Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[O:9].[BH4-].[Na+]>C1COCC1.O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1c(Cl)cncc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: OCc1c(Cl)cncc1Br
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To the solution of 3-Bromo-5-chloro-pyridine-4-carbaldehyde (270 mg, 1.23 mmol) in THF (5 mL) and water (1 mL) was added NaBH4 (139 mg, 3.67 mmol). The resulting mixture was stirred for another 1 h, and was diluted with DCM. The organic layer was washed with water and brine. The aqueous layer was extracted with DCM. The combined extracts were separated and concentrated in vacuo to give 270 mg of title compound without further purification. ESI-MS m/z: 223.9 [M+1]+, Retention time 1.01 min. 1H-NMR (CDCl3, 400 MHz) δ 4.88 (s, 2H), 8.46 (s, 1H), 8.56 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](Cl)Cl>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(Cl)nc1
Product: COC(=O)c1ccc(Cl)nc1
Reaction time: 8 h

Procedure:
An ethereal solution of CH2N2 (0.1 mole) is added to a suspension of 6-chloro nicotinic acid (15 g) in CH2Cl2 until bubbling ceases. The reaction mixture is stirred overnight, evaporated and dried in vacuo affording the desired product as a tan solid used in the next step without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1.[N:25]([C@H:28]([C:32]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=1)[C@@H:29]([OH:31])[CH3:30])=[N+]=[N-].[C:41]([O:45][C:46](=O)[O:47]C(C)(C)C)([CH3:44])([CH3:43])[CH3:42]>O>[C:41]([O:45][C:46](=[O:47])[NH:25][C@H:28]([C:32]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=1)[C@@H:29]([OH:31])[CH3:30])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: C[C@H](O)[C@H](N=[N+]=[N-])c1cc(F)c(F)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
In nitrogen atmosphere, triphenylphosphine (5.85 g) was added to a THF solution (75 mL) of (1R,2S)-1-azido-1-(3,4,5-trifluorophenyl)propan-2-ol (5.16 g). This reaction solution was stirred at room temperature for 10 min, then water (5 mL) was added the reaction solution. This mixture was stirred at 60° C. for 3.5 hr. The reaction solution was cooled to room temperature, and then di-tert-butylcarbonate (5.35 g) was added to the reaction solution. The resulting reaction solution was stirred at room temperature for 45 min and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene:ethyl acetate=9:1) to give 5.88 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[N:8][C:7]=1[CH3:23])=O)C.[NH3:24]>CO>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:9]2[S:10][C:6]([C:4]([NH2:24])=[O:3])=[C:7]([CH3:23])[N:8]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: N
Reactant: CCOC(=O)c1sc(-c2cc(OC)c(OC)c(OC)c2)nc1C
Solvent: CO
Product: COc1cc(-c2nc(C)c(C(N)=O)s2)cc(OC)c1OC
Reaction time: 168 h
Yield: 71 %

Procedure:
Into 200 ml of methanol, 16.9 g (0.05 mol) of 2-(3,4,5-trimethoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester produced in Example 3 was dissolved, and 25 ml of an aqueous 28% solution of ammonia was added to the solution. The mixture was left at room temperature for 7 days, and then condensed to dryness. The dried residue was recrystallized from a mixture of methanol and water to obtain the object amounting to 10.9 g (yield of 71%) consisting of colourless needle-like crystals melting at 196° to 197° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][CH2:4][CH2:3]1.[N:14]([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-]>Cl.O.C1COCC1>[CH3:1][N:2]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([NH2:14])[CH2:4][CH2:3]1
Reactant: CN1CCNc2ccccc2CC1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2ccccc2N(N)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 107.6 %

