Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][C:6]([NH:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:7][CH:8]=1.B(Br)(Br)Br.CO>ClCCCl>[OH:2][C:3]1[CH:4]=[N:5][C:6]([NH:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:7][CH:8]=1
Reactant: CCCCCC(=O)Nc1ncc(OC)cn1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCCl
Product: CCCCCC(=O)Nc1ncc(O)cn1
Yield: 58.1 %

Procedure:
N-(5-Methoxypyrimidin-2-yl)hexanamide (17.3 g, 77 mmol) was suspended in 1,2-dichloroethane (170 mL), the suspension was added with boron tribromide (20.5 mL, 216 mmol), and the mixture was refluxed by heating for 30 minutes. The reaction mixture was inactivated with methanol (170 mL) under ice cooling. The reaction mixture was concentrated under reduced pressure, the resulting residue was added with saturated ammonia in methanol (85 mL) under ice cooling, and the mixture was homogenized. The reaction mixture was concentrated under reduced pressure, and the resulting residue was added with water, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was isolated and purified by silica gel column chromatography (hexane:acetone=2:1) to obtain N-(5-hydroxypyrimidin-2-yl)hexanamide (9.36 g, 59%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][O:8][C:9](=[O:41])[CH2:10][C@H:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][C@H:21]3[C:29]4[C:24](=[C:25]([CH2:34][N:35]5[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)[C:26]([C:30]([F:33])([F:32])[F:31])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)=[CH:19][C:14]=2[O:13][CH2:12]1>>[CH3:7][O:8][C:9](=[O:41])[CH2:10][C@H:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][C@H:21]3[C:29]4[C:24](=[C:25]([CH2:34][N:35]5[CH2:36][CH2:37][N:38]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:39][CH2:40]5)[C:26]([C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: CCOC(=O)Cl
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCNCC3)ccc21
Product: CCOC(=O)N1CCN(Cc2c(C(F)(F)F)ccc3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)OC)CC1

Procedure:
The title compound is prepared from ethyl chloroformate and {(S)-6-[(R)-4-piperazin-1-ylmethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Intermediate 27. LC (method 4): tR=1.02 min; Mass spectrum (ESI+): m/z=563 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13](NC1C=CC(C(O)=O)=CN=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[NH2:34][C:35]1[N:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=1>>[Cl:41][C:38]1[N:37]=[N:36][C:35]([NH:34][C:13](=[O:14])[CH2:12][CH2:11][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:33])[N:8]2[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[CH:40][CH:39]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Product: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(Cl)nn1

Procedure:
The product of Example 11, Part D (150 mg, 0.453 mmol) and 3-amino-6-chloropyridazine (57.3 mg, 0.453 mmol) were converted to the title compound in a manner analogous to the method described in Example 27 (112 mg, 18%). 1H NMR (400 MHz, CDCl3) δ 9.71 (s, 1H), 8.45 (d, J=9 Hz, 1H), 7.61 (d, J=8 Hz, 1H); 7.49 (d, J=9 Hz, 1H); 7.39 (m, 1H); 7.30 (m, 2H), 7.17 (t, J=9 Hz, 1H); 7.01 (t, J=8.5 Hz, 2H); 5.29 (d, J=15 Hz, 1H), 4.69 (m, 1H), 4.25 (d, J=15 Hz, 1H), 2.63-2.52 (m, 2H); 2.29-2.17 (m, 2H). MS: m/z (MH+) 443.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].C(N1C=CN=C1)(N1C=CN=C1)=O.C(OC(=O)[NH:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH:52]([NH2:56])[CH2:51]1)(C)(C)C.C(OC(=O)NC1CCCN(C(C2C=CC(C3C=C(Cl)C(CC4CCN(C5CCCCC5)C4=O)=C(Cl)C=3)=CC=2)=O)C1)(C)(C)C.Cl.O1CCOCC1>ClCCl.O1CCOCC1>[NH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH:52]([NH:56][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:4]3[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][CH:9]4[CH2:13][CH2:12][N:11]([CH:14]5[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]5)[C:10]4=[O:20])=[C:6]([Cl:21])[CH:5]=3)=[CH:27][CH:26]=2)=[O:30])[CH2:51]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(N)C1
Reactant: O=C(O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Agent: CC(C)(C)OC(=O)NC1CCCN(C(=O)c2ccc(-c3cc(Cl)c(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)cc2)C1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1CCCC(NC(=O)c2ccc(-c3cc(Cl)c(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)cc2)C1
Temperature: 25 °C

