Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[CH2:14]([O:21][C:22](N1C=CC=CC1=O)=[O:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O.C1COCC1>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:22]([O:21][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:23])[C:6]([OH:8])=[O:7]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: CCCCCCCOC(=O)n1ccccc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCOC(=O)N[C@@H](C(=O)O)[C@H](C)O
Reaction time: 15 h
Yield: 91.8 %

Procedure:
To a stirred mixture of D-threonine (0.15 g, 1.25 mmol) and NaHCO3 (0.158 g, 1.89 mmol) in H2O (3.5 mL), the crude mixture containing heptyl-2-pyridyl-carbonate and heptyl-2-oxopyridine-1-carboxylate (0.45 g, 1.89 mmol) in THF (3.5 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.3 g, 91%) as transparent oil, which was used in the next step without further purification. 1H NMR (DMSO-d6) δ 0.86 (t, J=6.8 Hz, 3H), 1.08 (d, J=6.4 Hz, 3H), 1.18-1.36 (m, 8H), 1.46-1.61 (m, 2H), 3.87-4.01 (m, 3H), 4.01-4.14 (m, 1H), 6.67 (d, J=9.0 Hz, 1H) 12.20 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]1[O:8][C:9]2[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=2)[N:11]=1.[ClH:19].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:43][CH:44]1[CH2:51][CH:50]2[N:52]([CH3:53])[CH:46]([CH2:47][CH2:48][CH2:49]2)[CH2:45]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[ClH:19].[CH3:53][N:52]1[CH:46]2[CH2:47][CH2:48][CH2:49][CH:50]1[CH2:51][CH:44]([NH:43][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:6]4[S:5][CH:4]=[N:3][C:2]=4[CH3:1])=[N:11][C:10]=13)=[O:18])[CH2:45]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: Cc1ncsc1-c1nc2c(C(=O)O)cccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ncsc1-c1nc2c(C(=O)NC3CC4CCCC(C3)N4C)cccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
A mixture of 2-(4-methylthiazol-5-yl)benzoxazole-4-carboxylic acid (60 mg, 0.23 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (88 mg, 0.46 mmol), 1-hydroxybenzotriazole (62 mg, 0.46 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (65 mg, 0.29 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.29 mL, 2.11 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×100 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford the desired product (57 mg, 63%) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.92 (br s, 1H), 8.90 (s, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 7.69 (dd, J=8.1, 1.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 4.70-4.57 (m, 1H), 3.25-3.10 (m, 2H), 3.10 (s, 3H), 2.75-2.60 (m, 2H), 2.57 (s, 3H), 2.15-1.95 (m, 3H), 1.65-1.45 (m, 3H), 1.25-1.10 (m, 2H); MS (ESI+) m/z 397 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].O[C@H:13]1[CH2:17][CH2:16][O:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:13]1[CH2:17][CH2:16][O:15][CH2:14]1)[N:6]=[C:5]2[I:11]
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: O[C@H]1CCOC1
Product: Fc1ccc2c(c1)c(I)nn2[C@@H]1CCOC1
Yield: 56 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and (S)-3-hydroxytetrahydrofuran in 56% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 2.47-2.52 (2H, m), 3.95-4.00 (1H, m), 4.12-4.19 (2H, m), 4.19-4.28 (1H, m), 5.24-5.30 (1H, m), 7.12 (1H, dd, J=2.0, 8.4 Hz), 7.21 (1H, td, J=1.6, 8.8 Hz), 7.45 (1H, dd, J=4.0, 9.2 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15](=[CH:28][N:29](C)C)[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=O)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([NH:39]C1C=C(C(=CN(C)C)C(C2C=CC(F)=CC=2)=O)C=CN=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[N:39][NH:29][CH:28]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: CN(C)C=C(C(=O)c1cccc(C(F)(F)F)c1)c1ccnc(NC(=O)OC(C)(C)C)c1
Product: CC(C)(C)OC(=O)Nc1cc(-c2c[nH]nc2-c2cccc(C(F)(F)F)c2)ccn1
Yield: 96 %

Procedure:
The reaction was carried out in the same manner as in Example 2-2) except for using 8.71 g (20.0 mmol) of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(3-trifluoromethylphenyl)-2-propen-1-one obtained in Example 25-1) in place of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(4-fluorophenyl)-2-propen-1-one to obtain 7.76 g of the title compound as a white powder. (Yield: 96%)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.O(CCCO)[C:28]1C=CC=CC=1>>[C:6]1([CH2:7][CH2:8][CH2:9][O:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:5]=[CH:4][CH:3]=[CH:2][CH:28]=1
Reactant: OCCCCCCCCBr
Reactant: OCCCOc1ccccc1
Reactant: BrCCCCCCCCOC1CCCCO1
Product: c1ccc(CCCOCCCCCCCCOC2CCCCO2)cc1

