Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([CH2:21][C:22]1[N:23]([S:27]([N:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH:24]=[CH:25][N:26]=1)[CH2:9][C:10]1[N:11]([S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:12]=[CH:13][N:14]=1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].[C].C(O)C>[NH:8]([CH2:9][C:10]1[N:11]([S:15]([N:18]([CH3:20])[CH3:19])(=[O:16])=[O:17])[CH:12]=[CH:13][N:14]=1)[CH2:21][C:22]1[N:23]([S:27]([N:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH:24]=[CH:25][N:26]=1
Reactant: CN(C)S(=O)(=O)n1ccnc1CN(Cc1ccccc1)Cc1nccn1S(=O)(=O)N(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN(C)S(=O)(=O)n1ccnc1CNCc1nccn1S(=O)(=O)N(C)C
Temperature: 60 °C
Reaction time: 6 h
Yield: 62.9 %

Procedure:
To an ethanol (350 mL) solution of the compound (55.7 g) obtained in Example 2, 20% palladium hydroxide-carbon (13.6 g) was added under an argon atmosphere. The reaction mixture was stirred under a hydrogen atmosphere at 60° C. for 6 hours. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:10%-saturated aqueous ammonia-methanol=1:0→8:2) to obtain the title compound (28.5 g) having the following physical properties.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:23][C:24]1[O:28][CH:27]=[N:26][CH:25]=1>C(O)C>[C:3]([O:7][C:8]([NH:10][C:11]([CH2:23][C:24]1[O:28][CH:27]=[N:26][CH:25]=1)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: ClCc1cnco1
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1cnco1)(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
301 mg of a 60% dispersion of sodium hydride in mineral oil were added portionwise to 60 ml of anhydrous ethanol at 0° C. and the resulting suspension was stirred at 0° C. for 5 minutes. 1.88 g of diethyl 2-(tert-butoxyformamido)malonate were added and the mixture was warmed to room temperature. After stirring at room temperature for 10 minutes 805 mg of 5-(chloromethyl)oxazole were added. The mixture was stirred at room temperature for 30 minutes and at 60° C. for 1 hour. The solvent was evaporated and the crude product was dissolved in diethyl ether and washed with water. Sodium chloride was added to the aqueous layer, which was then extracted with diethyl ether. The combined organic layers were dried over magnesium sulphate and the solvent was removed by evaporation. Purification of the residue by chromatography on silica gel using ethyl acetate/hexane (1:2) for the elution gave diethyl 2-(tert-butoxyformamido)-2-[(5-oxazolyl)methyl]malonate, 1H NMR (250 MHz, CDCl3) δ: 1.3 (t,6H), 1.45 (s,9H), 3.75 (s,2H), 4.2 (m,4H), 5.85 (s,1H), 6.8 (s,1H), 7.75 (s,1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][N:8]2C(OC(C)(C)C)=O)[N:3]=1.[ClH:20]>ClCCl.O1CCOCC1>[ClH:20].[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[N:3]=1
Reactant: Cc1nc(C2CCCCN2C(=O)OC(C)(C)C)no1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc(C2CCCCN2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of tert-butyl 2-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (55 mg, 0.21 mmol; which may be prepared as described in Step 2) in dichloromethane (1.7 mL) was added dropwise HCl 4N in dioxane (1.3 mL). The solution was warmed to room temperature and stirred for 2 h. The solvent was evaporated under reduced pressure to give the title compound (47 mg, quantitative) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])/[C:4](/[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH3:15])=[CH:5]/[O:6][CH3:7].CC(N=NC(C#N)(C)C)(C#N)C.[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])/[C:4](/[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH2:15][Br:29])=[CH:5]/[O:6][CH3:7]
Reactant: CO/C=C(/C(=O)OC)c1ccc(Cl)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CO/C=C(/C(=O)OC)c1ccc(Cl)cc1CBr
Temperature: 25 °C

