Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[Li]CCCC.CN([CH:25]=[O:26])C>C1COCC1>[CH:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH:25]=[O:26])=[CH:3][C:4]=2[C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: FC(F)(F)c1cc(Br)ccc1C1CCCC1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C2CCCC2)c(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
In a 15 mL round-bottomed flask were placed 4-bromo-1-cyclopentyl-2-(trifluoromethyl)benzene (0.186 g, 0.635 mmol) and anhydrous THF (1.86 mL) under argon atmosphere. The solution was stirred well and cooled to −78° C. (dry ice IPA bath). BuLi (2.5 M in hexanes, 0.281 mL, 0.703 mmol) was added in drops (slowly) and the reaction mixture was stirred at low temperature for 25 min. Anhydrous DMF (0.1 mL, 0.766 mmol) was added in drops at −78° C. (slowly). The mixture was stirred at −78° C. for 20 min then at room temperature for 30 min. The reaction was quenched with water, acidified with 2 M HCl and extracted with EtOAc. The EtOAc layer was washed with water, dried over Na2SO4, and concentrated in vacuo to give the title compound as an oil (60 mg). LCMS m/z=243.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.7 (m, 4H), 1.79-1.94 (m, 2H), 1.95-2.09 (m, 2H), 3.29-3.37 (m, 1H), 7.86 (d, J=8 Hz, 1H), 8.12 (d, J=8 Hz, 1H), 8.16 (d, J=1.2 Hz, 1H), 10.46 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=1[F:27])C1C=CC=CC=1.C(OC1C=CC=CC=1C(=C=O)/C=C/C1C=CC(C([O-])=O)=CC=1)C1C=CC=CC=1.OC1C=CC=CC=1C(=C=O)CCC1C=CC(C(OC)=O)=CC=1>C(O)C>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=1[F:27]
Reactant: COC(=O)c1ccc(C=Cc2ccccc2OCc2ccccc2)c(F)c1
Agent: COC(=O)c1ccc(CCC(=C=O)c2ccccc2O)cc1
Agent: O=C=C(/C=C/c1ccc(C(=O)[O-])cc1)c1ccccc1OCc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(CCc2ccccc2O)c(F)c1

Procedure:
Methyl 4-[2-(2-hydroxyphenyl)ethyl]-3-fluorobenzoate was synthesised from methyl 4-(2-(2-benzyloxyphenyl) ethenyl]-3-fluorobenzoate using the hydrogenation method described in Example 1 (for the conversion of 4-[3-(2-benzyloxyphenyl)-3-carbonyl-1(E)-propenyl]-benzoate to methyl 4-[3-(2-hydroxyphenyl)-3-carbonylpropyl)benzoate but using ethanol as the reaction solvent).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([C:13]2([F:16])[CH2:15][CH2:14]2)[CH:10]=[CH:9][C:8]=1[O:17][CH3:18].CN([CH:22]=[O:23])C.C(=O)(O)[O-].[Na+]>C1COCC1>[F:16][C:13]1([C:11]2[CH:10]=[CH:9][C:8]([O:17][CH3:18])=[C:7]([CH:12]=2)[CH:22]=[O:23])[CH2:15][CH2:14]1
Reactant: COc1ccc(C2(F)CC2)cc1Br
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C2(F)CC2)cc1C=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.7M solution in hexane, 3.42 ml) was added at −78° C. to a solution of 2-bromo-4-(1-fluorocyclopropyl)-1-methoxybenzene (1.88 g) in THF (62 ml), followed by addition of a solution of DMF (650 μl) in THF. After the reaction mixture was stirred at −78° C. for 30 minutes, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (1.00 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.C(COC)OC>[C:9]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:10]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: Brc1ccc(Br)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Brc1ccc(-c2cccc(-c3ccccc3)c2)nc1
Yield: 72.7 %

