Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:18]=[C:19]=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].N1C=CC=CC=1>CN(C)C=O.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:19](=[O:20])[NH:18][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCN=C=O
Reactant: Oc1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCNC(=O)Oc1ccc2ncccc2c1
Temperature: 50 °C

Procedure:
Mixture of quinolin-6-ol (0.58 g., 4 mmol), hexyl isocyanate (0.70 ml, 4.8 mmol) and dry pyridine (0.2 ml) in dry dimethylformamide (1 ml) was heated at 50° C. for 5 hours. Reaction mixture was diluted with water (5 ml), extracted with ethyl acetate (2×5 ml) and dried over sodium sulphate. The combined ethyl acetate fractions were concentrated under vaccum and crystallized with ether to give 1a; yield: 0.7 g. (59.7%).
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[Br:75][C:76]1[CH:77]=[N:78][CH:79]=[C:80](/[CH:82]=[CH:83]/[C:84]2[CH:89]=[C:88]([F:90])[CH:87]=[CH:86][C:85]=2[F:91])[CH:81]=1>C(O)CC.O>[Br:75][C:76]1[CH:81]=[C:80]([C@@H:82]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@@H:83]([C:84]2[CH:89]=[C:88]([F:90])[CH:87]=[CH:86][C:85]=2[F:91])[OH:12])[CH:79]=[N:78][CH:77]=1
Reactant: Fc1ccc(F)c(/C=C/c2cncc(Br)c2)c1
Reactant: CC(C)(C)OCl
Reactant: CC(C)(C)OC(N)=O
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](c1cncc(Br)c1)[C@H](O)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 45.1 %

Procedure:
A solution of tert-butyl carbamate (4.18 g, 35.0 mmol) in propanol (39 ml) was sequentially treated with sodium hydroxide (1.376 g, 34.4 mmol) in water (72 ml) and tert-butyl hypochlorite (3.88 ml, 34.4 mmol). After 5 min of stirring, the reaction mixture was cooled to 0° C. A solution of (DHQD)2PHAL (0.555 g, 0.677 mmol) in propanol (39 ml), a solution of (E)-3-bromo-5-(2,5-difluorostyryl)pyridine (3.34 g, 11.28 mmol) in propanol (68 ml), and potassium osmate dihydrate (0.166 g, 0.451 mmol) were sequentially added. The reaction mixture was stirred for three additional hours at 0° C., warmed to ambient temperature and after an additional 16 hours the light yellow homogenous solution was quenched with saturated aqueous sodium sulfite (100 mL). The aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phases were washed with brine (100 mL), dried over anhydrous magnesium sulfate and concentrated to afford a residue which was purified via column chromatography (25% to 40% EtOAc/Hex) to provide tert-butyl (1R,2R)-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)-2-hydroxyethylcarbamate (2.2991 g, 5.09 mmol, 45.1% yield) as an optically enriched mixture of enantiomers. 1H NMR (500 MHz, DMSO-d6) δ 8.56 (d, J=1.8 Hz, 1H), 8.40 (s, 1H), 8.03 (s, 1H), 7.52 (d, J=9.5 Hz, 1H), 7.25 (br. s., 1H), 7.10 (t, J=5.6 Hz, 2H), 5.89 (d, J=4.9 Hz, 1H), 5.03 (t, J=5.0 Hz, 1H), 4.83 (dd, J=8.9, 5.2 Hz, 1H), 1.40-1.34 (m, 9H), MS Anal. Calcd. for [M+H]+ C18H20BrF2N2O3: 429.1. found 431.3.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10](=O)([O-])[O-].[K+].[K+].P(OC)(OC)(OC)=O>>[CH3:10][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccccc1O
Agent: [K+]
Solvent: COP(=O)(OC)OC
Product: COc1ccccc1C=O
Temperature: 85 °C
Yield: 188.9 %

