Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]([CH2:15][CH2:16]CC#N)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.[OH-:23].[Na+].[CH2:25]([OH:27])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]([CH2:15][CH2:16][CH2:26][C:25]([OH:23])=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1
Reactant: [OH-]
Reactant: N#CCCCN(Cc1cccc(Cl)c1)Cc1cccc(Cl)c1
Reactant: CCO
Agent: [Na+]
Product: O=C(O)CCCN(Cc1cccc(Cl)c1)Cc1cccc(Cl)c1

Procedure:
A solution of 4-[N,N-bis-(3-chlorobenzyl)amino]butyronitrile (8.59 g; 0.026 mol), NaOH (10 g; 0.25 mol) and ethanol (125 ml) was stirred and heated to reflux for 18 hours. After cooling the solvent was evaporated in vacuo and the solid residue taken up in water (75 ml). After further cooling in ice, conc. HCl was added until the mixture was strongly acid (ca. 25 ml required). The initially precipitated oil hardened to a solid, which was collected by filtration and recrystallised from dimethylformamide-ether and then from 10% v/v water-isopropanol followed by dilution with ether. After drying at 45° C./1 mm the hydrochloride hemihydrate salt of the title compound was obtained (5.60 g). m.p. 170°-173° (dec.; softens above 166°).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:30]=O.[CH3:36][O:37][C:38]1[CH:48]=[CH:47][C:41]([CH2:42][S:43][C:44](=[NH:46])[NH2:45])=[CH:40][CH:39]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]2[C:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:14])=[C:11]([CH2:10][O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[NH:46][C:44]([S:43][CH2:42][C:41]3[CH:47]=[CH:48][C:38]([O:37][CH3:36])=[CH:39][CH:40]=3)=[N:45]2)[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(CSC(=N)N)cc1
Reactant: O=C(COCCN1CCCCC1)CC(=O)OCCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSC2=NC(c3ccc(Cl)c(Cl)c3)C(C(=O)OCCCc3ccccc3)=C(COCCN3CCCCC3)N2)cc1
Temperature: 50 °C
Yield: 25.4 %

Procedure:
A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (1.0 g, 2.88 mmol), 3,4-dichlorobenzaldehyde (0.60 g, 3.45 mmol), 2-(4-methoxybenzyl)isothiourea (0.80 g, 3.45 mmol) and sodium hydrogen carbonate (0.29 g, 3.45 mmol) was stirred in N,N-dimethylformamide (10 mL) for 6 days at room temperature, then heated to 50° C. for 7 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. This oil was further purified by flash chromatography to give the title compound (0.50 g) as an oil. The oil can be converted into a mono or dihydrochloride salt, by dissolution in ether and addition of one or two equivalents of hydrogen chloride. Electrospray MSm /z 682/684 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][C:4]([CH:6]([CH2:16][CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:5].ClC([O-])=O>C(Cl)(Cl)Cl>[C:4]([CH:6]([CH2:16][CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:5])[CH:3]=[CH2:2]
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(=O)CCO
Agent: O=C([O-])Cl
Solvent: ClC(Cl)Cl
Product: C=CC(=O)C(CCCCCCC(=O)O)CCCC(O)CCCCC
Reaction time: 24 h

Procedure:
A solution of 8-(3-hydroxypropionyl)-12-hydroxyheptadecanoic acid · 1/3 chloroformate (Example 8, Step G) (3.58 g., 0.01 mole) in chloroform (5 ml.) is applied to a silica gel column (100 g., E. Merck, Darmstadt, 0.05--0.2 mm.). The column is allowed to stand at 25° for 24 hours, then eluted with chloroform-methanol (98:2) to slowly elute the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][N:6]=1.[NH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14]>>[OH:14][CH2:13][C:12]([NH:11][S:7]([C:4]1[S:3][C:2]([Cl:1])=[N:6][CH:5]=1)(=[O:9])=[O:8])([CH3:16])[CH3:15]
Reactant: CC(C)(N)CO
Reactant: O=S(=O)(Cl)c1cnc(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Yield: 67.7 %

