Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6].[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1>CC(N(C)C)=O>[CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([O:6][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: CNCC[C@@H](O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CNCC[C@@H](Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 90 °C
Yield: 85.5 %

Procedure:
To a solution of (R)-N-methyl-3-phenyl-3-hydroxypropylamine (7) (1.23 g, 7.45 mmol) in dimethyl acetamide (7 mL) was added sodium hydride (215 mg, 8.95 mmol) with cooling. The mixture was heated at 90° C. for 1.5 h, and an orange solution resulted. To this solution was then added 4-chlorobenzotrifluoride (3.23 g, 2.40 mL, 17.9 mmol), and the mixture was heated at 100°-105° C. for 2.5 h. After cooling and dilution with toluene, the mixture was washed with water, and the aqueous layer was separated and extracted with toluene. The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine, and dried over magnesium sulfate. Concentration provided (R)-fluoxetine as an orange oil (1.97 g, 86%). The oil was dissolved in ether and acidified with hydrogen chloride gas (pH=3-4) to give a acidic ethereal solution (no precipitate formed). The solution was concentrated at room temperature to give a yellow solid which was washed with ether to remove most of the orange color. The slightly yellow solid was then recrystallized from acetonitrile at -20° C. The solid was collected and washed with ether to provide (R)-fluoxetine hydrochloride (s) as a white powder (1.90 g, 75%): mp 140°-142° C. (lit.133b mp 140°-141.5° C.; [α]23D-2.16. (c 1.62, MeOH); (lit.133b [α]23D-1.97° [c 1.00, MeOH]); [α]23D+7.08. (c 1.30, H2O); (lit. [α]23D+10.32° [c 1.00, H2O]); IR (KBr, CDCl3 2950, 2640, 2450, 1620, 1595, 1520, 1360, 1250, 1180, 1170, 1130, 1114, 1070, 840 cm-1; 1H NMR (CDCl3) & 9.72 (br, s, 2H), 7.40-7.43 (d, J=8.7 Hz, 2H), 7.25-7.33 (m, 5H), 6.88-6.92 (d, J=8.7 Hz, 2H), 5.45-5.50 (dd, J=4.6, 7.9 Hz, 1H), 3.12 (br, s, 2H), 2.55-2.62 (br, s, 3H), 2.42-2.52 (m, 2H); Anal. Calcd. for C17H19ClF3NO: C, 59.05; H, 5.54; N, 4.05; F, 16.48; Cl, 10.25. Found: C, 58.84; H, 5.55; N, 3.94; F, 16.28; Cl, 10.50.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12])([O-])=O.B.C1COCC1.Cl.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(O)C>[NH2:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: N#CCc1ccccc1[N+](=O)[O-]
Agent: B
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: NCCc1ccccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a solution of (2-nitrophenyl)acetonitrile (3 g, 18.5 mmol) was added dropwise a 1 M BH3-THF solution (125 mL) at 0° C. After 4 h of stirring at 25° C., 6N HCl solution (125 mL) was added to the reaction mixture at 0° C. After evaporation of the organic solvent in vacuo, the aqueous phase was basified with 4N NaOH solution to pH 10. Then the product was extracted with EtOAc and the organic phase was dried over MgSO4 and concentrated in vacuo. A brown liquid (41, 2 g, 10.8 mmol) was isolated. Without further purification, it was mixed with SnCl2.2H2O (13.57 g, 60.2 mmol) and absolute ethanol (20 mL). The suspension was heated at 70° C. under nitrogen. After being stirred for 30 min, the starting material disappeared, the solution was allowed to cool, then poured into ice (100 g). The pH was made slightly basic (pH 8) by the addition of a 5% aqueous NaHCO3 solution, and the resulting basic mixture was stirred for 1 h. The precipitate was extracted with ethyl acetate (100 mL×3). The extract was washed with water (50 mL×3) and dried over MgSO4. The product was obtained in a yield of 52% (1.3 g, brown liquid, over two steps) after evaporation of the solvent: 1H NMR (400 MHz, CD3OD) δ6.97 (t, J=7.2 Hz, 2H), 6.72 (d, J=7.2 Hz, 2H), 6.64 (t, J=7.2 Hz, 1H), 2.82 (t, J=7.2 Hz, 2H), 2.66 (t, J=7.2 Hz, 2H). HRMS (EI) m/z (M+) calcd for C8H12N2 136.1000, found 136.1002.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1>CN(C=O)C.CCOC(C)=O.[Pd]>[CH2:25]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2[CH3:24])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[C:16]1=[O:27])[CH3:26]
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2nccc(C)c21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C)c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
To a solution of 3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (88.3 g) in DMF (540 mL) and EtOAc (1080 mL) was added 10% Pd—C (9.0 g) at room temperature under Ar atmosphere. The mixture was hydrogenated under balloon pressure at room temperature for 5 h. The reaction mixture was filtered through celite, and then insoluble materials were washed with EtOAc (500 mL). The filtrate was concentrated in vacuo. The residue was suspended in EtOAc (350 mL), and the mixture was stirred at room temperature for 2 h. The precipitate was collected by filtration, washed with EtOAc (250 mL) and IPE (100 mL), and dried in vacuo to give 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (56.0 g) as light purple powder.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:33]=[CH:32][CH:31]=[CH:30][C:14]=1[C:15]([C:17]1[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:18]=1[NH:24][CH:25]=[CH:26][N+:27]([O-:29])=[O:28])=O>C1C=CC=CC=1>[Cl:12][C:13]1[CH:33]=[CH:32][CH:31]=[CH:30][C:14]=1[C:15]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][N:24]=[C:18]2[S:19][C:20]([CH2:22][CH3:23])=[CH:21][C:17]=12
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(NC=C[N+](=O)[O-])s1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: CCc1cc2c(-c3ccccc3Cl)c([N+](=O)[O-])cnc2s1
Yield: 89.1 %

