Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][OH:7].S(OC)(OC)(=O)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C@H:22]([N:26]1[CH2:31][CH2:30][C:29]2[S:32][CH:33]=[CH:34][C:28]=2[CH2:27]1)[C:23](N)=[O:24]>ClCCl.O>[CH3:6][O:7][C:23](=[O:24])[C@@H:22]([N:26]1[CH2:31][CH2:30][C:29]2[S:32][CH:33]=[CH:34][C:28]=2[CH2:27]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Cl:15]
Reactant: NC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 45 °C

Procedure:
Concentrated sulfuric acid (˜98%; 496 ml; 9.30 mol) was charged into methanol (1.75 l) with sting between 25-38° C. followed by dimethyl sulfate (250 ml; 2.636 mol). The contents were heated to reflux for 3 hours, after which the reaction mixture was cooled to 40-50° C. and (+)-(S)-2-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5yl)acetamide (500 g; 1.55 mol) was charged. The reaction mixture was heated to 65° C. and maintained between 65-66° C. for a period of 60 hours. The reaction mixture was cooled to 25-30° C. and poured into water (10.0 l) with stirring. Dichloromethane (5.0 l) was added, stirred for 1 hour, after which the organic layer was separated. To the aqueous layer dichloromethane (2.5 l) was added and stirred for 1 hour and the separated organic layer was combined with the earlier separated layer and washed with water (2.5 l). 5% (w/v) aqueous sodium bicarbonate solution (2.5 l) was added to this organic layer and stirred for a period of an hour and the separated organic layer was washed with 0.25% sulfuric acid (2.5 l) followed by water (2.5 l) and treated with activated carbon (40.0 g) for a period of 3 hours with stirring. The activated carbon was removed by filtration through a celite bed and the celite bed was washed with dichloromethane (1.0 l). This washing was coupled with the filtrate and the solvent removed under vacuum to yield (+)-(S)-2-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetic acid methyl ester as a pale yellow oil. Yield: 380 g (73.0% by theory). The product was identified by IR spectrum, 1H and 13C NMR investigation.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2SC)=[N:12][N:11]=[N:10]1.O[O:25][S:26]([O-:28])=O.[K+].[CH3:30]C(C)=O>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:26]([CH3:30])(=[O:28])=[O:25])=[N:12][N:11]=[N:10]1
Reactant: CC(C)=O
Reactant: CSc1ccccc1CNc1nnnn1-c1cccc(Cl)c1Cl
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccccc1CNc1nnnn1-c1cccc(Cl)c1Cl

Procedure:
The product of Example 20 (0.14 g, 0.39 mmol) was dissolved in 10 mL acetone and treated with OXONE (0.94 g, 1.54 mmol) for 24 h. The resulting slurry was taken up in 100 mL ethyl acetate and washed with water (3×50 mL), brine (1×50 mL), dried (MgSO4) and concentrated. Flash chromatography (gradient elution; 25% ethyl acetate/hexanes to 50%) gave 0.08 g of the title compound as a white solid. MS (ESI/NH3) m/z 397 (M+H)+
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1.O>CN(C=O)C.C(N(CC)CC)C.[Cu]I.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>[NH:20]1[CH:21]=[CH:22][CH:23]=[C:19]1/[CH:18]=[C:11]1\[C:12](=[O:17])[NH:13][C:14]2[C:10]\1=[CH:9][C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:16][CH:15]=2
Reactant: C#C[Si](C)(C)C
Reactant: O=C1Nc2ccc(Br)cc2/C1=C/c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si](C)(C)C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Temperature: 70 °C