Procedure:
To a 1000 mL, 3-necked flask equipped with a stir bar, nitrogen inlet, and a reflux condenser were added 2,5-dibromopyridine (39.9 g, 84.2 mmol), 3-biphenylboronic acid (20.0 g, 101 mmol), palladium(II) acetate (0.47 g, 2.1 mmol), triphenylphosphine (2.2 g, 8.4 mmol), sodium carbonate (24.1 g, 227 mmol), dimethoxyethane (170 mL), and water (114 mL). The reaction mixture was heated at reflux for 16 h, after which ethyl acetate (200 mL) was added. The organic layer was then dried over magnesium sulfate and evaporated to dryness. Purification of the resulting solid on a silica gel column with ethyl acetate/hexane as the eluent yielded 19.0 g (73%) of 2-(biphenyl-3-yl)-5-bromopyridine as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:24]=1>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[O:14])=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: NCCCCc1cccnc1
Reactant: CCCc1c(OCCC(C)(C)C(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCCC(C)(C)C(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
4(4-Acetyl-3-hydroxy-2-propylphenoxy)-2,2-dimethyl butanoic acid was allowed to react with 3-pyridine butanamine according to procedure A and the product was purified by HPLC to give 4-(4-acetyl-3-hydroxy-2-propylphenoxy)-2,2-dimethyl-N-[4-(3-pyridinyl)butyl]-butanamide, the title compound, mp 80°-83° (from hexane) in 83% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]([S:7][CH2:8][CH2:9][CH3:10])[CH3:6].[CH2:12](O)[CH:13](C)[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:2][C:3](=[O:11])[CH2:4][CH:5]([S:7][CH2:8][CH2:9][CH3:10])[CH3:6])[CH:13]([CH3:14])[CH3:12]
Reactant: CCCSC(C)CC(=O)OC
Reactant: CC(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCSC(C)CC(=O)OCC(C)C

Procedure:
Into a 25 cc micro flask equipped with spin bar, hot plate (equipped with magnetic stirrer), reflux condenser and thermometer are placed 5 grams (0.0284 moles) of methyl-3-(propylthio)butyrate; 8.4 grams (0.1136 moles) of isobutyl alcohol and 0.05 grams of para-toluene sulfonic acid. With stirring, the reaction mass is heated to reflux and refluxed for a period of 14 hours. At the end of the 14 hour period, the reaction mass is cooled and distilled on a micro Vigreux column yielding the following fractions:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)[C:2]#[C:3]C.C([Li])CCC.[CH3:21][O:22][C:23]1[C:32]([CH:33]=[O:34])=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:39])([CH3:38])[O:28]2.CCOCC>C1COCC1.O=[Mn]=O>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([O:5][CH2:1][C:2]#[C:3][C:33]([C:32]2[C:23]([O:22][CH3:21])=[C:24]3[C:29](=[CH:30][C:31]=2[N+:35]([O-:37])=[O:36])[O:28][C:27]([CH3:39])([CH3:38])[CH:26]=[CH:25]3)=[O:34])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: CC#CCOc1ccc(OC)c(OC)c1
Reactant: COc1c2c(cc([N+](=O)[O-])c1C=O)OC(C)(C)C=C2
Agent: O=[Mn]=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(OCC#CC(=O)c2c([N+](=O)[O-])cc3c(c2OC)C=CC(C)(C)O3)cc1OC
Reaction time: 0.5 h

Procedure:
To a solution of 4-but-2-ynyloxy-1,2-dimethoxy-benzene (1.66 g, 8.66 mmol) in THF (75 mL) is added n-butyl lithium (5.54 ml of 1.6 M solution in THF, 8.86 mmol) at −78° C. After 30 min., 5-methoxy-2,2-dimethyl-7-nitro-2H-chromene-6-carbaldehyde (2.17 g, 8.25 mmol) in THF (50 mL) is added. The reaction is stirred for 1 h and then quenched with sat. NH4Cl and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over Na2SO4. The resulting crude material is dissolved in dichloromethane (20 mL) and MnO2 (5.3 g, 61 mmol) is added. After the reaction is stirred overnight at room temperature, ether is added and the suspension is filtered through a pad of celite and silica gel to afford 4-(3,4-dimethoxy-phenyoxy)-1-(5-methoxy-2,2-dimethyl-7-nitro-2H-chromen-6-yl)-but-2-yn-1-one.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2[C:12]([O:14]CC)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ncsc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ncsc1-c1ccccc1
Yield: 72 %

Procedure:
The ethyl 5-phenylthiazole-4-carboxylate was hydrolyzed according to known methods with 2N aqueous sodium hydroxide solution at 70° for 30 minutes, whereby, after acidification, there was obtained in 72% yield 5-phenyl-4-thiazolecarboxylic acid which melted at 189°-190° after recrystallization from methanol/diethyl ether.
Reaction SMILES: [F:1][C:2]1([F:12])[CH2:4][CH:3]1[CH2:5][S:6][CH2:7][CH2:8][C:9](O)=[O:10].S(Cl)([Cl:15])=O>ClCCl>[F:1][C:2]1([F:12])[CH2:4][CH:3]1[CH2:5][S:6][CH2:7][CH2:8][C:9]([Cl:15])=[O:10]
Reactant: O=C(O)CCSCC1CC1(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CCSCC1CC1(F)F
Temperature: 40 °C
Yield: 96.4 %