Procedure:
To a solution of DBU (5.1 g) in benzene (50 ml) was added dropwise a solution of 3-(2-chlorobenzoyl)-2-(2-nitroethenylamino)-5-ethylthiophene (5.1 g) in dioxanebenzene (1:1, 30 ml) over one hour with stirring under reflux. After refluxing for additional one hour, the mixture was washed with water and dried over MgSO4. The solvent was distilled off and to the residue was added isopropyl ether to obtain 4-(2-chlorophenyl)-2-ethyl-5-nitrothieno[2,3-b]pyridine as crystals (4.3 g, 89.0%). The crystals were recrystallized from isopropyl ether to obtain pale yellow prisms, mp: 72°-73° C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].CS(O[C@H:11]([CH3:27])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(=O)=O>>[C:1]([O:4][C@@H:11]([CH3:27])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: C[C@H](COc1ccc(Oc2ccccc2)cc1)OS(C)(=O)=O
Agent: [Na+]
Product: CC(=O)O[C@@H](C)COc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 70.7 %

Procedure:
A mixture of anhydrous sodium acetate (82 mg, 1.0 mmol), (R)-1-methyl-2-(4-phenoxyphenoxy)ethyl methanesulfonate (250 mg, 0.78 mmol; ee.: 99.4%) and dimethylformide (5 ml) was stirred at an inner temperature of 100° to 110° C. for 5 hours. After allowed to cool, ice-water was added thereto, and the reaction mixture was extracted with toluene three times. The toluene layer was dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by thin layer chromatography using silica gel to give (S)-(-)-1-methyl-2-(4-phenoxyphenoxy)ethyl acetate (158 mg). [α]D23 =-30.6° (CHCl3, c=1). ee.: 88.8%.
Reaction SMILES: ClC1C(Cl)=NC2C(C=1)=CC=CC=2.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(C([O-])=O)#CC([O-])=O.ClC1C=C(C=C(Cl)C=1)N.[C:37]([C:43]([O:45][CH3:46])=[O:44])#[C:38][C:39]([O:41][CH3:42])=[O:40]>>[NH:13](/[C:38](=[CH:37]\[C:43]([O:45][CH3:46])=[O:44])/[C:39]([O:41][CH3:42])=[O:40])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccccc1
Agent: Clc1cc2ccccc2nc1Cl
Agent: Nc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])C#CC(=O)[O-]
Product: COC(=O)/C=C(\Nc1ccccc1)C(=O)OC
Yield: 80 %