Procedure:
9.7 g (40 mmol) of the compound obtained in Step 2 was dissolved in 200 ml of carbon tetrachloride, and 0.7 g (4 mmol) of AIBN and 7.9 g (44 mmol) of N-bromosuccinimide were added thereto. The mixture was refluxed for 5 hours, and cooled to room temperature. The reaction mixture was washed with 50 ml of water twice and 50 ml portions of a brine solution, dried over anhydrous MgSO4, and distilled under a reduced pressure to obtain (E)-methyl-2-(2-bromomethyl-4-chlorophenyl)-3-methoxyacrylate containing a small amount of the starting material as an oil.
Reaction SMILES: [F:1][C:2]([F:23])([S:19](F)(=[O:21])=[O:20])[C:3]([F:18])([F:17])[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].C[Si](C)(C)[O-:26].[K+:29]>CCOCC>[F:1][C:2]([F:23])([S:19]([O-:26])(=[O:21])=[O:20])[C:3]([F:18])([F:17])[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].[K+:29]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 53.6 %

Procedure:
The procedure of Example 1 was followed using perfluorohexanesulfonyl fluoride (7.9 g, 19.6 mmol), potassium trimethylsilanolate (2.52 g, 19.6 mmol), dry ether (150 mL), and a reaction time of nine days. Potassium perfluorohexanesulfonate (4.6 g, 53% yield) was isolated as a white solid: 19F NMR (methanol) δ -81.1 (m, --CF3 --, 3F), -114.4 (m, --CF2SO3⃝, 2F), -120.6 (m, --CF2CF2SO3⃝, 2F), -121.7 (m, --CF2 (CF2)2SO3⃝, 2F), -122.6 (m, CF3CF2CF2, 2F), 126.1 ppm (m, CF3CF2 --, 2F).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.C1N=CN([C:19](N2C=NC=C2)=[O:20])C=1.C(#N)C>O>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:13])([F:11])[F:12])[CH:7]=[C:8]2[NH:9][C:19]1=[O:20]
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: O
Product: Cn1c(=O)[nH]c2cc(C(F)(F)F)cnc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A mixture of 1.91 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 3.24 g of carbodiimidazole and 10 ml of acetonitrile was stirred at 50° C. for 1 hour and at 80° C. for 2 hours. Water was poured into the cooled reaction mixture, and the precipitated crystal was obtained by filtration and dried to obtain 2.0 g of 3-methyl-6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:16]1[C:20]2[CH:21]=[C:22]([C:25](O)=[O:26])[CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]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.C(N(CC)CC)C>O1CCCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH:12][C:25]([C:22]1[CH:23]=[CH:24][C:19]2[N:18]=[CH:17][S:16][C:20]=2[CH:21]=1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cccc(Oc2ccccc2)c1
Reactant: O=C(O)c1ccc2ncsc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc(Oc2ccccc2)c1)c1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62 %

Procedure:
To a solution of 3-phenoxybenzylamine described in Preparation Example 4 (33 mg, 0.167 mmol) and benzothiazole-6-carboxylic acid (30 mg, 0.167 mmol) in tetrahydrofuran (1 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (89 mg, 0.20 mmol) and triethylamine (28 μl, 0.20 mmol), and the solution was stirred at room temperature for 17 hours. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (37 mg, 62%) was obtained as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH3:13].C1(P(=C=[CH:34][C:35]([O:37][CH3:38])=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[OH:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH3:13]
Reactant: COC(=O)C=C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCOc1cc(C=O)ccc1O
Product: CCCOc1cc(/C=C/C(=O)OC)ccc1O
Yield: 78.2 %

Procedure:
The preparation is carried out analogously to Example 2 from 0.76 g (4.22 mmol) of 4-hydroxy-3-propoxybenzaldehyde and 1.48 g (4.43 mmol) of methyl (triphenylphosphoranylidene)acrylate and gave 0.78 g of methyl (E)-4-hydroxy-3-propoxycinnamate.
Reaction SMILES: Br[C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[F:25]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[NH:6][CH:5]=[N:4][C:3]=2[C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)=[CH:18][C:17]=1[F:25]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: N#Cc1ccnc(-c2nc[nH]c2Br)c1
Product: N#Cc1ccnc(-c2nc[nH]c2-c2ccc(Cl)c(F)c2)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro-3-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C15H8ClFN4, 300. Found, 299, 301.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH:22][C:14](=[O:15])[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:8][CH:9]=1)[CH3:17]
Reactant: CC(C(=O)Cl)c1ccc(C2=CCCCC2)cc1
Reactant: CN(C)CCN
Solvent: Cc1ccccc1
Product: CC(C(=O)NCCN(C)C)c1ccc(C2=CCCCC2)cc1
Reaction time: 2 h