Procedure:
To a three-necked 100 ml flask equipped for reflux and fitted with a mechanical stirrer was added 5.0 mol (0.047 mol) of salicylaldehyde, 2.0 g (0.014 mol) of potassium carbonate, and 10.0 ml (0.085 mol) of trimethyl phosphate. The mixture was heated to 85° C. for two hours, then cooled to 50° C. and quenched with 20 ml of water. After two hours the mixture was extracted with 50 ml of methylene chloride, the extracts washed with dilute caustic and then water. The organic extracts were dried over anhydrous potassium carbonate then filtered and concentrated in vacuo to give 3.6 g (53%) of o-methoxybenzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1([NH:36][C:37](=[O:46])[CH:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[OH:39])[C:34](=[O:35])[N:5]2[C:6]([C:18]([O:20]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:19])=[C:7]([CH:10]([S:12][C:13]3[NH:17][N:16]=[N:15][N:14]=3)[CH3:11])[CH2:8][S:9][C@H:4]12>C1COCC1.C(O)=O>[CH3:1][O:2][C:3]1([NH:36][C:37](=[O:46])[CH:38]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[OH:39])[C:34](=[O:35])[N:5]2[C:6]([C:18]([OH:20])=[O:19])=[C:7]([CH:10]([S:12][C:13]3[NH:14][N:15]=[N:16][N:17]=3)[CH3:11])[CH2:8][S:9][C@H:4]12
Reactant: COC1(NC(=O)C(O)c2ccccc2)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(C)Sc3nnn[nH]3)CS[C@@H]21
Solvent: O=CO
Solvent: C1CCOC1
Product: COC1(NC(=O)C(O)c2ccccc2)C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@@H]21
Temperature: 25 °C

Procedure:
The ester, 100 mg. was dissolved in 1 ml of a 50:50 mixture of THF and 97% formic acid at 0° C. The mixture was allowed to warm to room temperature and was then evaporated to dryness. Ethyl acetate was added to dissolve the residue and the solution was extracted twice with a saturated solution of sodium bicarbonate. The bicarbonate extracts were combined and were then acidified with dilute hydrochloric acid to pH 2.5. The product was extracted from the acidified bicarbonate extracts with ethyl acetate. The ethyl acetate was dried and evaporated to yield 53 mg of product, 7-methoxy-7-mandelamido-3-(1-methyltetrazole-5-ylthiomethyl)-3-cephem-4-carboxylic acid having the following NMR spectrum (60 megacycles run in acetone d6)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH2:15][CH3:16].[OH-].[Na+]>CC#N.O>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:15][CH3:16])[N:7]=1
Reactant: Clc1nc(Cl)nc(-c2ccccc2)n1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CNc1nc(Cl)nc(-c2ccccc2)n1
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a cooled (0° C.) solution of 2,4-dichloro-6-phenyl-1,3,5-triazine (16.0 g, 70.8 mmol, 1.00 equiv) dissolved in 1:1 CH3CN:H2O (80 mL) was added NH2Me (8.00 g, 27.5% solution in H2O, 70.8 mmol, 1.00 equiv). The solution was treated with 1 N NaOH to maintain a pH of 9-10 and stirred for 15 min. The resulting suspension was diluted with water and filtered to provide 12 g of crude product. A portion of this material (8 g) was purified by reverse-phase HPLC to afford 3.6 g of the title compound. MS (ES+): m/e 221.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl[CH:20]([CH3:24])[C:21](Cl)=[O:22].O>CN(C)C=O>[CH3:11][O:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:21](=[O:22])[CH:20]([CH3:24])[O:12][C:3]=2[CH:4]=1)=[O:9]
Reactant: CC(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)OC(C)C(=O)N2
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a solution of 2-amino-5-methoxycarbonylphenol [Tetrahedron, 46(15), 5177-5186 (1990)] (8.3 g) in dimethylformamide (65 ml) were added potassium carbonate (20.5 g) and 2-chloropropionyl chloride (6.9 g) and the mixture was stirred at room temperature for a day. The reaction solution was poured into water to give precipitates, which were taken by filtration and dried to give 7-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (7.78 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:4]([C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:21])#[N:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1cccc(N)c1C#N
Product: Cc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N