Procedure:
In a 3 L 3-neck round bottomed-flask equipped with an overhead stirrer, a temperature probe, and addition funnel and an nitrogen inlet was charged with 3-(((2,2-difluorocyclopropyl)methyl)thio)propanoic acid (90.0 g, 459 mmol) that was immediately taken up in dichloromethane (140 mL) with stirring. At room temperature, thionyl chloride (170 mL, 2293 mmol) in dichloromethane (100 mL) was added drop-wise with stirring. The reaction mixture was heated to 40° C. and heated for 2 hours. The reaction was determined to be complete by 1H NMR (An aliquot of the reaction mixture was taken, and concentrated down via rotary evaporator). The reaction was allowed to cool to room temperature and the mixture was transferred to a dry 3 L round bottomed flask and concentrated via the rotary evaporator. This resulted in honey-colored oil (95 g). The contents were gravity filtered through paper and the paper rinsed with diethyl ether (10 mL). The rinse was added to the flask. This gave a clear yellow liquid. The liquid was placed on a rotary evaporator to remove the ether. This gave a yellow oil (92.4 g). The oil was Kugelrohr distilled (bp 100-110° C./0.8-0.9 mm Hg) to provide the title compound as a colorless oil (81.4 g, 81%): 1H NMR (400 MHz, CDCl3) δ 3.27-3.12 (m, 2H), 2.89 (t, J=7.1 Hz, 2H), 2.67 (ddd, J=6.8, 2.6, 1.0 Hz, 2H), 1.78 (ddq, J=13.0, 11.3, 7.4 Hz, 1H), 1.64-1.46 (m, 1H), 1.09 (dtd, J=13.2, 7.7, 3.7 Hz, 1H).
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[CH3:11][C:12]1[CH:32]=[CH:31][CH:30]=[CH:29][C:13]=1[O:14][CH2:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[C:18](N1CCCC1)=[O:19]>C(OCC)C>[CH3:11][C:12]1[CH:32]=[CH:31][CH:30]=[CH:29][C:13]=1[O:14][CH2:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[C:18]([C:7]1[O:6][CH:10]=[CH:9][CH:8]=1)=[O:19]
Reactant: Cc1ccccc1OCc1ccccc1C(=O)N1CCCC1
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccccc1OCc1ccccc1C(=O)c1ccco1
Temperature: -20 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
27.8 g (0.1 mol) of 23% pure n-butyllithium are added dropwise within 15 minutes to a solution of 6.8 g (0.1 mol) of furan in 100 ml of diethyl ether which had been cooled to −20° C. The mixture was stirred at 20° C. for 2 hours, cooled once more to −20° C., and 14.8 g (0.05 mol) of N-[2-(2-methylphenoxymethyl)-benzoy]-pyrrolidine dissolved in 100 ml of diethyl ether are added dropwise within 15 minutes. After complete conversion (DC control), the mixture is poured into 300 ml of ice-cold ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and concentrated under reduced pressure. 13.1 g (89.7% of theory) of 2-[2-(2-methylphenoxymethyl)-benzoyl]-furan are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([O:9]C)[C:3]=1[OH:11].B(Br)(Br)Br>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([OH:9])[C:3]=1[OH:11]
Reactant: COc1c(F)ccc(F)c1O
Agent: BrB(Br)Br
Product: Oc1c(F)ccc(F)c1O

Procedure:
Using the procedure of Step B of Preparation 1, 21.15 g oil the product of Step C and 260 ml of a molar solution of boron tribromide were reacted to obtain 17.62 g of the desired product.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]3[N:28]=[N:29][N:30](COC)[N:31]=3)[CH2:22]2)=[O:20])=[CH:13][C:12]=1[N+:35]([O-:37])=[O:36])([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]3[NH:28][N:29]=[N:30][N:31]=3)[CH2:22]2)=[O:20])=[CH:13][C:12]=1[N+:35]([O-:37])=[O:36])([CH3:3])[CH3:2]
Reactant: COCn1nnc(C2CCCN(C(=O)/C=C/c3ccc(Sc4ccccc4C(C)C)c([N+](=O)[O-])c3)C2)n1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccccc1Sc1ccc(/C=C/C(=O)N2CCCC(c3nnn[nH]3)C2)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 74.6 %