Procedure:
Prepared by general procedure III from 2-chloro-thiazole-5-sulfonyl chloride (2.0 g, 9 mmol, example B.13, step 1) and 2-amino-2-methyl-1-propanol (0.95 g, 9 mmol) to give the title compound (1.65 g, 33%) as an off-white solid. MS (EI) 269.2[(M)+] and 271.2[(M+2)+].
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][OH:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C>[C:1]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][O:15][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h
Yield: 49.2 %

Procedure:
To N-Boc-(2S,4R)-4-hydroxy-2-hydroxymethylpyrrolidine (0.199 g, 0.92 mmol) in DMF (2 ml) was added imidazole (0.125 g) and t-butyldimethylsilyl chloride (0.14 g). After 1.5 h, the reaction was concentrated by evaporation under reduced pressure, and the residue dissolved in diethyl ether, washed with water and brine, dried and evaporated. Purification by chromatography on silica gel eluting with 0-30% ethyl acetate in hexane gave the title material, (0.15 g, 49%). NMR (CDCl3) 0.02 (s, 3H), 0.03 (s, 3H), 0.9 (s, 9H), 1.45 (s, 9H), 1.9 (bm, 9H), 2.2 (bm, 1H), 3.3-4.0 (bm, 5H), 4.5 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.C[O-].[Na+].CO.Br[CH2:19][CH:20]1[O:24][CH2:23][CH2:22][O:21]1.[C:25](OCC)(=[O:27])C>CN(C)C=O.[Cu]Br.O>[O:21]1[CH2:22][CH2:23][O:24][CH:20]1[CH2:19][N:9]1[C:8](=[O:10])[CH:7]=[N:6][C:5]2[N:11]=[CH:12][C:2]([O:27][CH3:25])=[CH:3][C:4]1=2
Reactant: BrCC1OCCO1
Reactant: CCOC(C)=O
Reactant: O=c1cnc2ncc(Br)cc2[nH]1
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc2ncc(=O)n(CC3OCCO3)c2c1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To a suspension of 4.0 g of 7-bromopyrido(2,3-b)pyrazin-2(1H)-one in 40 mL of N,N-dimethylformamide, 8.2 g of a 28% sodium methoxide/methanol solution and 0.25 g of copper (I) bromide were added at room temperature, and the mixture was stirred at 80 to 90° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to 55° C., thereto was added 2.8 mL of 2-bromomethyl-1,3-dioxolan, and the mixture was stirred at 80 to 90° C. for 1 hour 30 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and then left overnight. The mixture was further stirred at 80 to 90° C. for 1 hour, and then stirred at 90 to 100° C. for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added thereto. The insoluble substance was filtered off, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=100:0 to 95:5, ethyl acetate was added to the orange oily substance thus obtained, and the solid was filtered off to obtain 0.12 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxypyrido(2,3-b)pyrazin-2(1H)-one as an orange solid.
Reaction SMILES: [OH:1][N:2]1[C@@H:5]([CH3:6])[C@H:4]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:3]1=[O:15].Br[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(N(CC)CC)C>CN(C)C=O>[C:11]([O:10][C:8]([NH:7][C@H:4]1[C@H:5]([CH3:6])[N:2]([O:1][CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C:3]1=[O:15])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Reactant: O=C(CBr)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
(3S-trans)-1-Hydroxy-3-[(t-butyloxycarbonyl)-amino]-4-methyl-2-azetidinone (21.6g) was dissolved in 300ml of dimethylformamide, 25.2g of bromoacetic acid. phenylmethyl ester was added. 17 ml of triethylamine was added. and the mixture was stirred for 3 hours at room temperature. The resulting precipitate was filtered off. The filtrate evaporated in vacuo, the residue dissolved in ethyl acetate and the solution treated with water, the pH of which was adjusted to 7. The organic phase was washed twice with water, dried (MgSO4) and evaporated to yield 33.4g of the title compound as an oil.
Reaction SMILES: C(OC(=O)C([O:8][C:9]1[CH:30]=[C:29]2[C:12]([N:13]=[CH:14][CH:15]=[C:16]2[CH:17]([OH:28])[C@@H:18]2[N:23]3[CH2:24][CH2:25][C@H:20]([C@@H:21]([CH:26]=[CH2:27])[CH2:22]3)[CH2:19]2)=[CH:11][CH:10]=1)CC)C.Br[CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[OH:28][C@@H:17]([C:16]1[C:29]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH:30]=2)[N:13]=[CH:14][CH:15]=1)[C@@H:18]1[N:23]2[CH2:24][CH2:25][C@H:20]([C@@H:21]([CH:26]=[CH2:27])[CH2:22]2)[CH2:19]1
Reactant: CCOC(=O)CCCBr
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@@H]2C(O)c1ccnc2ccc(OC(CC)C(=O)OCC)cc12
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccc(OCCCC(=O)O)cc12