Procedure:
To a solution of 4-methyl-1,2,3,4,5,6-hexahydro-benzo[e][1,4]diazocine (1.2 g, 6.8 mmole) in hydrochloric acid (2 N, 30 mL) cooled to 0° C. was added sodium nitrite (0.9 g, 13 mmole) in water (5 mL). The mixture was stirred for 1 hour at 0° C. and then neutralized with solid sodium bicarbonate and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated aqueous sodium chloride (200 mL), dried and concentrated to a light brown oil. This oil was redissolved in THF (50 mL) and added to a suspension of lithium aluminum hydride (1.0 g, 25 mmole) in THF (50 mL) and the mixture refluxed for 3 hours under nitrogen. The excess hydride was destroyed at 0° C. by the cautious addition of water. The mixture was diluted with THF (200 mL) and filtered. Evaporation of the filtrate in vacuo provided 1.4 g of the title compound as a light yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@H:4]([CH2:14][CH2:15][CH2:16][CH3:17])[NH:5][C:6]([O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])=[O:7].[OH-].[Na+].CCOC(C)=O.Cl>C1COCC1>[CH2:9]([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:18])=[O:2])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])[CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCCOC(=O)N[C@@H](CCCC)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCCOC(=O)N[C@@H](CCCC)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution of [(4-pentenyloxy)carbonyl]-L-norleucine methyl ester (1.8 g, 7.0 mmol) in THF (5 mL) at RT was added 1M sodium hydroxide solution (5 mL). The reaction mixture was stirred at RT for 3 h. The reaction mixture was then worked up with EtOAc and 1M HCl. The organic layer was separated and washed with H2O, brine, dried over Na2SO4, filtered and concentrated to give [(4-pentenyloxy)carbonyl]-L-norleucine (1.4 g, 82% yield). 1H NMR (500 MHz, CD3OD) ppm: δ 5.82 (m, 1H), 5.05 (d, 1H), 4.98 (d, 1H), 4.86 (brs, 2H), 4.10 (m, 1H), 4.08 (t, 2H), 2.16 (q, 2H), 1.82 (m, 1H), 1.72 (m, 3H), 1.38 (m, 4H), 0.93 (t, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(C=O)cn1
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(C=C2N=C(c3cccs3)OC2=O)cn1
Temperature: 90 °C
Yield: 65.2 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 6-methoxy-3-pyridinecarboxaldehyde (45 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 56 mg of the above-captioned compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:28])=[C:11]([N:15]4[CH2:19][CH2:18][C@H:17]([NH:20]C(OC(C)(C)C)=O)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:29])[C:6]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:5]2)[CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[NH2:20][C@H:17]1[CH2:18][CH2:19][N:15]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:29])[C:6]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:28])[CH2:16]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC[C@H](N)C3)c(F)cc2c1=O
Yield: 94.3 %

Procedure:
A solution of 23.9 g (50 mmol) of (S)-1-cyclopropyl-7-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, ethyl ester in 150 ml of trifluoroacetic acid was stirred at room temperature for four hours. The solvent was removed in vacuo and the residue was triturated with 5% sodium bicarbonate. The solid was removed by filtration, washed 5% sodium bicarbonate, water and dried in vacuo to give 17.8 g of the title compound, mp 227°-228°.
Reaction SMILES: [C:1]([O:4][C:5]1[N:6]=[C:7]([CH3:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)(=[O:3])[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:45])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:4][C:5]1[N:6]=[C:7]([CH2:19][Br:45])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2cc(OC(C)=O)nc(C)c2cc1OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2cc(OC(C)=O)nc(CBr)c2cc1OC
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-yl acetate SIL 32158 (261 mg, 1.00 mmol) in dry CCl4 (5 mL) in a 10 mL microwave vial equipped with a magnetic stirrer was added benzoyl peroxide (12 mg, 0.05 mmol) followed by NBS (178 mg, 1.00 mmol) and the mixture was stirred for 15 min at 130° C. under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2 (20 mL), washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 75:25) gave 1-(bromomethyl)-6,7-dimethoxyisoquinolin-3-yl acetate SIL 32162 as a yellow solid (140 mg, 41% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][OH:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26].Cl>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Reaction time: 1 h
Yield: 51.8 %

