure:
The nitrile (compound 2, 0.78 g, 6.44 mmol), nitromethane (0.80 g, 13.11 mmol) and tetrabutyl ammonium fluoride (1.0 M in tetrahydrofuran, 10 mL, 10 mmol) were heated in 20 mL tetrahydrofuran to 70° C overnight. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 3:1 to give the required product as a yellow oil (0.83 g, 71%).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=2)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[N+:19]([C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=1)[CH2:7][N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)([O-:21])=[O:20]
Reactant: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CN2CCOCC2)cc(C(F)(F)F)c1

Procedure:
To a solution of morpholin-4-yl-(3-nitro-5-(trifluoromethyl)phenyl)methanone (304 mg, 1.0 mmol) in 15 mL of THF was added lithium aluminum hydride (152 mg, 4 mmol) in THF (7 mL) under nitrogen. The dark colored solution was refluxed for 2 hours and then cooled. NaOH solution was added (0.5 N, 15 mL) dropwise. The basic solution was washed with methylene chloride (3×40 mL) and the pooled organic layers were washed with HCl solution (5%). The aqueous layer was separated, basified with NaOH to pH 8, and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous Na2SO4. The solution was used in further reactions without further work-up.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[C:8](=[CH:12][CH:13]=1)[C:9]([OH:11])=[O:10])([OH:3])=[O:2].[C:17]1([C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N+]=[N-])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[C:17]1([CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:15][C:14]([C:7]2[CH:6]=[C:5]([CH2:4][C:1]([OH:3])=[O:2])[CH:13]=[CH:12][C:8]=2[C:9]([O:11][CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:10])=[O:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)Cc1ccc(C(=O)O)c(C(=O)O)c1
Solvent: CC(C)=O
Product: O=C(O)Cc1ccc(C(=O)OC(c2ccccc2)c2ccccc2)c(C(=O)OC(c2ccccc2)c2ccccc2)c1

Procedure:
0.52 g of 4-carboxymethylphthalic acid was dissolved in 10 ml of acetone, and a solution of 0.89 g of diphenyldiazomethane in acetone (20 ml) was dropwise added over a period of 15 minutes at room temperature with stirring. After completion of the dropwise addition, the mixture was stirred at room temperature overnight. Then, the solvent was distilled off, and then, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1→ethyl acetate) to obtain 0.67 g of the above identified compound as a colorless oily substance.
Reaction SMILES: NCCOCCOCCOCCOCCN.O=[C:18]1[CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][C:35](=O)[NH:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][NH:19]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1C=CC=CC=1.O1CCCC1>[O:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:18][NH:19][CH2:20][CH2:21]1
Reactant: O=C1COCCOCC(=O)NCCOCCOCCOCCOCCN1
Agent: NCCOCCOCCOCCOCCN
Agent: [Al+3]
Agent: [H-]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: C1COCCOCCNCCOCCOCCOCCOCCN1

Procedure:
In a manner similar to that described in Example 3, and 4, treat 1,14-diamino-3,6,9,12-tetraoxatetradecane with tetraglycolyl chloride in benzene utilizing high dilution technique. Then treat the thereby formed 5,12-dioxo-1,7,10,16,19,22-hexaoxa-4,13-diazacyclotetracosane with lithium aluminum hydride in tetrahydrofuran to obtain 1,7,10,16,19,22-hexaoxa-4,13-diazacycloteracosane.