Procedure:
The first step in the synthesis of the tracer of the present invention, as for the hapten, is the alkylation of 6-hydroxyquinidine using preferably one or less molar equivalent of alkylating reagent. The first step is the alkylation of 6-hydroxyquinidine(1) to (9S)-4-[(9-Hydroxycinchonan-6'-yl) oxybutanoic acid ethyl ester (5) using one molar equivalent of ethyl 4-bromobutyrate, most preferably using 0.9 molar equivalent of ethyl 4-bromobutyrate. The alkylated product (5) is hydrolyzed to obtain the corresponding acid (9S)-4-[9-Hydroxycinchonan-6'-yl)oxybutanoic acid (6). The acid is activated to form N-hydroxysuccinimide using a method well-known in the literature. This activated ester is coupled with 5-aminomethylfluorescein in the presence of pyridine to give the quinidine tracer (9S)-N-[(3',6'-dihydroxy-3-oxospiro[isobenzofuran-1(3H),9'-[9H]xanthen]-5yl) methyl]-4-[(9-hydroxycinchonan-6'-yl)oxy]butamide (7).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([S:13]C#N)=[CH:11][CH:10]=[C:9]2[CH:16]=[O:17])=[N:4][CH:5]=[CH:6][CH:7]=1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([SH:13])=[CH:11][CH:10]=[C:9]2[CH:16]=[O:17])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CSc1ccc(C=O)n1-c1ncccc1Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccc(S)n1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A mixture of 0.70 g of 1-(3-chloro-2-pyridinyl)-5-thiocyanato-1H-pyrrole-2-carbaldehyde, 0.64 g of sodium sulfide nonahydrate and 10 ml of water was stirred for 1 hour under heat refluxing. The reaction mixture was allowed to cool to room temperature, adjusted to pH 5 by an addition of acetic acid, and then extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with methyl tert-butyl ether to obtain 0.50 g of 1-(3-chloro-2-pyridinyl)-5-mercapto-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]([O:28][CH2:29][O:30][CH3:31])[CH2:14][N:15]1[C:20](=[O:21])[CH:19]=[N:18][C:17]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[N:25][C:16]1=2.C(N(CC)CC)C>ClCCl>[CH3:31][O:30][CH2:29][O:28][CH:13]([CH2:14][N:15]1[C:20](=[O:21])[CH:19]=[N:18][C:17]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[N:25][C:16]1=2)[CH:12]=[O:11]
Reactant: COCOC(CO)Cn1c(=O)cnc2ccc(OC)nc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCOC(C=O)Cn1c(=O)cnc2ccc(OC)nc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.022 ml, 0.260 mmol) was dissolved in dichloromethane (1 ml), a solution of dimethyl sulfoxide (0.037 ml, 0.521 mmol) in dichloromethane (0.5 ml) was added to the solution at −78° C. and mixed for 30 minutes. While maintaining at −78° C., a solution of 4-[3-hydroxy-2-(methoxymethoxy)propyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (64 mg, 0.217 mmol) in dichloromethane (3 ml) was added to the reaction solution and the mixture was stirred for 1 hour. While maintaining the temperature at −78° C., triethylamine (0.181 ml, 1.302 mmol) was added to the reaction solution and the mixture was stirred for 30 minutes. The temperature was raised to 0° C., the reaction solution was stirred for 1 hour, then diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 67 mg (quantitative) of the title compound in the form of a yellow-orange oily product. The product was used as such for next reaction without purification.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:27])[CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:17][CH2:16]1.[C@H:28]1([NH:37][C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH2:48])[CH:44]=3)[N:39]=2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1>>[C@H:28]1([NH:37][C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH:48][C:1]([NH:14][CH:15]4[CH2:16][CH2:17][N:18]([C:21](=[O:27])[CH2:22][C:23]([F:24])([F:25])[F:26])[CH2:19][CH2:20]4)=[O:12])[CH:44]=3)[N:39]=2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: NC1CCN(C(=O)CC(F)(F)F)CC1
Agent: Cl
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCN(C(=O)CC(F)(F)F)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-(4-amino-piperidin-1-yl)-3,3,3-trifluoro-propan-1-one hydrochloride and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=512.6 (M+H+).
Reaction SMILES: [Cr:1]([O-])([O-])(=O)=O.[Na+:6].[Na+].[S:8]([O-:12])([OH:11])(=[O:10])=[O:9].[Na+].C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.C=O>>[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[Cr+3:1].[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[Cr+3:1].[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[Na+:6].[Na+:6]
Reactant: O=[Cr](=O)([O-])[O-]
Reactant: O=S(=O)([O-])O
Agent: C=O
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Product: O=S(=O)([O-])[O-]
Product: [Cr+3]