Procedure:
(Trimethylsilyl)acetylene (1.36 g,13.8 mmol) (Aldrich) and (Z)-5-bromo-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (2.0 g, 6.9 mmol) (Starting Material 7) were dissolved in 30 mL DMF and 40 mL triethylamine. The solution was degassed for 30 minutes by bubbling argon through the solution. At this time CuI (130 mg, 0.68 mmol) (Aldrich) and (Ph3P)2PdCl2 (400 mg, 0.57 mmol) (Aldrich) were added, and the reaction was heated, under argon, at 70° C. for 22 hours. Water (20 mL) was then added and the precipitate was filtered off and dried. The product was purified via flash column chromatography (SiO2, 230-400 mesh) with 1% MeOH/CHCl3 to give (Z)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-5-(trimethylsilyl)ethynyl-2H-indol-2-one as a yellow powder. (Yield 1.07 g, 51%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7].[N:13]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[CH3:22][C:23]([SH:26])([CH3:25])[CH3:24]>O>[C:23]([S:26][N:13]=[N:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7])([CH3:25])([CH3:24])[CH3:22]
Reactant: CC(C)(C)S
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)O)cc1N=NSC(C)(C)C
Reaction time: 0.17 h
Yield: 95.4 %

Procedure:
To a stirred solution of aqueous HCl (15 mL of concentrated HCl and 50 mL of water) is added 3-amino-4-methyl benzoic acid (5.0 g, 33 mmol). The mixture is cooled in an acetone-ice water bath, followed by the slow addition of a solution of sodium nitrite (2.28 g, 33 mmol) in water (12 mL). The mixture is allowed to stir for 10 min at which point the mixture becomes homogeneous. A saturated aqueous solution of sodium acetate is added until pH˜6. 2-Methylpropane-2-thiol (1.8 mL, 16 mmol) is added and the mixture is stirred for 1 h. The resulting precipitate is collected by filtration, washed with water and dried in vacuo to give 3.85 g (96%) of 3-(tert-butylthio)diazenyl-4-methylbenzoic acid as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ 13.2, 7.8, 7.5, 7.3, 2.1, 1.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([OH:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][O:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11](=[O:22])[CH:10]=[C:9]2[NH:8][C:7]1[C:6]([Cl:23])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: BrCCCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCBr

Procedure:
8-(4-Bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one was prepared from 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (Example 11, Step 1) and 1,4-dibromobutane following the procedure outlined in Example 11, Step 2. MS (ESI): 485.8.
Reaction SMILES: [OH-:1].[Na+].C(O)C.C1(N=[C:13]([OH:59])[C:14]2[C:15](=[C:19]([O:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:50][CH:49]=3)[C:20](=[C:24]([C:34]=2[O:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:38][CH:37]=2)[C:25](=NC2C=CC=CC=2)[OH:26])[C:21]([OH:23])=[O:22])[C:16]([OH:18])=[O:17])C=CC=CC=1.Cl.[OH2:61]>>[C:43]([O:42][C:39]1[CH:38]=[CH:37][C:36]([O:35][C:34]2[C:14]([C:13]([OH:59])=[O:1])=[C:15]([C:16]([OH:18])=[O:17])[C:19]([O:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([CH3:56])([CH3:58])[CH3:57])=[CH:50][CH:49]=3)=[C:20]([C:21]([OH:23])=[O:22])[C:24]=2[C:25]([OH:26])=[O:61])=[CH:41][CH:40]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: O
Reactant: [OH-]
Reactant: CC(C)(C)Oc1ccc(Oc2c(C(=O)O)c(C(O)=Nc3ccccc3)c(Oc3ccc(OC(C)(C)C)cc3)c(C(O)=Nc3ccccc3)c2C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)Oc1ccc(Oc2c(C(=O)O)c(C(=O)O)c(Oc3ccc(OC(C)(C)C)cc3)c(C(=O)O)c2C(=O)O)cc1
Temperature: 25 °C