Procedure:
5.00 g (24.4 mmol) (S)-2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid in 5 ml dimethylformamide were added to a suspension of 2.25 g (51.7 mmol) sodium hydride (55%) in 5 ml dimethylformamide at 0° C. The suspension was stirred for 1 hour and then 4.5 ml (26.8 mmol) 2,5-difluoro-nitrobenzene was added. After additional 3 hours of stirring at 0° C. the mixture was poured on ice/water. The ph was adjusted to 1 by adding 7 ml 25% aqueous hydrochloric acid. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 1:1 yielded 4.35 g (52%) (S)-2-tert-butoxycarbonylamino-3-(4-fluoro-2-nitro-phenoxy)-propionic acid as yellow solid, MS m/e (%): 343.0 (M−H+, 100).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([OH:11])[CH2:10][CH2:9][CH2:8]1.Cl.F[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[CH2:24][CH2:23][NH:22][CH2:21]2)[N:15]=1.ClCCl>CS(C)=O.O>[CH:7]1([O:11][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)[N:15]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: OC1CCC1
Reactant: Fc1cccc(C2CCNC2)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: c1cc(OC2CCC2)nc(C2CCNC2)c1
Reaction time: 48 h

Procedure:
Potassium tert-butoxide (337 mg, 3 mmol, 3 eq) is added portionwise at room temperature to a solution of cyclobutanol (144 mg, 2 mmol, 2 eq) in DMSO (2 ml) and the mixture is stirred for 2 days. 2-Fluoro-6-(pyrrolidin-3-yl)pyridine hydrochloride (202 mg, 1 mmol, 1 eq) in DMSO (2 ml) is added and the mixture is stirred for 48 hours. Dichloromethane and water are then added to the reaction mixture, and the two phases are separated after vigorous shaking. The aqueous layer is reextracted with dichloromethane. The combined organic layers are dried on MgSO4, filtered and the filtrate condensed under reduced pressure to afford crude 2-(cyclobutyloxy)-6-(pyrrolidin-3-yl)pyridine a1-72, which is used in the next step without any further purification.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Li]CCCC.CCCCC.[NH4+].[Cl-]>O.C1COCC1>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:3]#[CH:2]
Reactant: COc1ccncc1C=C(Br)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCC
Product: C#Cc1cnccc1OC
Temperature: 25 °C

Procedure:
A flask is charged with 3-(2,2-dibromo-vinyl)-4-methoxy-pyridine (3.7 g, 12.63 mmol) and THF (100 mL), and 1.6 M nBuLi in pentane (17.4 mL, 27.79 mmol) is added dropwise at −78° C. The mixture is stirred at −78° C. for 1 h before addition of saturated aqueous NH4Cl (0.5 mL). The mixture is warmed to room temperature and poured into water (100 mL). The mixture is extracted with ethyl acetate and the combined organic phase is dried over Na2SO4. Concentration followed by silica gel flash chromatography eluting with a 0 to 5% methanol-dichloromethane gradient gives 4-methoxy-3-ethynyl-pyridine. 1H NMR (400 MHz, CDCl3) δ ppm 3.39 (s, 1H), 3.96 (s, 3H), 6.82 (d, J=5.8 Hz, 1H), 8.46 (d, J=5.8 Hz, 1H), 8.58 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17].C(Cl)Cl>CN(C=O)C>[Br:1][C:2]1[N:3]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[C:4]([Br:8])=[C:5]([Br:7])[N:6]=1
Reactant: Brc1nc(Br)c(Br)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Yield: 82.8 %