Procedure:
The dichloroquinoline (represented by 4) may be synthesized as described by Heindel, N. D., et al., “CYCLIZATION OF ANILINE-ACETYLENE DICARBOXYLATE ADDUCTS: A MODIFIED CONRAD-LIMPACH METHOD FOR THE SYNTHESIS OF POTENTIAL ANTIMALARIALS,” J. Med. Chem. 11 1218–1221 (1968). 3,5-Dichloroaniline, (1) a dihaloaniline, is refluxed with dimethyl acetylenedicarboxylate to produce substituted diester (3) in approximately 80% yield. Upon heating in diphenyl ether, the fumarate ester under goes cyclization to the quinoline carboxylate (4). The ester (4) can be readily aminated to the tosylamine (5) as described by Harrison, B. L., et al., “4-[(CARBOXYMETHYL)OXYL]-AND 4-[(CARBOXYMETHYL)AMINO]-5,7-DICHLOROQUINOLINE-2-CARBOXYLIC ACID: NEW ANTAGONISTS OF THE STRYCHNINE-INSENSITIVE GLYCINE BINDING SITE ON THE N-METHYL-D-ASPARTATE RECEPTOR COMPLEX,” J. Med. Chem. 33 3130–3132 (1990). The tosylamine (5) was acylated with diphenylcarbamoyl chloride (6), followed by hydrolysis, to form the diphenyl urea derivative (7).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=1[NH2:10].[CH3:11][CH:12]([CH3:15])[C:13]#[CH:14]>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:9][O:8][C:6]1[N:5]=[CH:4][C:3]([NH2:10])=[C:2]([C:14]#[C:13][CH:12]([CH3:15])[CH3:11])[CH:7]=1
Reactant: COc1cc(I)c(N)cn1
Reactant: C#CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1cc(C#CC(C)C)c(N)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-iodo-6-methoxypyridin-3-amine (Compound 3, 845 mg, 3.4 mmol) in Et3N (12 ml) in a re-sealable pressure tube was added Pd(PPh3)2Cl2 (24 mg, 0.034 mmol), CuI (7.0 mg, 0.034 mmol), and 3-methyl-1-butyne (0.66 ml, 6.8 mmol). The mixture was stirred at room temperature for 20 h and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as beige solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1.CO>C1COCC1>[Br:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[O:38])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncccc2Cl)C1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N(C(=O)c2ccc(Br)cc2)c2ncccc2Cl)C1
Temperature: -10 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
Preparation 1 tert-Butyl (3R)-3-[(3-chloropyridin-2-yl)amino]piperidine-1-carboxylate (214.4 g, 687.7 mmol) was dissolved in 260 mL of THF and the resulting suspension was cooled to −10° C. Lithium bis(trimethylsilyl)amide (1 mol/L in THF, 687.7 mL, 687.1 mmol) was added over 25 min followed by warming to 20° C. and stirring for 1 h before cooling back to −10° C. 4-Bromobenzoyl chloride (140.0 g, 625.2 mmol) was added as a solution in 230 mL of THF over 1.5 h, maintaining the internal temperature at less than −7° C. After complete addition, the reaction mixture was warmed to 0° C. at which point HPLC indicated the reaction was complete. MeOH was added (101 mL), then the reaction was warmed to room temperature and concentrated in vacuo to a low volume. The solvent was then exchanged to 2-MeTHF. The crude product solution (700 mL in 2-MeTHF) was washed with 700 mL of half-saturated aqueous NaHCO3, followed by 200 mL of half-saturated brine. The 2-MeTHF solution was concentrated to a low volume followed by addition of 400 mL of heptane resulting in precipitation of solids which were collected via filtration. The collected solids were dried to afford the title compound as a tan powder (244 g, 79% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([C:19](N2[C@@H](C3C=CC=CC=3)COC2=O)=[O:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][OH:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC[C@H](c2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To (S)-3-((3R,4S)-1-benzyl-4-phenyl-pyrrolidine-3-carbonyl)-4-phenyl-oxazolidin-2-one (9.96 g, 23.35 mmol) in THF (100 mL) in a three-necked flask equipped with a thermometer and addition funnel was added lithium aluminium hydride (48 mL, 1M in THF) dropwise so that the temperature did not exceed 40° C. When addition was complete, the reaction was stirred at room temperature overnight. The reaction was carefully quenched with water (1.6 mL), NaOH (1.6 mL, 2N) and water (4.5 mL). After stirring for 15 minutes, the reaction mixture was filtered through a pad of celite and rinsed with THF (40 mL). The filtrate was concentrated to give a pale yellow oil, which was purified by flash silica gel chromatography eluting with ethyl acetate:hexanes (1:1) to give 3.38 g (55%) of ((3R,4S)-1-benzyl-4-phenyl-pyrrolidin-3-yl)-methanol.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](Cl)([Cl:10])=[O:9].C(Cl)(Cl)=O.C1(O)C=CC=CC=1.[OH-].[Na+].Cl>P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>[Cl:10][C:8]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: Oc1ccccc1
Reactant: O=C(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Cl)Oc1ccccc1
Temperature: 140 °C
Yield: 96.3 %