Procedure:
Into 150 ml of 10% NaOH solution made from 1:1 (v:v) mixture of ethanol and water were dissolved 2 g of N,N'-diphenyl-3,6-bis[4-(t-butyloxy)phenyloxy]pyromellitic diimide obtained from above. This solution was refluxed for 72 hr under nitrogen atmosphere and then cooled to ambient temperature. When it was neutralized with 5% aqueous HCl, white precipitates were formed. These precipitates were filtered, air-dried and recrystallized from 1:1 (v:v) mixture of hexane and ethyl acetate to obtain 3,6-bis[4-(t-butyloxy)phenyloxy]pyromellitic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[Cl:10][C:11]1[CH:16]=[C:15](I)[CH:14]=[CH:13][C:12]=1[F:18].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:15]2[CH:14]=[CH:13][C:12]([F:18])=[C:11]([Cl:10])[CH:16]=2)[CH:7]=1
Reactant: Fc1ccc(I)cc1Cl
Reactant: C#Cc1cncc(Cl)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2cncc(Cl)c2)cc1Cl
Temperature: 60 °C
Yield: 71 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (64 mg, 0.091 mmol), copper (I) iodide (35 mg, 0.18 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (250 mg, 1.8 mmol) to a solution of 2-chloro-1-fluoro -4-iodobenzene (560 mg, 2.2 mmol) in triethylamine (3.8 mL, 27 mmol) and heat at 60° C. for 5 h. Cool to room temperature and concentrate. Purify by silica gel chromatography, eluting with 50:50 to 100:0 dichloromethane:hexanes, followed by a second silica gel chromatography, eluting with 100:0 to 90:10 hexanes:ethyl acetate, to give the title compound as a white solid (340 mg, 70%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:24])[CH2:19][C:20](=[O:23])[CH2:21]Br)[C:15](=[O:25])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[NH2:2].[S-:26][C:27]#[N:28].[K+]>C(#N)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:24])[CH2:19][C:20](=[O:23])[CH2:21][S:26][C:27]#[N:28])[C:15](=[O:25])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[NH2:2]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2SC1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC#N
Product: N#CSCC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.9 %

Procedure:
A mixture of 3-carbamoyloxymethyl-7-(3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (0.52 g.) and potassium thiocyanate (0.174 g.) in acetonitrile (10 ml.) was stirred for 6 hours at room temperature, and then acetonitrile was distilled off therefrom. To the residue were added ethyl acetate (50 ml.) and a saturated aqueous solution of sodium chloride (20 ml.), and the mixture was adjusted to pH 2 with 50% phosphoric acid with stirring, and then ethyl acetate layer was separated therefrom. The remaining aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined together, dried over magnesium sulfate, treated with activated carbon, and then the solvent was distilled off therefrom. The residue was pulverized in diethyl ether, collected by filtration and then dried to give 3-carbamoyloxymethyl-7-(3-oxo-4-thiocyanatobutyramido)-3-cephem-4-carboxylic acid (0.36 g.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[C:14]([CH3:28])[O:13][N:12]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.ClCCl>N1C=CC=CC=1>[CH3:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:9][C:4]3[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=3)(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[C:14]([CH3:28])[O:13][N:12]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C)nc(N)n1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C)nc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
To a solution of 4,6-dimethylpyrimidin-2-amine (84 mg, 0.682 mmol) in pyridine (8 mL), stirred under nitrogen at room temperature, was added 4-((3,5-dimethylisoxazol-4-yl)methoxy)benzene-1-sulfonyl chloride (346 mg, 1.147 mmol). The reaction mixture was stirred at room temperature overnight. 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.142 mL, 0.682 mmol) was then added to the mixture and the reaction heated by microwaves to 150° C. for 15 minutes. Dichloromethane (DCM) (15 mL) was added to the mixture and the organic phase washed with water (2×25 mL), then dried using a hydrophobic frit. Solvent was removed in vacuo to give the crude product (100 mg) as an orange oil. This was used directly in the next step without further purification. LCMS (2 min, formic) Rt 0.81 min, m/z (ES+) 389 (M+H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:13]1[NH:14][C:15]([CH2:20][OH:21])=[C:16](CO)[N:17]=1)[CH2:10][CH2:11][CH3:12].C(O)C>O1CCOCC1>[CH2:9]([C:13]1[NH:14][C:15]([CH2:20][OH:21])=[C:16]([Br:1])[N:17]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1nc(CO)c(CO)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCc1nc(Br)c(CO)[nH]1