Procedure:
A solution of 6 g of α-[p-(1-cyclohexenyl)-phenyl]-propionic acid chloride in 10 ml of toluene is added dropwise with stirring at room temperature to a solution of 6 g of β-dimethylamino-ethylamine in 40 ml of toluene. The reaction mixture is stirred for two hours, then extracted with 2N hydrochloric acid, the hydrochloric acid solution washed with ethyl acetate and rendered alkaline with 4N sodium hydroxide solution. The batch is extracted with ethyl acetate, washed with water, dried over sodium sulphate and evaporated in vacuo. The solid residue is recrystallized from methylene chloride and petroleum ether to yield N-(β-dimethylamino-ethyl)-α-[p-(1-cyclohexenyl)-phenyl]-propionic acid amide of the formula ##SPC13##
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH3:12])[CH2:6]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:33]>>[Cl:33][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH3:12])[CH2:6]1
Reactant: CC1CN(CCCO)CC(C)O1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1CN(CCCCl)CC(C)O1

Procedure:
This intermediate (2.3 g.) was prepared using the procedure described in Example 4c except using 5.0 g. (28 mmoles) of 4-(3-hydroxypropyl)-2,6-dimethylmorpholine and 9.5 g. (30 mmoles) of triphenylphosphine in 50 ml. of carbon tetrachloride and was isolated as a colorless liquid.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH2:5]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:27]=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[BH4-].[Na+].N>C(O)C.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].ClCCl>[CH3:2][N:3]([CH2:27][C:26]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[C:24]([O:23][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:25]=1)[CH3:4]
Reactant: CNC
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOc1ccc(C=O)cc1OCCCCCCCC/C=C\C/C=C\CCCCC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCOc1ccc(CN(C)C)cc1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 10 h
Yield: 74.4 %

Procedure:
To a solution of triethylamineamine (2.0 mL, 14 mmol) in ethanol (20 mL) was added dimethylamine hydrochloride (1.63 g, 20 mmol), titanium tetraisopropoxide (5.96 mL, 20 mmol) and 3,4-dilinoleyloxybenzaldehyde (6.35 g, 10 mmol). The mixture was allowed to stir under argon for 10 h at room temperature. Sodium borohydride (0.57 g, 15 mmol) was added to the reaction mixture which was then allowed to stir at room temperature overnight. 6N Aqueous ammonia (30 mL), was added slowly to the reaction mixture followed by dichloromethane. The reaction mixture was filtered. The filtrate was dried over K2CO3, filtered and concentrated. The resultant oil was purified via flash chromatography (2-10% acetone in dichloromethane, 0.5% TEA gradient) to afford 4.94 g (74%) of a yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12](=[O:27])[C@H:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:14][CH3:15].[C:28]([NH:35][C@H:36]([C:45](O)=[O:46])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12](=[O:27])[C@H:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[N:14]([C:45](=[O:46])[C@H:36]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)[NH:35][C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Oc1ccc2ccccc2c1
Product: CN(C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Oc1ccc2ccccc2c1
Yield: 55.1 %

Procedure:
Using Procedure D, crude Nδ-Boc-Nα-methylornithinyl 2-naphthyl ether (133 mg) and Boc-tyrosine (222 mg) is coupled to afford intermediate (125 mg) as a glassy solid: 1H NMR (400 MHz, CDCl3) δ1.44 (m, 21H), 1.63 (m, 1H), 2.75 (s, 3H), 3.15 (m, 2H), 3.92 (m, 2H), 4.84 (m, 1H), 5.06 (m, 1H), 6.62 (d, J=10.2 Hz, 2H), 7.08 (m, 4H), 7.35 (m, 1H), 7.42 (m, 1H), 7.66 (d, J=10.9 Hz, 1H), and 7.75 (m, 3H).
Reaction SMILES: C([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)(=O)C.[C:17]([O:20]O)(=[O:19])[CH3:18].OC1C=CC(OC(C)C(OC)=O)=CC=1>C(O)(=O)C>[C:17]([O:20][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:15][CH:16]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OO
Reactant: COC(=O)C(C)Oc1ccc(C(C)=O)cc1
Agent: COC(=O)C(C)Oc1ccc(O)cc1
Solvent: CC(=O)O
Product: COC(=O)C(C)Oc1ccc(OC(C)=O)cc1
Temperature: 70 °C
Yield: 71 %