Procedure:
To a solution of 2,4,5-tribromoimidazole (3.05 g, 10 mmol) in anhydrous DMF (50 mL) was added powdered K2CO3 (19 g, 137 mmol), and the resulting suspension was stirred vigorously and treated dropwise with SEMCl (2.3 g, 13.8 mmol). The suspension was then stirred vigorously overnight. The solid was filtered off and washed with fresh DMF (20 mL). The combined filtrates were then evaporated under reduced pressure. Methylene chloride (30 mL) was then added and the solution washed with 0.1 N Na2CO3 (3×50 mL), dried (Na2SO4), filtered and evaporated to give a residue, which was passed through a silica gel pad (CH2Cl2) and evaporated to give 3.6 g (83%) of the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 0.01 (s, 9H), 0.93 (t, 2H, J=8.0 Hz), 3.60 (t, 2H, J=8.0 Hz), 5.32 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][NH:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:13]=2[N:14]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][NH:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:13]=2[N:14]=1
Reactant: CN1CCCC1CCNc1nc2cc([N+](=O)[O-])ccc2s1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCCC1CCNc1nc2cc(N)ccc2s1
Temperature: 25 °C

Procedure:
To 5 mL of ethanol was added [2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-(5-nitro-benzothiazol-2-yl)-amine (Example 25(a), 177.4 mg, 0.577 mmol) and tin(II) chloride dihyrdate (948 mg, 5 eq.). The resulting solution was heated at reflux for 4 hours. After cooling to room temperature, the mixture was poured onto 100 mL of a 1.5 M NaOH solution. The mixture was extracted using ethyl acetate (3×100 mL). The combined organic fractions were dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel using 10% 2M ammonia/methanol in dichloromethane (98.4 mg, 62%). 1H NMR (CDCl3) δ: 7.32 (d, 1H, J=8.5 Hz), 6.91 (d, 1H, J=1.9 Hz), 6.49 (dd, 1H, J=1.9, 8.5 Hz), 3.67 (br s, NH2), 3.51 (m, 2H), 3.13–3.09 (m, 1H), 2.36 (s, 4H), 2.19 (m, 1H), 1.93–1.68 (m, 6H).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH2:23][CH3:24].Cl>C(#N)C>[C:22]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])(=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)CC)C(=O)OCC
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
To magnesium chloride (2.96 g, 31.2 mmol) was added dry acetonitrile (5 mL) and the mixture was then cooled in ice and treated with diethyl malonate (5 g, 31.2 mmol). Once the mixture was cold, triethylamine (8.6 mL, 62.5 mmol) was added and the resulting suspension was stirred for 15 min. Propionyl chloride (2.71 mL, 31.2 mmol) was added dropwise and the mixture was stirred at 0° C. for 1.5 h and at ambient temperature for 5 h. The mixture was cooled in an ice-bath and treated with aqueous hydrochloric acid (2M, 10 mL) and the product extracted with ether. The organic phase was washed with water then brine, dried and concentrated to afford 6.31 g of a yellow oil. This was dissolved in ether and washed with aqueous hydrochloric acid (2M) then brine, dried and concentrated to afford 5.93 g of the title compound.
Reaction SMILES: CC[C:3]1[CH:4]=[CH:5][CH:6]=[C:7](C)[C:8]=1[N:9]([C:14]([CH2:16][Cl:17])=[O:15])COCC.CCC1C=CC=C(CC)C=1N(C(CCl)=O)COC.CCCCOCN(C(CCl)=O)C1C(CC)=CC=CC=1CC.CC1C(N(C(CCl)=O)C(COC)C)=C(C)SC=1.CC(N(C(CCl)=O)C1C=CC=CC=1)C.CC1C=CC=C(C)C=1N(C(CCl)=O)CN1N=CC=C1.CCC1C(N(C(CCl)=O)C(COC)C)=C(C)C=CC=1.CCCOCCN(C(CCl)=O)C1C(CC)=CC=CC=1CC.CC1C=CC=C(C)C=1N(C(CCl)=O)CC1SC=CC=1OC.CCOCCN(C(C1C=CC=CC=1)=C(C)C)C(CCl)=O>>[Cl:17][CH2:16][C:14]([NH:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15]
Reactant: CCOCN(C(=O)CCl)c1c(C)cccc1CC
Agent: CC(C)N(C(=O)CCl)c1ccccc1
Agent: CCCCOCN(C(=O)CCl)c1c(CC)cccc1CC
Agent: CCCOCCN(C(=O)CCl)c1c(CC)cccc1CC
Product: O=C(CCl)Nc1ccccc1