Procedure:
3.56 Grams (20 mmol) of the N-bromosuccinimide was added to a solution consisting of 3.68 g (20.0 mmol) of the 2-butyl-4,5-bis(hydroxymethyl) imidazole, 40 ml of ethanol and 15 ml of dioxane maintained at a temperature of 45° to 50° C. with stirring. The mixture was further reacted at the same temperature for 30 minutes with stirring, and then the solvent was distilled off under reduced pressure. The obtained reaction product was washed with water and was recrystallized from acetonitrile to obtain a pale yellowish scale-like crystalline 2-butyl-4-bromo-5-(hydroxymethyl) imidazole in an amount of 2.36 g (yield, 51%).
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37](=[O:47])[C:38]4[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=4)[CH:35]=3)[N:30]([CH3:48])[C:29](=[O:49])[CH:28]=2)[CH:24]=[CH:25][CH:26]=1>C1COCC1.O>[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37]([OH:47])([C:11]4[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=4)[C:38]4[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=4)[CH:35]=3)[N:30]([CH3:48])[C:29](=[O:49])[CH:28]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc21
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reaction time: 0.25 h
Yield: 26.9 %

Procedure:
n BuLi (1.6M in hexane) (4.4 ml, 0.0071 mol) was added dropwise at −70° C. to a solution of 1-methyl-1H-imidazole (0.0071 mol) in THF (8 ml) under N2 flow. The mixture was stirred for 15 minutes. ClSiEt3 (0.0073 mol) was added dropwise at −70° C. The mixture was stirred for 15 minutes. BuLi (1.6M in hexane) (3.9 ml, 0.0062 mol) was added dropwise at −70° C. The mixture was stirred at −70° C. for 15 minutes. A solution of 4-(3-chlorophenyl)-1-methyl-6-(4-nitrobenzoyl)-2(1H)-quinolinone (described in Example A3d) (0.0040 mol) in THF (15 ml) was added. The mixture was stirred at −70° C. for 15 minutes, poured out into H2O and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.2; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 0.54 g (27%) of (±)-4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-5-yl)(4-nitrophenyl)methyl]-1-methyl-2(1H)-quinolinone, mp. 230° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)[CH3:2].C(O[O:16][C:17]([CH3:20])(C)C)(C)(C)C.[C]=O.[CH2:23]([OH:25])C>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:23]([O:16][CH2:17][CH3:20])=[O:25])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCO
Reactant: CCOc1ccc(C)cc1
Reactant: CC(C)(C)OOC(C)(C)C
Agent: [C]=O
Product: CCOC(=O)Cc1ccc(OCC)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
p-Ethoxy toluene (2.04 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 89 mg ethyl p-ethoxyphenylacetate was obtained by column chromatography, in a yield of 86%. 1HNMR (400 MHz, CDCl3) δ 1.22 (t, J=7.2 Hz, 3H), 1.38 (t, J=7.2 Hz, 3H), 3.54 (s, 2H), 3.98 (q, J=7.2 Hz, 2H), 4.11 (q, J=6.8 Hz, 2H), 6.83-6.86 (m, 2H), 7.17-7.20 (m, 2H); 13CNMR (100 MHz, CDCl3) δ 13.2, 13.8, 39.5, 59.7, 69.7, 62.4, 113.5, 125.1, 129.2, 156.9, 170.9; HRMS (ESI) calcd. for C12H16NaO3 [M+Na]: 231.0992. found: 231.0989. The ethyl p-ethoxyphenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 72 mg product p-ethoxyphenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 93%.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C.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>[C:25]1([C:31]#[C:32][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCN(CC)CC
Product: C(#Cc1ccc2cc[nH]c2c1)c1ccccc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
6-Bromoindole (3.84 g, 19.6 mmol) was dissolved in triethylamine (40 ml.). A catalytic amount of phenothiazine was added, and the solution was degassed by bubbling argon through it. Phenylacetylene (8.60 mL, 78.3 mmol) was added via syringe. Bis(triphenylphosphine)palladium(II) chloride (0.69 g, 0.98 mmol) was added, and the reaction mixture was heated at 75°-85° C. for 5 hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo. The crude material was purified by chromatography on silica gel to give 6-phenylethynylindole (2.55 g, 60%).
Reaction SMILES: FC(F)(F)C(O)=O.C([NH:12][C:13](=[O:26])[C@@H:14]1[CH2:18][C@H:17](OC2C=CC=CC=2)[CH2:16][NH:15]1)(C)(C)C.[C:27]1([OH:37])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.C1(O)C=CC=CC=1>>[C:27]1([O:37][N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13]([NH2:12])=[O:26])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Oc2ccccc2)CN1
Reactant: Oc1cccc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: Oc1ccccc1
Product: NC(=O)[C@@H]1CCCN1Oc1cccc2ccccc12