Procedure:
Dissolve racemic 3′, 5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (1.00 eq.) in dichloromethane (5-10 mL) and add 1,1′-carbonyl-diimidazole (1.50 eq.). Stir under argon atmosphere at room temperature and check reaction progress via TLC. Add (3-amino-cyclohexyl)-carbamic acid tert-butyl ester (1.05-2.0 eq.) and continue to stir, checking progress via LC/MS. Once starting material has been fully consumed, dilute reaction with dichloromethane (50 mL) and wash with 1.0 N sodium hydroxide (30 mL) and brine (30 mL). Collect the organic phase, dry over anhydrous magnesium sulfate and concentrate under reduced pressure. Purify via flash chromatography by eluding with gradient of 100% dichloromethane to 10% ammonia methanol/90% dichloromethane to recover {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester. Dissolve the {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester (0.40, 0.65 mmol) in dioxane (20 mL), add 4N hydrochloric acid -dioxane (10 mL) and stir 30 min. Concentrate under vacuum, dilute in dichloromethane (100 mL) and add saturated aqueous sodium bicarbonate (50 mL). Dry the organic phase with magnesium sulfate and concentrate to a foam: MS (m/z): 528 (M+).
Reaction SMILES: [Na].[OH:2][CH:3]([CH3:20])[CH2:4][CH:5]([S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[S:6]([C:9]([F:12])([F:11])[F:10])(=[O:8])=[O:7].[C:21]12([C:31](Cl)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.C(N(CC)CC)C.[Cl-].[C:42]1([S+:48]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O.C(#N)C>[C:55]1([S+:48]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1.[C:21]12([C:31]([O:2][CH:3]([CH3:20])[CH2:4][CH:5]([S:6]([C:9]([F:10])([F:11])[F:12])(=[O:7])=[O:8])[S:13]([C:16]([F:18])([F:19])[F:17])(=[O:15])=[O:14])=[O:32])[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: CC(O)CC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: [Cl-]
Agent: [Na]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(CC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)OC(=O)C12CC3CC(CC(C3)C1)C2
Reaction time: 4 h
Yield: 42.5 %

Procedure:
A glass flask was charged with 10 g (0.028 mol) of 3-hydroxy-1,1-bis(trifluoromethanesulfonyl)butane sodium salt, 16.7 g (0.084 mol) of 1-adamantanecarbonyl chloride, and 50 ml of acetonitrile, followed by stirring. Then, 8.6 g (0.084 mol) of triethylamine was added dropwise. After terminating the dropping, stirring was conducted at 55° C. for 4 hr. Then, the reaction liquid suspended was filtered to remove solid, and the solvent was distilled out of the filtrate by an evaporator. Then, 50 ml of chloroform was added to make a solution, and a 50 ml-water solution of 8.3 g (0.028 mol) of triphenylsulfonium chloride was added dropwise. After terminating the dropping, stirring was continued at room temperature for 1 hr. Then, the organic layer of the reaction liquid was washed three times with 40 ml of water, followed by distilling solvent off with an evaporator. The obtained liquid of a pale brown color was further washed three times with 40 ml of diethyl ether, followed by drying with a vacuum pump, thereby obtaining 9.1 g (yield 50%, purity 95%) of 3-(1-adamantanecarbonyl)oxy-1,1-bis(trifluoromethanesulfonyl)butane triphenylsulfonium salt as a pale brown color liquid.
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1)=[CH2:1].[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)CCl
Reactant: C#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OCC(=O)OC(C)(C)C)cc1
Reaction time: 2 h