Procedure:
Prepared as in example 1a from 2-amino-6-methylbenzonitrile and benzoyl isocyanate as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.19 (d, J=7.6 Hz, 1H), 7.52-7.68 (m, 5H), 8.02-8.08 (m, 2H), 11.32 (s, 1H), 11.46 (s, 1H). MS 280 (MH+).
Reaction SMILES: C=O.[C:3](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:21][C:22]1[CH:49]=[CH:48][C:47]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][NH:51]2)=[CH:46][C:23]=1[C:24]([NH:26][C:27]1[CH:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25]>C(Cl)Cl>[OH:21][C:22]1[CH:49]=[CH:48][C:47]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][N:51]2[CH3:3])=[CH:46][C:23]=1[C:24]([NH:26][C:27]1[CH:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCCCN2)ccc1O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCCCC1c1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 37% aqueous solution of formaldehyde (8.2 μL), acetic acid (9.7 μL), and sodium triacetoxyborohydride (0.045 g) were sequentially added to a methylene chloride (1.5 mL) solution of the obtained tert-butyl 2-(2-hydroxy-5-(piperidin-2-yl)benzamido)-4-phenylbenzoate (0.040 g), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and chloroform was added thereto. The insoluble substance was removed by filtration, and then a saturated aqueous solution of sodium bicarbonate was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-92% chloroform/methanol] to obtain 0.040 g of tert-butyl 2-(2-hydroxy-5-(1-methylpiperidin-2-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[CH2:11]N1C=CN=C1.C[N:21]([CH2:23][CH2:24][N:25]([CH3:27])C)C.[CH:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[C:29]1=[O:38])[CH2:35]2>CCCCCC.C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:11]([C:29]2([OH:38])[CH:30]3[CH2:36][CH:34]4[CH2:33][CH:32]([CH2:37][CH:28]2[CH2:35]4)[CH2:31]3)[C:27]2[NH:25][CH:24]=[CH:23][N:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: CN(C)CCN(C)C
Reactant: COc1cccc(Cn2ccnc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C(c2ncc[nH]2)C2(O)C3CC4CC(C3)CC2C4)c1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
55 ml (85 mmol) of a 1.55 molar solution of n-butyllithium in hexane were added dropwise to a solution of 7.52 g (40 mmol) of N-(3-methoxybenzyl)-imidazole and 4.65 g (40 mmol) of TMEDA in 90 ml of absolute THF at -70° C. The mixture was stirred for a further 20 minutes at -70° C., and a solution of 6.01 g (40 mmol) of adamantanone in 30 ml of absolute THF was then added dropwise at -70° C. in the course of about 10 minutes. The procedure was then continued as described in Example 100. The residue (13 g) from the CH2Cl2 extract was crystallized from acetonitrile. 7.5 g of pure 3-methoxyphenyl-(2-hydroxy-2-adamantyl)-1-imidazolylmethane of melting point 182° C. were obtained.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:21]([I:22])=[CH:20][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1.Cl[C:24]1[CH:33]=[CH:32][C:27]([C:28]([NH:30][CH3:31])=[O:29])=[CH:26][N:25]=1>CS(C)=O.O.ClCCl>[I:22][C:21]1[C:4]([O:3][C:24]2[CH:33]=[CH:32][C:27]([C:28]([NH:30][CH3:31])=[O:29])=[CH:26][N:25]=2)=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)c(I)cc2CC1
Reactant: CNC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(Oc2cc3c(cc2I)CCN(C(=O)OC(C)(C)C)CC3)nc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 240 mg, 6 mmol) was added to a stirred solution of 1,1-dimethylethyl 7-hydroxy-8-iodo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (D41) (1.94 g, 5 mmol) in dimethyl sulfoxide (10 ml). After 10 minutes, 6-chloro-N-methyl-nicotinamide (D10) (850 mg, 5 mmol) was added and the reaction mixture was heated to 100° C. for 20 hours. After cooling to room temperature the reaction mixture was diluted with water and dichloromethane. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (1:1 ethyl acetate:hexanes) to afford the title product (D42).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([N+]([O-])=O)[C:13]=1[O:14][CH3:15])[CH:9]=[O:10].Cl.C#N>O.O1CCOCC1.CCOCC>[OH:10][CH:9]([C:8]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:6]([O:5][CH3:4])[CH:7]=1)[C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Agent: C#N
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C(O)C#N)cc1OC
Reaction time: 0.5 h