Procedure:
A four-necked flask equipped with a gas inlet, a dry ice condenser, a mechanical stirrer, a thermocouple and a sampling port is charged with phenol (Aldrich, 287.5 g, 2.907 mol) and triphenyl phosphite (10.12 g, 32.61 mmol). The temperature is raised to 140° C. and phosgene (274 g, 2.77 mol) is added over a 465 minute period. Phosgene/phenol molar ratio is 0.95. A recirculating aqueous sodium hydroxide scrubber is used to neutralize the coproduct hydrochloric acid and to destroy traces of phosgene which are not condensed in the condenser. After the phosgene addition is stopped, a nitrogen stream is used to purge residual phosgene and the reactor is cooled to ambient temperature. The colorless crude product is isolated by vacuum distillation to give phenyl chloroformate (417.84 g, bp 73°-77° C. at 14 mm Hg) containing 6.6 percent by weight residual phenol. Selectivity to phenyl chloroformate is 95 mole percent based on phenol, 90 mole percent based on phosgene.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1
Reactant: C1=COCCC1
Reactant: OCCCCCCBr
Product: BrCCCCCCOC1CCCCO1
Reaction time: 1 h
Yield: 91.1 %

Procedure:
197.8 g (1.09 mol) of 6-bromo-1-hexanol was put in a 500-ml reactor and was cooled to 5° C. or below. 102.1 g (1.21 mol) of dihydropyran was dropped thereto at a temperature of not higher than 10° C. After the dropping was finished, the mixture was returned to room temperature and stirred for one hour. Residue obtained as a result of the reaction was subjected to purification by silicagel column with use of hexane/diisopropyl ether (IPE)=5/1, whereby 263.4 g of 6-bromo-1-(tetrahydropyranyloxy)hexane was obtained. The yield of the same was 90.9%. The reaction of the step 1 is expressed by a formula (12) shown below: BrCH26OH→BrCH26OTHP  (12) Step 2: Synthesis of N-[6-(tetrahydropyranyloxy)hexyl]pyrrole
Reaction SMILES: [CH2:1]=[O:2].S(=O)(=O)(O)O.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.C(C1C=CC=CC=1)C>C(O)CCC.O>[C:16]1([CH:1]=[O:2])[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: C=O
Reactant: c1ccc2ccccc2c1
Agent: O=S(=O)(O)O
Solvent: CCc1ccccc1
Solvent: O
Solvent: CCCCO
Product: O=Cc1cccc2ccccc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 102.1 %

Procedure:
A bottom-removable four-necked flask having an inner volume of 2 L and equipped with a Dimroth condenser, a thermometer and a stirring blade was charged with 384 g of 86% by mass paraformaldehyde (11.0 mol as formaldehyde, produced by Mitsubishi Gas Chemical Company, Inc.), 437 g of ion-exchange water (produced by Mitsubishi Gas Chemical Company, Inc.), 297 g of 1-butanol (produced by Wako Pure Chemical Industries, Ltd.) and 398 g of 98% by mass sulfuric acid (produced by Mitsubishi Gas Chemical Company, Inc.) in a nitrogen stream, 256 g of naphthalene (2.0 mol, produced by Wako Pure Chemical Industries, Ltd.) was dropped thereto over 6 hours while stirring under reflux under ordinary pressure at about 100° C., and the reaction was performed as it was for further 2 hours. Thereto was added 500 g of ethylbenzene (produced by Wako Pure Chemical Industries, Ltd.) as a dilution solvent and left to still stand, and then an aqueous phase as a lower phase was removed. Furthermore, the resultant was subjected to neutralization and washing with water, and ethylbenzene and unreacted naphthalene were distilled off under reduced pressure to thereby provide 319 g of a naphthalene formaldehyde resin as a light yellow liquid.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[N+:16]([C:19]1[CH:20]=[N:21][NH:22][CH:23]=1)([O-:18])=[O:17]>CC(C)=O.O>[N+:16]([C:19]1[CH:20]=[N:21][N:22]([CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:23]=1)([O-:18])=[O:17]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cnn(CCN2CCCC2)c1