Procedure:
Following substantially the same procedure for synthesizing N-t-butyl-4(S)-phenoxy-L-prolineamide trifluoroacetic acid salt as outlined in Example 1, Steps 6 through 8, but substituting 1-naphthol for the phenol used therein, the 1-naphthyloxy proline amide was produced.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].C(O)C.C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:24][CH2:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC(F)(F)C(=O)O
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCC(F)(F)C(=O)O)ccc3c2)CC1
Temperature: 25 °C

Procedure:
A solution of 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (150 mg, 0.483 mmol) and 3-amino-2,2-difluoro-propionic acid (60.4 mg, 0.483 mmol) in ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 h. The yellow solution was then cooled to room temperature and sodium cyanoborohydride (36.4 mg, 0.580 mmol) was added to the stirring solution. The resulting mixture was heated to reflux for 1 h. After cooling to room temperature, citric acid was added, and the solvent removed under vacuum. The resulting solid was suspended in water and collected via filtration. The filtrate was washed thoroughly with water (4×), ether (3×), and hexane (3×). The resulting solid was dried on the filter to give the title compound as a white solid (128.8 mg, 64%). 1H NMR (400 MHz, CDCl3) δ: 7.92 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.52 (dd, J=8.4, 1.8 Hz, 1H), 7.30 (d, J=2.2 Hz, 1H), 7.19 (dd, J=9.0, 2.4 Hz, 1H), 4.45 (s, 2H), 4.40 (m, 1H), 3.61 (t, J=13.8 Hz, 2H), 2.28-2.31 (m, 2H), 1.92-1.95 (m, 2H), 1.49-1.14 (m, 5H), 0.94 (s, 9H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15](O)=[O:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B.C1COCC1.[OH-].[Na+]>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N-BOC-2-(piperidin-4-yl)acetic acid (15.8 g) is dissolved in THF (150 ml) and 1M borane/THF (70 ml) is added dropwise. The solution is stirred at room temperature for about 20 hours and 1N sodium hydroxide solution (200 ml) is added dropwise. The THF is evaporated in vacuo and the aqueousresidue extracted with ethyl acetate. The ethyl acetate solution is washed with water, dried over sodium sulfate, filtered, and evaporated in vacuo to give N-BOC-2-(piperidin-4-yl)ethanol.
Reaction SMILES: [CH2:1]([N:9]=[C:10]=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[OH:22]>C1(C)C=CC=CC=1>[C:3]1([CH2:2][CH2:1][NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[OH:22])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=NCCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NCCc1ccccc1)Nc1ccc([N+](=O)[O-])cc1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of phenethyl isocyanate (382 mg, 2.6 mmol) in toluene, 2-amino-5-nitrophenol (400 mg, 2.6 mmol) was added. The reaction mixture was stirred at 80° C. for 24 hours, then cooled to room temperature. The product was purified by precipitation from toluene and filtering (650 mg, 83%). m.p: 188.6-189.4° C.; EI-MS m/z 302 (M+H)+.