Procedure:
A suspension of poly(p-hydroxystyrene) (4.0 g) obtained in the same manner as described in Synthesis Example 7-(2), tert-butyl monochloroacetate (3.0 g) and anhydrous K2CO3 (2.8 g) in acetone (35 ml) was reacted with stirring for 2 hours under reflux. After cooling, the precipitate was filtered off, the filtrate was poured into H2O (1 l) and was precipitated. The precipitate was filtered, washed with H2O and dried under reduced pressure to give 5.2 g of poly(tert-butyl p-vinylphenoxyacetate/p-hydroxystyrene) as white powder having Mw 11000 (GPC with polystyrene calibration). The polymer was found to have tert-butyl p-vinylphenoxyacetate unit and p-hydroxystyrene unit in a molar ratio of ca. 1:1 based on 1HNMR.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1.C(O[C:44](=[O:62])[CH:45]=[C:46]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([Br:61])=[CH:57][CH:56]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[CH:48]=1)CCC>>[Br:61][C:58]1[CH:59]=[C:60]2[C:55](=[CH:56][CH:57]=1)[N:54]=[C:46]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[CH:48]=1)[CH:45]=[C:44]2[OH:62]
Reactant: CCCCOC(=O)C=C(Nc1ccc(Br)cc1)c1cccc(F)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Oc1cc(-c2cccc(F)c2)nc2ccc(Br)cc12
Temperature: 250 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a 3 L three-neck flask, equipped with mechanical stirrer, Claisen adapter holding a thermocouple probe and reflux condenser with nitrogen inlet was added 0.75 L of Dowtherm A (a eutectic mixture of 26.5% diphenyl and 73.5% diphenyl oxide) and the solvent was heated to 250° C. To this was cautiously added in small portions 77.0 grams (0.215 moles) of 3-(4bromo-phenylamino)-3-(3-fluorophenyl)-acrylic acid butyl ester over the course of 0.25 hours. The mixture was maintained at 250° C. for 1.5 hours and then allowed to cool to 90° C. over the course of 2 hours. The mixture was treated with 1.0 L of hexanes, and allowed to cool to room temperature while stirring overnight. The tan solids were collected by suction filtration and washed with three 0.15 L portions of hexanes. The solids were dried under vacuum at 50° C. overnight to yield 58.63 grams (96.0%) of the title compound.
Reaction SMILES: [CH2:1]([Cl:5])[C:2](=[CH2:4])[CH3:3].[S:6]([O-:9])([O-:8])=[O:7].[Na+:10].[Na+]>>[CH2:1]([S:6]([O-:9])(=[O:8])=[O:7])[C:2](=[CH2:4])[CH3:3].[Na+:10].[Cl-:5].[Na+:10]
Reactant: C=C(C)CCl
Reactant: O=S([O-])[O-]
Agent: [Na+]
Product: C=C(C)CS(=O)(=O)[O-]
Product: [Cl-]

Procedure:
In the first synthetic route, isobutene is reacted with chlorine to form the intermediate methallyl chloride. This compound reacts with sulfites to give the target products. For example, the reaction of methallyl chloride with sodium sulfite gives sodium methallylsulfonate and sodium chloride. Disadvantages of this synthesis are that the molar yield of target product is only 85% based on isobutene and inorganic chlorides are formed as coproducts and organic chlorine compounds are formed as by-products.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1.[CH3:21][O-:22].[Na+]>CO.C(OCC)(=O)C>[CH3:21][O:22][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1
Reactant: Fc1ccc(-c2cc(Cl)nc(-c3ccccn3)n2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(-c2ccc(F)cc2)nc(-c2ccccn2)n1
Yield: 77 %

Procedure:
5.5 g (0.02 mol) of 4-chloro-2-(2-pyridyl)-6-(4-fluorophenyl)-pyrimidine are dissolved in 50 ml of dry methanol, 8.6 g of a 22% strength solution of sodium methylate in methanol (corresponds to 0.04 mol) are added, and the mixture is refluxed for 40 hours. After the solvent has been removed, the residue obtained is taken up in ethyl acetate and the mixture is washed twice with water and dried over sodium sulphate. After the solvent has been removed, 4.3 g (77% of theory) of 4-methoxy-2-(2-pyridyl)-6-(4-fluorophenyl)-pyrimidine of melting point 97°-98° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:5]=2[N:6]=1.CO.S(OC)(O[CH3:23])(=O)=O>[OH-].[Na+]>[CH3:23][N:6]1[C:5]2[CH:7]=[C:8]([N+:14]([O-:16])=[O:15])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=[C:2]1[CH3:1]
Reactant: Cc1nc2cc([N+](=O)[O-])c([N+](=O)[O-])cc2[nH]1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2cc([N+](=O)[O-])c([N+](=O)[O-])cc2n1C
Temperature: 92.5 °C