Procedure:
acetochlor, alachlor, butachlor, dimethenamid, propachlor, metazachlor, metolachlor, pretilachlor, thenylchlor, and pethoxamid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.ClC(OC(Cl)(Cl)Cl)=O.C([O:22][C:23]([N:25]1[CH2:46][CH2:45][CH2:44][C@H:26]1[C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH:34]([OH:43])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:28])=O)(C)(C)C>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:23]([N:25]2[CH2:46][CH2:45][CH2:44][C@H:26]2[C:27]([N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[CH:34]([OH:43])[CH2:35][O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:28])=[O:22])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Product: O=C(NCc1ccc(Cl)cc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Yield: 48.4 %

Procedure:
By the same procedure as in Example 28-B), while using 4-chlorobenzylamine (0.71 g), trichloromethyl chloroformate (0.3 ml) and (2S)-1-[N-(tert-butoxycarbonyl)-L-prolyl]-2-(1-hydroxy-2-phenoxyethyl)pyrrolidine (2.00 g), there was obtained 1.13 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[CH2:11][C:12]#[N:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][C:12]#[N:13])=[CH:5][CH:4]=1
Reactant: N#CCCl
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OCC#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-methoxyphenol (10 g, 80 mmol), chloroacetonitrile (7.0 mL, 111 mmol) and K2CO3 (26 g, 188 mmol) in acetone (150 mL) was stirred at r.t. for 18 h. The mixture was filtered, concentrated and purified by flash chromatography (Hex:EtOAc, 4:1) to yield (4-methoxyphenoxy)acetonitrile as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:22]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH:21]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[CH2:20]3)=[CH:13][CH:12]=2)O)=[CH:5][CH:4]=1.[C:82](=[O:87])([O:84][CH2:85][CH3:86])[NH2:83].CS(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:83][C:82](=[O:87])[O:84][CH2:85][CH3:86])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:22]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH:21]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:8]=1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C(O)c3ccc(OC)cc3)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: CCOC(N)=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C(NC(=O)OCC)c3ccc(OC)cc3)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 110 °C
Reaction time: 2 h
Yield: 108.6 %

Procedure:
To (4-methoxy-phenyl)-[4-(3,4,5-tris-octadecyloxy-cyclohexylmethoxy)-phenyl]-methanol (110 mg, 97.2 μmol) were added toluene (2 mL), ethyl carbamate (17.8 mg, 200 μmol), and methanesulfonic acid (1 μL, 15 μmol), and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, sodium carbonate (5 mg, 47 μmol) was added and the solvent was evaporated. The residue was crystallized from methanol (5 mL) to give ethyl {(4-methoxy-phenyl)-[4-(3,4,5-tris-octadecyloxy-cyclohexylmethoxy)-phenyl]-methyl}-carbamate (127 mg, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][C@@H:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[NH:20][C:19]1=[O:29]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([N:17]([CH3:16])[C@@H:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[NH:20][C:19]1=[O:29])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@@H]1CCc2ccccc2NC1=O
Product: CN(C(=O)CC(C)(C)NC(=O)OC(C)(C)C)[C@@H]1CCc2ccccc2NC1=O

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step B by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.30 (br s,15H), 2.19 (m,1H), 2.42 (m,1H), 2.5-2.8 (m,3H), 2.91 (m,1H), 3.15 (s,3H), 5.32 (dd;6,8 Hz;1H), 5.52 (br s,1H), 6/97 (d,5 Hz,1H), 7.1-7.3 (m,3H), 7.35 (br s,1H).