Procedure:
To a solution of methyl 2-(4-acetylphenoxy)propanoate (5.6g, 25.0 mmol) in acetic acid (25 mL) is added peracetic acid (35%, 6.5g, 30.0 mmol) dropwise over 30 minutes at 25° C. The reaction is refluxed at 70° C. for 5 hours to give an orange-brown liquid. Acetic acid and residual peracetic acid are removed by high vacuum. The solution is kugelrohr distilled to give a light brown-orange product which contains methyl 2-(4-acetoxyphenoxy)propanoate (conversion 93%, selectivity 76%, yield 71%) and methyl 2-(4-hydroxyphenoxy)propanoate.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23].CN(C)[CH:30]=[O:31].Cl>O1CCCC1.O>[F:13][C:14]1[C:19]([CH:30]=[O:31])=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23]
Reactant: CCCS(=O)(=O)Nc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Reaction time: 0.5 h

Procedure:
To diisopropyl amine (0.210 mL, 1.49 mmol) in tetrahydrofuran (3 mL) was added n-butyllithium (2.50 M in hexane, 0.600 mL, 1.49 mmol) at −78° C. under an atmosphere of nitrogen. After 30 minutes, propane-1-sulfonic acid (2,4-difluoro-phenyl)-amide (9, 113 mg, 0.480 mmol) in tetrahydrofuran (2 mL) was added at −78° C. under am atmosphere of nitrogen. After 1 hour, N,N-dimethylformamide (0.050 mL, 0.64 mmol) was added. The reaction was stirred for 1 hour, then allowed to come to room temperature for 15 minutes. The reaction was poured into water, acidified with 1M HCl (aq.) to pH=1, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a solid (10, 25 mg, 20%). MS (ESI) [M−H+]−=262.0.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH:10]=[C:11]([S:13][CH2:14][CH3:15])[N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:14]([S:13][C:11]1[N:12]=[C:8]([NH2:7])[S:9][CH:10]=1)[CH3:15]
Reactant: CCSc1csc(NC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCSc1csc(N)n1
Reaction time: 3 h
Yield: 71.3 %

Procedure:
(4-Ethylsulfanyl-thiazol-2yl)-carbamic acid tert-butyl ester (0.583 g, 2.24 mmole) was dissolved in methylene chloride (9 mL) and the resulting solution was cooled in an ice-water bath. Trifluoroacetic acid (5 mL) was added dropwise to this solution. The solution was stirred under an argon atmosphere for 3 hours, allowing the cooling bath to slowly warm up. At the conclusion of the reaction, the bath temperature was 12° C. The reaction was concentrated. The residue was redissolved in methylene chloride and concentrated. This was repeated two additional times to remove most of the trifluoroacetic acid. Following the final concentration, the residue was dissolved again in methylene chloride and washed with saturated sodium bicarbonate, water and brine. The organic phase was dried over sodium sulfate and concentrated to yield 4-ethylsulfanyl-thiazol-2-ylamine (0.256 g, 65%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[CH2:8][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:2].[BH4-].[Na+]>CO.O1CCCC1>[CH2:16]([C:3]1([CH2:1][CH3:2])[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:17]
Reactant: CCC1(CC)CC(=O)c2cc(C#N)ccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC1(CC)CC(O)c2cc(C#N)ccc2O1
Yield: 101.3 %