Procedure:
The compound from Example 279 (75 mg, 0.14 mmol) was dissolved in 1 mL of neat TFA and left at ambient temperature for overnight. The reagent was then removed in vacuo and the residue was evaporated twice with benzene. The crude product was purified using Gilson Preparative HPLC as described in Example 38B to give the title compound as a light-yellow solid (50 mg, 72%); 1H NMR (CDCl3, 300 MHz) δ 1.17 (d, J=6.5 Hz, 6H), 1.25-1.39 (m, 1H), 1.69-1.81 (m, 1H), 2.09 (br s, 1H), 2.14-2.30 (m, 1H), 2.57-2.71 (m, 1H), 3.35-3.66 (m, 3H), 3.90-4.03 (m, 1H), 4.66-4.78 (m, 1H), 6.73 (d, J=8.7 Hz, 1H), 6.86 (d, J=15.3 Hz, 1H), 7.32 (dd, J=2.1, 6.9 Hz, 1H), 7.42 (dd, J=2.1, 8.7 Hz, 1H), 7.47-7.57 (m, 3H), 7.76 (d, J=15.3 Hz, 1H), 8.46 (d, J=2.1 Hz, 1H). MS (ESI+) (M+H)+ at m/z 479. Anal. Calcd for C24H26N6O3S.0.28 H2O: C, 59.61; H, 5.54; N, 17.38. Found: C, 59.71; H, 5.44; N, 16.99.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[O:8]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:15]([C:11]1[S:10][CH:14]=[CH:13][CH:12]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)Cc1cccs1
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)C(C(=O)c1ccccc1)c1cccs1

Procedure:
From benzoyl chloride and ethyl 2-(thiophene-2-yl)acetate, the title compound was prepared using a similar method to the one described in Example 1.14, Step A to give a clear oil. 1H NMR (400 M Hz, CDCl3) δ ppm 1.22 (t, J=7.07 Hz, 3H), 4.16-4.26 (m, 2H), 5.88 (s, 1H), 6.96-7.02 (m, 1H), 7.07 (d, J=3.03 Hz, 1H), 7.31 (dd, J=5.18, 1.14 Hz, 1H), 7.46 (t, J=7.71 Hz, 2H), 7.57 (t, J=7.33 Hz, 1H), 7.98-8.02 (m, 2H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:21]([CH3:30])[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>>[C:22]([CH:21]([N:17]1[CH2:18][CH2:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)[CH3:30])(=[O:23])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: CC(C(=O)c1ccccc1)N1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 2-bromopropiophenone to produce the above.
Reaction SMILES: [C:1]1(=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:15]O>>[CH3:15][O:12][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][C:1]2=[O:14])=[CH:6][CH:7]=1)=[O:13]
Reactant: O=C(O)c1ccc2c(c1)C(=O)CCC2
Reactant: CO
Product: COC(=O)c1ccc2c(c1)C(=O)CCC2
Temperature: 0 °C
Yield: 48.6 %

Procedure:
Part A--A mixture of 1-tetralon-7-carboxylic acid (7.0 g, 0.037 mol) in methanol (13.6 mL, 10.8 g, 0.30 mol) with a catalytic amount of hydrochloriic acid (0.07 mL, 0.12 g, 0.0012 mol) was stirred at reflux over 5 hours. The cooled reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were backwashed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting solid was purified by flash chromatography using hexane:ethyl acetate::75:25. The resulting solid was triturated with hexane to give 1-tetralon-7-carboxylic acid methyl ester (3.61 g, 0.018 mol, 49%) as a yellow solid. mp=170-172° C.; 1H NMR (CDCl3) d 8.7 (s, 1H), 8.15 (d, 1H, J=8.1 Hz), 7.35 (d, 1H, J=8.1 Hz), 3.95 (s, 3H), 3.05 (d, 2H, J=6.1 Hz), 2.7 (t, 2H, J=6.4 Hz), 2.15 (quintet, 2H, J=6.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[NH2:58][C:59]([CH3:63])([CH3:62])[CH2:60][OH:61]>C1COCC1.CO.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:58][C:59]([CH3:63])([CH3:62])[CH2:60][OH:61])=[O:20])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.58 mmol) in THF (6 mL) was added 1-hydroxybenzotriazole hydrate (90.8 mg, 0.58 mmol), N-ethyldiisopropylamine (254 μL, 1.45 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (114 mg, 0.58 mmol) and 2-amino-2-methyl-1-propanol (53.4 mg, 0.58 mmol). The reaction mixture was stirred overnight at room temperature. Chromatography (silica, dichloromethane:methanol=0:100 to 95:5) afforded the title compound (160 mg, 66%) as a colorless oil. MS: m/e=416.2 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:15][CH2:16][S:17][CH3:18])[CH2:10][S:11]([O-:14])(=[O:13])=[O:12])=O)(C)(C)C.[Na+].[ClH:20]>O>[ClH:20].[NH2:8][C@@H:9]([CH2:15][CH2:16][S:17][CH3:18])[CH2:10][S:11]([OH:14])(=[O:12])=[O:13]
Reactant: CSCC[C@@H](CS(=O)(=O)[O-])NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CSCC[C@H](N)CS(=O)(=O)O
Yield: 21 %