Procedure:
A process, as claimed in claim 1, wherein sodium hydrogen sulfate is added to the extractive liquor, to obtain a Ph value of 6-7, and the neutral sodium chromate solution is acidified with sodium hydrogen sulfate again; and further, sucrose or formaldehyde is added, followed by heating to above 100° C., to form chromium sulfate and sodium sulfate, which, after completion of reaction, are cooled to 21°-24 C., and separated, to obtain sodium sulfate decahydrate crystals and chromium sulfate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Br:15])=[CH:13][CH:14]=1)[CH3:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Reactant: CI
Solvent: CN(C)C=O
Product: CN(Cc1ccc(Br)cc1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
In a 60-mL vial, tert-butyl-4-bromobenzylcarbamate (1.25 g, 4.37 mmol) was dissolved in DMF (12 mL). To this solution was added Ag2O (4.0 g, 17 mmol) followed by the addition of CH3I (0.68 mL, 11 mmol). The mixture was stirred at 50° C. for 18 hours. The reaction mixture was filtered through a bed of celite and the celite was washed with methanol (2×20 mL) and dichloromethane (2×20 mL). The filtrate was concentrated to remove most of the DMF. The residue was treated with water (50 mL) and a white emulsion formed. This mixture was extracted with ethyl acetate (4×25 mL), dried over Na2SO4, and the solvent was evaporated to yield tert-butyl-4-bromobenzyl(methyl)carbamate (1.3 g, 98%) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.53 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 4.32 (s, 2H), 2.74 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].[Br:19]Br>C(O)(=O)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH:2]([Br:19])[CH3:1])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
Scheme X depicts the bromination of 4-benzyloxypropiophenone in acetic acid with bromine to yield 4′-(benzyloxy)-2-bromopropiophenone. When this reaction is complete, the mixture can be quenched with water. The resulting precipitate can be collected, washed with dilute acetic acid, water and heptane, and dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2C)[CH2:4][O:3]1.[Cl:22]C1C=C(C=C(C)C=1O)C#N>>[Cl:22][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:19])[C:9]=1[O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:21])([CH3:1])[O:6]1)[C:13]([NH:15][OH:16])=[NH:14]
Reactant: Cc1cc(C#N)cc(Cl)c1O
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Product: Cc1cc(C(=N)NO)cc(Cl)c1OC[C@@H]1COC(C)(C)O1

Procedure:
The title compound is obtained as a colorless oil (1.39 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 3-chloro-4-hydroxy-5-methyl-benzonitrile and L-α,β-isopropyliden glycerol; LC-MS: tR=0.66 min, [M+H]+=314.96.
Reaction SMILES: [CH2:1]([C@:4]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH2:9][CH2:10][CH2:11][CH2:12][B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1)[C:5]([O:7][CH3:8])=[O:6])[CH:2]=C.[O:30]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:26]([O:25][C:23]([NH:22][C@@:4]([CH2:1][CH:2]=[O:30])([CH2:9][CH2:10][CH2:11][CH2:12][B:13]1[O:14][C:15]([CH3:20])([CH3:21])[C:16]([CH3:18])([CH3:19])[O:17]1)[C:5]([O:7][CH3:8])=[O:6])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: C=CC[C@@](CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@](CC=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 67 %