Procedure:
To a solution of 2-methyl-5,6-dinitro-benzimidazole in 5% NaOH was added methanol and dimethyl sulfate. The reaction mixture was heated for 30 min at 90-95° C. and then cooled to room temperature. The precipitate which formed was filtered, washed with 10% NaOH and then water, and dried overnight at 40° C. to yield 1,2-dimethyl-5,6-dinitrobenzimidazole.
Reaction SMILES: FC(F)(F)C([O-])=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][NH2+:21]3)[S:18][CH:19]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[O:42]([CH2:49][C:50](Cl)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][N:21]3[C:50](=[O:51])[CH2:49][O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: Clc1ccc(-c2csc([C@H]3CCCC[NH2+]3)n2)cc1
Reactant: O=C(Cl)COc1ccccc1
Agent: CN(C)c1ccccn1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COc1ccccc1)N1CCCC[C@@H]1c1nc(-c2ccc(Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-[4-(4-chloro-phenyl)-thiazol-2-yl]-piperidinium trifluoroacetate (0.077 g, 0.20 mmol) in dry dichloromethane (2 mL) under argon was treated with triethylamine (0.079 g, 0.11 mL), dimethylaminopyridine (0.002 g, 0.020 mmol) and phenoxyacetyl chloride (0.033 g, 0.20 mmol). The mixture was stirred at room temperature for 16 h. The mixture was washed with water and saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The residual oil was purified by preparative HPLC: Column: YMC-Pack Pro C18 RS, 20×50 mm, S-5 um, 8 nm, No 200504707(W); Gradient: 0-0.4 min: 30% acetonitrile in (water+0.1% HCO2H), 0.4-2 min: increse of acetonitrile fraction from 30% to 95%, 2.4-3.7 min: 95% acetonitrile, 3.7-3.8 min: decrease of acetonitrile fraction from 95% to 30%; Program end at 4 min; Flow: 30 ml/min. 1-{(R)-2-[4-(4-Chloro-phenyl)-thiazol-2-yl]-piperidin-1-yl}-2-phenoxy-ethanone was obtained after lyophilization as a light yellow oil (0.037 g, 46%), MS (ISP): 413.1, 415.4 (M+H)+.. 1H-NMR (CDCl3, 300 MHz): 7.81 (2H, d), 7.38 (3H, m), 7.27 (2H, m), 6.98 (3H, m), 6.11+5.58 (1H, bs), 4.82 (2H, m), 4.56+3.91 (1H, bd), 3.36+2.86 (1H, bt), 2.59 (1H, m), 1.75 (5H, m).
Reaction SMILES: [NH:1]1[CH2:6][C:5](=[O:7])[CH2:4][CH2:3][C:2]1=[O:8].[CH3:9]O.[CH2:11]([OH:13])C>C(O)CO>[CH3:9][O:7][C:5]1([O:13][CH3:11])[CH2:6][NH:1][C:2](=[O:8])[CH2:3][CH2:4]1
Reactant: CCO
Reactant: O=C1CCC(=O)NC1
Reactant: CO
Solvent: OCCO
Product: COC1(OC)CCC(=O)NC1

Procedure:
Piperidine-2,5-dione (A) described in a literature (J. Am. Chem. Soc., 80, 3717 (1958)) is allowed to react with a lower monoalcohol such as methanol or ethanol, or a with a diol such as ethylene glycol in the presence of an acid catalyst or dehydrating agent, and then the product is treated with an orthoester in the presence of an acid catalyst to obtain 5,5-dimethoxy-2-piperidone (B) whose carbonyl group at the 5-position is protected as an acetal. 5,5-Dimethoxy-2-piperidone (B) is subjected to hydrogen/deuterium exchange reaction using a deuterated compound in the presence of a base to obtain 3,3-dideutero-5,5-dimethoxy-2-piperidone (C), and then the resulting product is subjected to acidic hydrolysis to obtain 2,2-dideutero-5-aminolevulinic acid as a corresponding acid salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=1)(=[O:22])=[O:21]
Reactant: OCCOc1cccc(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold mixture of 2-(3-bromophenoxy)ethanol (15) (16.06 g, 74.0 mmol) and triethylamine (9.12 g, 90.13 ml) in anhydrous CH2Cl2 (120 ml) under argon was slowly added neat methanesulfonyl chloride (6 ml, 77.2 mmol) and the reaction mixture stirred at 0° C. for 15 min A precipitate formed after the addition was complete. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc, washed twice with water, once with brine, dried over MgSO4 and concentrated under reduced pressure. 2-(3-Bromophenoxy)ethyl methanesulfonate (16) was isolated as a brown oil and used in the next synthetic step without further purification. Yield (21.32 g, 98%): 1H NMR (400 MHz, CDCl3) δ 7.16 (t, J=7.8 Hz, 1H), 7.11-7.14 (m, 1H), 7.07 (m, 1H), 6.39 (ddd, J=7.6, 2.5, 1.8 Hz, 1H), 4.56 (m, 2H), 4.22 (m, 2H), 3.08 (s, 3H).
Reaction SMILES: CO[CH:3]([O:9]C)[CH2:4][C:5]1([OH:8])[CH2:7][CH2:6]1.C(Cl)Cl.O([Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])S(C(F)(F)F)(=O)=O.FC(F)(F)S(O[Si](CC)(CC)CC)(=O)=O>O>[Si:22]([O:8][C:5]1([CH2:4][CH:3]=[O:9])[CH2:6][CH2:7]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(CC1(O)CC1)OC
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1(CC=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 2.0 L RBF containing 1-(2,2-dimethoxyethyl)cyclopropanol (17.400 g, 119 mmol) was added DCM (550 ml) and the mixture was allowed to stir at 0° C. for 15 min. 2,4,6-Colliding (63.1 ml, 476 mmol) was added and the reaction was allowed to chill for 5 min before the addition of tert-butyldimethylsilyl triflate (27.3 ml, 119 mmol) over 10 min. The reaction was allowed to stir for 20 min and then analyzed by tlc which showed that all of the tertiary alcohol had been protected as its TBS ether. So, triethylsilyl trifluoromethanesulfonate (53.8 ml, 238 mmol) was added via syringe over 10 min. After 20 min, tic showed all of the material was converted to a baseline Rf material (mixed acetal) and then water (300 mL) was added and the reaction was allowed to stir overnight. The layers were separated. The DCM was washed with dilute HCl to remove the 2,4,6-collidine. The aq. layer was back extracted with DCM. The combined organics were washed with sodium bicarbonate, brine, dried with sodium sulfate and filtered though a plug of silica gel. Desired fractions were collected to give the product.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:16][C:17]1[N:22]=[C:21](F)[C:20]([F:24])=[CH:19][N:18]=1.[F-].[Na+]>CN(C=O)C>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19]1[C:20]([F:24])=[CH:21][N:22]=[C:17]([F:16])[N:18]=1)[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1
Reactant: Fc1ncc(F)c(F)n1
Agent: [F-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1nc(F)ncc1F
Temperature: 27 °C
Reaction time: 0.25 h