Procedure:
Sodium (S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butane-1-sulfonate (350 mg) was treated with 6 N HCl in water at 40° C. for 1 h. The reaction mixture was purified on Diaion HP-20 column eluting with water (200 mL), then 20% CH3CN in water. The fractions were concentrated and dried under vacuum to give (S)-2-amino-4-(methylthio)butane-1-sulfonic acid hydrochloride as a light yellow solid (53 mg, 21%). 1H NMR (DMSO-d6, 300 MHz) d 8.05 (br s, 3H, NH3), 3.4 (br s, 1H, NCH), 2.65 (m, 4H, SCH2 and OSCH2), 2.1 (s, 3H, SCH3), 1.8-2.1 (m, 2H, NCHCH2CH2SCH3). LC-MS: 0.15 min (eluted along with solvent peak); MS (ESI−) m/z 198 (M−1)+. Purity: >95% by 1H NMR and LC-MS. The chirality of the final product was based on the commercially available starting material, (S)-tert-butyl 1-hydroxy-4-(methylthio)butan-2-ylcarbamate, which has a natural configuration (L−). The reactions did not change the chiral center.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[C@H:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:30])CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([F:30])[C@H:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H]1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
The title compound was prepared in a similar manner as described by J. A. Hodges et al., J. Amer. Chem. Soc. 2005, 127, 15923-15932: To a solution of (2S,3R)-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (490 mg, 1.53 mmol) in CH2Cl2 (30 mL), cooled to −78° C., was added dropwise DAST (1.01 mL, 7.62 mmol). The reaction mixture was stirred at −78° C. for 5 h, and then was allowed to warm to RT and stirred overnight. After cooling to 0° C., the reaction was quenched with MeOH, followed by addition of aqueous NaHCO3 solution. Volatiles were removed under reduced pressure and the residue was taken up in EtOAc. The organics were washed with aqueous NaHCO3 (3×), water and brine, dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:9) to give the title compound (89% purity by HPLC/215 nm). MS (LC/MS): 346 [M+Na]+, 268 [MH−tBu]+, 224 [MH−Boc]+; tR (HPLC conditions b): 5.31 min.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[Si:20]([O:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: O=C(CO)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ccccc1
Yield: 42.8 %

Procedure:
To a solution of 2-hydroxyacetophenone (10 g, 74.5 mmol) and imidazole (15 g, 220 mmol) in N,N-dimethylformamide (50 ml) was added tert-butyldimethylchlorosilane (22 g, 146 mmol) at room temperature for 6 hours. The mixture was poured into water (200 ml) and extracted twice with 200 ml of ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/1) to give 2-(tert-butyldimethylsilanyloxy)-1-phenylethanone (8.0 g, 31.9 mmol, 43%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)([O:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:19][C:20]1[C:21](=[O:31])[N:22]([CH3:30])[C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:12][O:11][C:8]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:19][C:20]2[C:21](=[O:31])[N:22]([CH3:30])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:3]=1)[CH2:9][CH3:10]
Reactant: CCC(OC)(c1cccc(O)c1)c1nccs1
Reactant: Cn1c(=O)c(CBr)cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(OC)(c1cccc(OCc2cc3ccccc3n(C)c2=O)c1)c1nccs1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.9 %

Procedure:
A mixture of 2-[1-(3-hydroxyphenyl)-1-methoxypropyl]thiazole (0.5 g, 2 mmol), 3-bromomethyl-1,2-dihydro-1-methylquinolin-2-one (0.5 g, 2 mmol), potassium carbonate (0.35 g, 2.5 mmol) and dimethylformamide (3 ml) was stirred at ambient temperature for 48 hours. The mixture was filtered, the filtrate was added to water (30 ml) and the mixture was extracted with ethyl acetate (3×15 ml). The organic extracts were combined, washed with a dilute aqueous sodium hydroxide solution and with a saturated sodium chloride solution, dried (Na2SO4) and evaporated. The residue was purified by column chromatography eluting with toluene/ethyl acetate (7/3 v/v) to give 2-[1-methoxy-1-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-3-ylmethoxy)-phenyl]propyl]thiazole (0.84 g, 100%), m.p. 123°-125° C.