Procedure:
N-(2-chloroethyl)pyrrolidine hydrochloride (752 mg, 4.42 mmol), potassium carbonate (0.534 ml, 8.84 mmol) and 4-nitro-1H-pyrazole (500 mg, 4.42 mmol) were combined in acetone (20 ml) and the reaction was stirred at reflux for 16 hours. The reaction mixture was diluted with 75 mL water and extracted with ethyl acetate (3×20 mL). The combined organics were dried (Na2SO4), filtered, and concentrated to give the title compound. MS (ESI(+)) m/e 210.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20]([OH:22])=O)=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:23])[CH:3]=1.[CH:24]([O:26][CH2:27][CH2:28][O:29][NH2:30])=[CH2:25].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>CN(C)C=O.C(OCC)(=O)C>[CH:24]([O:26][CH2:27][CH2:28][O:29][NH:30][C:20]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[Cl:23])=[C:18]([F:19])[C:13]2[N:14]=[CH:15][N:16]([CH3:17])[C:12]=2[CH:11]=1)=[O:22])=[CH2:25]
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc21
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.1 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid 10c (2.00 g, 5.0 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (0.776 g, 7.5 mmol), HOBt (0.88 g, 6.5 mmol), triethylamine (1.61 mL, 2.3 mmol) and EDCI (1.3 g, 6.5 mmol) are dissolved in dimethylformamide (52 mL) and stirred at room temperature for 48 hours. The reaction mixture is diluted with ethyl acetate, washed with water (3×), saturated potassium carbonate (2×), saturated ammonium chloride (2×), brine, dried (Na2SO4) and concentrated under reduced pressure to an off-white solid. Trituration of the solid with diethyl ether provides 2.18 g (90%) desired product as an off-white solid. MS ESI (+) m/z 483, 485 (M+Br pattern) detected.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@@H:2]1[C:7]([OH:9])=[O:8].N[C@H](C(O)=O)CCC(=O)O.N[C@H](C(O)=O)CCC(=O)N>>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: O=C1CC[C@H](C(=O)O)N1
Agent: NC(=O)CC[C@H](N)C(=O)O
Agent: N[C@@H](CCC(=O)O)C(=O)O
Product: O=C1CC[C@@H](C(=O)O)N1

Procedure:
D-PyroGlu, Glu, Gln
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[OH:18])[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(C(OC(C)(C)C)=O)CCNCC1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]3[O:18][C:9]2=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1cccc(Cl)c1)C1CCCCC1O
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OC2CCCCC2C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (3-chlorophenyl)(2-hydroxycyclohexyl)acetic acid (Reference Example 2-d) (1.25 g, 4.66 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.1 g, 7.0 mmol), and tert-butyl 1-piperazinecarboxylate (0.87 g, 4.66 mmol) in methylene chloride (12 mL) was treated with triethylamine (0.98 mL, 7.0 mmol). The reaction was stirred at 25° C. for 16 h, after which time the solvent was removed in vacuo and the product was purified via Biotage Horizon (FLASH 40 M, silica, gradient from 0% EtOAc/hexane to 25% EtOAc/hexane) to yield 0.97 g (83%) the lactone, 3-(3-chlorophenyl)hexahydro-1-benzofuran-2(3H)-one as a clear oil. HRMS: calcd for C14H15ClO2+H, 251.0861; found (ESI, [M+H]+), 251.0844.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].P([O-])([O-])([O-])=O>>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=P([O-])([O-])[O-]
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 42.7 %

Procedure:
Ethyl (2R/S) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (13 g) was added to an aqueous 0.1 M phosphate buffer pH 7 (2.6 μl). Protease 2A from Aspergillus oryzae (Fluka No: 82463; 0.51 units/mg) (7.9 g) was added and the mixture was stirred for 14 hours at room temperature. The conversion of ester to acid was followed by the described isocratic HPLC method 1. After stirring for 6 hours the reaction mixture was extracted 5× with ethyl acetate until no more ester could be detected in the aqueous phase (pH of the aqueous phase 6.8). A 4 M aqueous hydrogen chloride solution (200 ml) was added (pH of the aqueous phase 1) followed by tert-butyl-methylether (500 ml). The emulsion was filtered through hyflo and the two phases separated. The aqueous phase was extracted with tert-butyl-methylether (500 ml×3). The pooled organic phases were dried with Na2SO4 and evaporated to give 4.9 g of the title product (CCE method 1: ee=97%). δ(400 MHz; [2 H6]DMSO) 1.04 (3H, t); 2.78 (2H, ddd), 3.38 (1H, dq); 3.49 (1H, dq); 3.90 (1H, m), 6.62 (2H, d); 7.0 (2H, d); 9.1 (1H, bs); 12.53 (1H, bs).