Procedure:
A solution of (R)-methyl 2-allyl-2-(tert-butoxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (1.90 g, 4.62 mmol) in dichloromethane (90 mL, 0.05 M) was cooled to −78° C. and treated with ozone until a pale blue-gray color appeared. After TLC indicated the absence of starting material, the ozone inlet tube was replaced with nitrogen and nitrogen was bubbled through the solution for 20 min to remove any excess ozone. Triphenylphosphine (3.6 g, 13.8 mmol, 3 equiv) was added in one portion, the cooling bath was removed and the mixture was stirred for 4 h. The solution was concentrated and purified by MPLC (1-50% ethyl acetate in heptane over 6 CV) gave (R)-methyl 2-(tert-butoxycarbonylamino)-2-(2-oxoethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a colorless oil (1.28 g, 67%). Rf 0.55 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 9.66 (s, 1H), 5.62 (br s, 1H), 3.75 (s, 3H), 3.60 (br d, J=17.4 Hz, 1H), 2.95 (d, J=17.4 Hz, 1H), 2.30-2.15 (m, 1H), 1.70-1.54 (m, 1H), 1.40 (s, 9H), 1.39-1.24 (m, 4H), 0.74 (t, J=7.8 Hz, 2H); ESI-LCMS m/z calcd for C20H36BNO7: expected 413.3. found 414.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1I)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]([CH3:22])([CH3:21])[C:19]#[CH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1.O.[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>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[C:20]#[C:19][C:18]([CH3:22])([CH3:21])[CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C#Cc1cc(Cl)ncc1NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a deoxygenated solution of (6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (23.3 g, 65.6 mmol), 3,3-dimethyl-but-1-yne (53.8 g, 0.656 mol), CuI (623 mg, 3.3 mmol) and triethylamine (13.3 g, 0.13 mol) in toluene (150 mL) and water (50 mL) was added Pd(PPh3)2Cl2 (2.30 g, 3.28 mmol) under N2. The mixture was heated at 70° C. and stirred for 24 hours. The solid was filtered off and washed with ethyl acetate (200 mL×3). The filtrate was evaporated under reduced pressure to obtain a residue, which was purified by column (petroleum ether/ethyl acetate=10/1) to give [6-chloro-4-(3,3-dimethyl-but-1-ynyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (15.8 g, 78%). 1H NMR (300 MHz, CDCl3) δ 9.10 (br s, 1H), 7.21 (s, 1H), 6.98 (br s, 1H), 1.53 (s, 9H), 1.36 (s, 9H).
Reaction SMILES: Cl.Cl.[OH:3][CH:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C@@H:8]1[CH2:21][C:22]([O:24]C)=[O:23].[OH-].[Na+].C(Cl)(Cl)Cl>O1CCOCC1.C(OCC)C>[OH:3][CH:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C@@H:8]1[CH2:21][C:22]([OH:24])=[O:23]
Reactant: COC(=O)C[C@H]1CN(CCSC2CCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CCSC4CCCC4)C[C@@H]3CC(=O)O)c2c1
Temperature: 65 °C
Reaction time: 6 h
Yield: 99.4 %

Procedure:
A solution of 1.6 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetate dihydrochloride in 30 cm3 of dioxane, to which had been added 2.6 cm3 of 5N aqueous sodium hydroxide solution, was stirred for 6 hours at a temperature in the region of 65° C. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 40° C., a residue was obtained, which residue was taken up in 2 times 30 cm3 of chloroform and which was concentrated as under the above conditions. The residue was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm; diameter 3 cm; silica volume 100 cm3), elution was carried out with a chloroform/methanol/28% aqueous ammonia (12/3/0.5 by volume) mixture, and 30-cm3 fractions were collected. The fractions comprising the expected product were combined and concentrated as above. 1.5 g of a colorless lacquer were obtained, which product was taken up in 20 cm3 of diethyl ether, filtered, and washed with 2 times 10 cm3 of diethyl ether. The product was dried under partial pressure (5 kPa) and then to constant weight in an oven under reduced pressure (10 Pa) at a temperature in the region of 40° C. 1.35 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetic acid were obtained in the form of a white solid.