Procedure:
A solution of 14.68 g of potassium cyanide in 20 ml of water is added to a solution of 10.0 g of 3,4-dimethoxy-5-nitrobenzaldehyde in 100 ml of dioxane. 18.81 ml of 37 percent hydrochloric acid are now added dropwise thereto within 30 minutes while stirring vigorously. After the addition of 120 ml of ether, the excess hydrogen cyanide gas is driven off by passing argon through the mixture. The reaction mixture is filtered a siliceous earth filter aid, and the organic phase is washed with water dried over sodium sulfate and evaporated. The α-hydroxy-3,4-dimethoxy- phenylacetonitrile (yellowish oil) which is formed is dissolved in 200 ml of ether, whereupon the solution is treated with 20 ml of ethanol, cooled to 0° and hydrochloric acid gas is passed in for 30 minutes. After 3 hours, the separated colorless precipitate is filtered under suction and recrystallized from ethanol/ether. There is obtained ethyl (3,4-dimethoxy-5-nitrophenyl)hydroxy- acetimidate hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-])=O.[CH3:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20]O)[CH2:13]1.CO.O.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(OCC)(=O)C>[S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=1)([OH:34])(=[O:33])=[O:32].[CH3:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:13]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C[C@H]1CCCN(CCCO)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H]1CCCN(CCCOc2ccc(N)cc2)C1

Procedure:
4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}aniline was obtained as a light brown oily substance by the method according to Example 18, using 4-nitrophenol and 3-[(3S)-3-methylpiperidin-1-yl]propan-1-ol as starting materials. The obtained oily substance was dissolved in ethyl acetate, 1 Eq of a methanol solution of p-toluenesulfonic acid monohydrate was added, and the target compound was obtained as a light peach-colored solid by filtering off the solid produced.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[C:13]3=[O:27])=[CH:6][CH:5]=1.I[CH3:31].O>O1CCCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([O:26][CH3:31])[C:22]([F:24])([F:25])[F:23])[C:13]3=[O:27])=[CH:28][CH:29]=1
Reactant: O=C1c2ccc(OCc3ccc(F)cc3)cc2C(=O)N1CC(O)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(CN1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O)C(F)(F)F
Reaction time: 14 h
Yield: 33.6 %