Procedure:
A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (5 g, 26.7 mmol) in DMF (50 mL) was cooled to −5° C. under N2 atmosphere. Internal temperature was monitored and maintained at ca. −5° C. during the portionwise addition of 60% NaH (1.28 g, 32 mmol) over 5 mins (no appreciable exotherm seen, but effervescence observed and cloudy suspension resulted). Added 2,4,5-trifluoropyrimidine (3.76 g, 28 mmol) dropwise whilst still maintaining the temperature at ca. −5° C. After complete addition the reaction mixture was stirred at this temperature for 15 mins before removing the cooling bath and allowing the rm to warm to room temperature (ca. 27° C. internal temp). Left stirring at room temperature for 6 h. Sampled reaction mixture and quenched with water, extracted into EtOAc; TLC and LCMS show significant product but remaining oxazolidinone sm. Cooled reaction mixture to 0° C. and added an additional portion of trifluoropyrimidine (1.2 g, 8.95 mmol), warmed to room temperature and left stirring for 3 h at rt. Still faint residual sm seen by TLC of sample, but quenched reaction mixture at this point. Workup: [Safety Note: NaF salt present. Do not acidify workup] Quenched the reaction mixture with water (100 mL) which resulted in considerable effervescence. Added EtOAc (75 mL) and separated, extracted the aqueous with EtOAc (2×75 mL), combined the organics, washed with water (100 mL), brine (50 mL), dried (MgSO4) and concentrated to dryness to give crude product as a pale yellow oil. Crude was purified by silica gel chromatography (initial neat DCM, then ramp to 20% EtOAc/DCM). Pure product fractions were combined and concentrated to dryness to give a colourless oil which was placed under high vacuum. Upon standing the oil converted into a white solid. 1H NMR (400 MHz, CDCl3) δ 8.47 (dd, J=3, 1 Hz, 1H); 4.73-4.68 (m, 1H); 4.62-4.52 (m, 2H); 4.34-4.28 (m, 1H); 1.20 (s, 9H); 1.11 (d, 3H). MS m/z 302.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Cl:10]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:10][C:3]1[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1]
Reactant: Cc1cc(O)cc(=O)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Cc1cc(O)c(Cl)c(=O)[nH]1
Temperature: 115 °C
Yield: 60.2 %

Procedure:
4-Hydroxy-6-methyl-1H-pyridin-2-one (25 g, 0.2 mol) and N-chlorosuccinimide (29.4 g, 0.22 mol) were dissolved in 200 mL of acetic acid. The reaction was heated at 115° C. for 6 hours. The reaction was cooled to room temperature, the solid was filtered, and washed with acetic acid and hexanes. The solid was dried in a vacuum oven overnight to give a white solid (19.2 g, 60%): 1H NMR (300 MHz, DMSO-d6) δ 11.46 (br s, 1H), 11.04 (s, 1H), 5.79 (s, 1H), 2.09 (s, 3H).