Procedure:
To a solution of 2,2-diethyl-3,4-dihydro-4-oxo-2H-1-benzopyran-6-carbonitrile (2.29 g) in a mixture of methanol (23 ml) and tetrahydrofuran (5 ml) was added sodium borohydride (0.37 g) at ambient temperature. The reaction mixture was stirred for an hour at the same temperature and evaporated in vacuo. The residue was dissolved in ethyl acetate, and then washed with water and brine successively. The extract was dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified with silica gel column chromatography using a mixture of methanol and methylene chloride (1:20) as an eluent to give 2,2-diethyl-3,4-dihydro-4-hydroxy-2H-1-benzopyran-6-carbonitrile (2.34 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[F:18].[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>C1COCC1>[F:18][C:8]1[CH:9]=[C:10]([O:13][C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][C:7]=1[B:19]([OH:24])[OH:20]
Reactant: Fc1cc(OC(F)(F)F)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OC(F)(F)F)cc1F
Temperature: -98 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-butyllithium (2.5 M solution in hexanes, 14.1 mL) in THF (30 mL) at −98° C. was added a solution of 4-bromo-3-fluorotrifluoromethoxy-benzene in THF (3 mL). After stirring for 10 min. at −98° C., triisopropyl borate (4.88 mL, 3.98 g, 21 mmol) was added at a rate needed to keep the temperature below −97° C. The reaction mixture was allowed to warm to −30° C. over 30 minutes, re-cooled to −78° C. and stirred at this temperature for 30 min. Concentrated hydrochloric acid (2 mL) was added and the reaction mixture was concentrated under reduced pressure. Dilute hydrochloric acid (0.2 N, 15 mL) was added and the mixture was extracted with ether (3×20 mL). The combined ethereal layers were extracted with dilute sodium hydroxide (0.02 N, 3×30 mL). The combined aqueous extracts were cooled to 0° C., acidified to pH 3.5 using concentrated hydrochloric acid and extracted with ether (3×30 mL). The combined ethereal layers were then washed with water (15 mL) and brine (15 mL), dried over magnesium sulphate and concentrated under reduced pressure to leave 2.3 g of yellow solid. Recrystallisation from hexane afforded pink needles (1.25 g, 41%): mp 89-93° C.; 1H NMR (CDCl3) δ 7.89 (t, 1H), 7.07 (d, 1H), 6.94 (d, 1H), 5.11 (d, 2H); EI/MS 223 m/e (M−1).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[N:9]([C@@H:10]2[CH2:19][C:18]3[C:13](=[C:14]([F:21])[CH:15]=[C:16]([F:20])[CH:17]=3)[O:12][CH2:11]2)[C:8](=[S:22])[NH:7][CH:6]=1.[CH3:23][CH:24](O)[CH3:25]>O1CCCC1>[CH2:23]([NH:2][CH2:3][CH2:4][C:5]1[N:9]([C@@H:10]2[CH2:19][C:18]3[C:13](=[C:14]([F:21])[CH:15]=[C:16]([F:20])[CH:17]=3)[O:12][CH2:11]2)[C:8](=[S:22])[NH:7][CH:6]=1)[C:24]1[CH:25]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1
Reactant: CC(C)O
Agent: Cl
Solvent: C1CCOC1
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
(R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (12 g, 29.9 mmol) was dissolved with heating to reflux in Tetrahydrofuran (300 ml), the solution was cooled to 5-10° C., Water (510 ml) was added slowly (approx 10 min) with stirring. The mixture was stirred for 1 h, solid was collected, washed with water, dried to give 11.73 g of product, by HPLC 1% of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride and 1% of less polar impurity. The product was dissolved in Tetrahydrofuran (300 ml) with heating to reflux, 2-Propanol (150 ml) was added, the solution was concentrated to approx 100 ml (crystallisation occurred), stirred in ice for 1.5 h. Solid was collected, washed with 2-propanol, dried to give 11.2 g of product, by HPLC 0.8% of (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione hydrochloride and 0.5% of less polar impurity. The product was dissolved in Tetrahydrofuran (300 ml) with heating to reflux, 2-Propanol (150 ml) was added, the solution was concentrated to approx 100 ml (crystallisation occurred), stirred at 20-25° C. for 1 h. Solid was collected, washed with 2-propanol, dried to give (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (10.22 g, 25.5 mmol, 85% yield).,