Procedure:
To a suspension of sodium hydride (45 mg, 1.0 mmol) in tetrahydrofuran (8 mL) was added 5-(4-fluoro-benzyloxy)-2-(3,3,3-trifluoro-2-hydroxy-propyl)-isoindole-1,3-dione (360 mg, 0.9 mmol) at room temperature and then iodomethane (159 mg, 1.1 mmol) was added and then after 14 h, water was added. The mixture was then extracted with ethylacetate and the combined organic extracts washed with water, brine and then dried over sodium sulfate. Filtration and evaporation gave a residue which was purified by chromatography (SiO2, hexane-EtOAc 3:1) to afford the title compound (120 mg, 32%) as a white solid. MS: m/e=398.4 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C@H:4]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.FC(F)(F)C(O)=O.[NH2:26][CH:27]([CH2:37][CH3:38])[C@@H:28]([C:30]1[N:34]=[C:33]([CH2:35][CH3:36])[O:32][N:31]=1)[OH:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:35]([C:33]1[O:32][N:31]=[C:30]([CH:28]([OH:29])[C@@H:27]([NH:26][C:5](=[O:7])[C@@H:4]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH2:3][C:2]([CH3:1])([CH3:18])[CH3:17])[CH2:37][CH3:38])[N:34]=1)[CH3:36]
Reactant: CC(C)(C)C[C@H](CC(=O)N1CCOCC1)C(=O)O
Reactant: CCc1nc([C@@H](O)C(N)CC)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(C(O)[C@H](CC)NC(=O)[C@@H](CC(=O)N2CCOCC2)CC(C)(C)C)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid (200 mg, 0.778 mmol) in dimethylformamide (10 ml) was treated successively with (S)-2-Amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound with trifluoro-acetic acid (233 mg, 0.779 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (296 mg, 0.779 mmol) and diisopropylethylamine (0.271 ml, 1.559 mmol). Reaction stirred at room temperature overnight. Solvent evaporated under reduced pressure. Residue taken up in ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous bicarbonate solution and water, dried over Na2SO4 and solvent evaporated under reduced pressure to give (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid {(S)-1-[(5-ethyl-1,2,4-oxadiazol-3-yl)-hydroxy-methyl]-propyl}-amide as a yellow solid (277 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([I:13])[C:4]=1[OH:14].[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O)(=O)C>C1C=CC=CC=1>[CH3:12][C:9]([C:7]1[CH:6]=[C:5]([I:13])[C:4]2[O:14][C:19]3([CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)[NH:1][CH2:2][C:3]=2[CH:8]=1)([CH3:11])[CH3:10]
Reactant: CN1CCC(=O)CC1
Reactant: CC(C)(C)c1cc(I)c(O)c(CN)c1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CN1CCC2(CC1)NCc1cc(C(C)(C)C)cc(I)c1O2
Yield: 57.5 %

Procedure:
A mixture of 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol (6.0 g., 0.02 mole), 1-methyl-4-piperidone (2.24 g., 0.02 mole), acetic acid (2 ml.) and benzene (100 ml.) is refluxed under a Dean-Stark trap for 4 hrs. The clear yellow solution then is washed with 2% sodium hydroxide solution, water and salt brine and dried (MgSO4). The residue that remains after evaporation of the benzene is crystallized from ethanol to obtain 3,4-dihydro-6-(1,1-dimethylethyl)-8-iodo-1'-methylspiro[2H-1,3-benzoxazin-2,4'-piperidine], (4.6 g.), m.p. 155°-156.5° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:27]=[C:28]([CH3:31])[S:29][CH:30]=4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:27]=[C:28]([CH3:31])[S:29][CH:30]=4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2csc(C)n2)cc1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2csc(C)n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.8 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-[(2-methylthiazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (550 mg) in a mixture of tetrahydrofuran (33 ml) and methanol (33 ml) was added solution (11 ml), and the mixture was stirred at room temperature for 2 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(2-methylthiazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (427 mg) as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14](OC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].CC(O)=O>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
(2R,4R)-1-(tert-Butyloxycarbonyl)-2-carbomethoxy-4-hydroxypyrrolidine 36 (7.0 g, 28.6 mmol) was dissolved in dry THF (100 ml) and cooled in ice salt bath under argon atmosphere. To this cold solution was added lithium borohydride (1.88 g, 85.8 mmol) in small portions during 15 min period. After the addition of lithium borohydride, the reaction mixture was allowed to stir at 0° C. for 1 h followed by 15 h at room temperature under argon. The solution was cooled to 0° C. and diluted with water (50 ml) and the pH was adjusted with AcOH to 6. The reaction was evaporated to dryness and dissolved in EtOAc (200 ml), washed with water (100 ml) and brine (100 ml). The EtOAc extract was dried and evaporated to dryness. The residue was purified by flash column chromatography over silica gel using CH2Cl2 →EtOAc as the eluent. The pure fractions were collected and evaporated to dryness to afford 5.00 g (81%) of clear oil. The oil on standing gave colorless solid. mp: 95-97C. 1HNMR (CDCl3): 1.45 (s, 9H, Boc), 1.90 (dd, 1H), 2.34 (m, 1H), 3.40 -3.62 (m, 3H), 4.00 (m, 2H), 4.28 (bs, 1H), 4.44 (m, 1H).