Procedure:
The title compound, m/e=405.7 ([M−H]−), was produced in analogy with example 54, steps 1 to 6. Thus, 8-bromo-1-octanol was protected in step 1, leading to 2-(8-bromo-octyloxy)-tetrahydro-pyran, which was reacted in step 2 with 3-phenoxypropanol, affording 2-(8-(3-phenyl-propoxy)-octyloxy)-tetrahydro-pyran, which after deprotection in step 3 gave 8-(3-phenyl-propoxy)-octan-1-ol. This was oxidized in step 4 to 8-(3-phenyl-propoxy)-octanoic acid, which was coupled in step 5 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride, leading to (R)-4-dimethylamino-3-[8-(3-phenyl-propoxy)-octanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 6.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][OH:10])=[C:5]([Cl:11])[C:4]([Cl:12])=[N:3]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][O:10][S:14]([CH3:13])(=[O:16])=[O:15])=[C:5]([Cl:11])[C:4]([Cl:12])=[N:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc(Cl)c(Cl)c1SCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc(Cl)c(Cl)c1SCCOS(C)(=O)=O
Yield: 76 %

Procedure:
A solution of 5 g (0.022 moles) 1-methyl-3,4-dichloro-5-(2-hydroxyethylthio)pyrazole and 2.52 g (0.022 moles) methane sulfonyl chloride in 100 ml methylene chloride was stirred at room temperature for two days. To that mixture, 2.4 g (3.3 ml) triethylamine was added. The reaction mixture was then stirred over the weekend. The mixture was filtered and the filtrate was washed with water, then dried over magnesium sulfate, and then cooled with dry ice. Stripping of the solvent, followed by chromatography on silica gel, eluting with 5% ethyl acetate/methylene chloride gave 5.1 g of the product as a viscous yellow oil.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:23]#[C:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.C(O)C.O>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:23]#[C:24][CH2:25][N:26]([CH3:27])[CH3:28])[C:13]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(C#CCN(C)C)cccc2c1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1cc2c(C#CCN(C)C)cccc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Temperature: 50 °C
Yield: 19.9 %

Procedure:
To a solution of ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-5-(3-(dimethylamino)prop-1-ynyl)-3-methylnaphthalen-2-yl)acetate (6.5 mg, 0.013 mmol) in tetrahydrofuran:ethanol:water (2:2:1, 4 mL) was added lithium hydroxide (2 mg, 0.066 mmol) and the reaction was heated to 50° C. overnight. The reaction was purified by reverse phase HPLC (Gemini, 40-60% ACN/H2O+0.1% TFA). The product was lyophilized to give a white powder (1.2 mg). 1H-NMR: 400 MHz, (CD3OD) δ: 8.14 (s, 1H), 7.74 (d, J=6.4 Hz, 1H), 7.58 (s, 2H), 7.56 (as, 1H), 7.33 (m, 3H), 5.18 (s, 1H), 4.42 (s, 2H), 3.04 (s, 6H), 2.67 (s, 3H), 0.99 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H31ClNO3: 464.19; found: 464.51.
Reaction SMILES: C=CC1C=CC=CC=1.[N+](=CC(OCC)=O)=[N-].[C:17]1([C@@H:23]2[CH2:25][C@H:24]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)CCC(C(C)C)C(O)C1.C1([C@@H]2C[C@H]2C([O-])=O)C=CC=CC=1>ClCCl>[C:17]1([CH:23]2[CH2:25][CH:24]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccccc1
Agent: CC1CCC(C(C)C)C(O)C1
Agent: CCOC(=O)C=[N+]=[N-]
Agent: O=C([O-])[C@@H]1C[C@H]1c1ccccc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1ccccc1

Procedure:
To a mixture of styrene (2.15 g, 20.7 mmol) and Rh2 (4S-BNOX)4 (0.0113 g, 0.0131 mmol) in 5.0 mL of anhydrous dichloromethane was added, by syringe at room temperature, ethyl diazoacetate (0298 g, 2.62 mmol) in 3.0 mL of dichloromethane under nitrogen and at an addition rate of 0.8 mL/h (syringe pump). After addition was complete, the dichloromethane solution was passed through a plug of neutral alumina to separate the catalyst, and solvent and excess styrene were removed under reduced pressure. Gas chromatographic separation of the trans-isomer produced a material whose specific rotation was -6.4° which corresponded to an enantiomeric excess of the ethyl (1R,2R)-2-phenylcyclopropanecarboxylate. Conversion of the ethyl esters to the 1-menthyl esters by base hydrolysis, acid chloride formation, and esterification with (-)-menthol provided a gas chromatographically separable mixture that showed 25% enantiomeric excess for the (1R,2R)-enantiomer of the trans-2-phenylcyclopropanecarboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:8][C:4]1[N:3]=[C:2]([N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CCCCNCCCC
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1cccc(Br)n1
Temperature: 90 °C
Yield: 43 %

Procedure:
To a solution of 2,6-dibromopyridine (Aldrich, 1.42 g, 6.00 mmol) in DMF (2.0 mL) were added dibutylamine (Aldrich, 388 g, 3.00 mmol) and potassium carbonate (829 mg, 6.00 mmol). The reaction mixture was heated at 90° C. for 20 h. After cooling to room temperature, the reaction mixture was quenched by adding cold water. The mixture was extracted with DCM (3×), and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give a crude oil. Purification using flash column chromatography (eluting with DCM) provided the title compound (368 mg, 43%) as a light brown oil. 1H NMR (CDCl3) δ 0.22 (dd, J=8.4, 7.4 Hz, 1H), 6.62 (d, J=7.0 Hz, 1H), 6.33 (d, J=8.3 Hz, 1H), 3.49-3.37 (m, 4H), 1.65-1.52 (m, 4H), 1.44-1.30 (m, 4H), 0.98 (t, J=7.3 Hz, 6H); MS(ESI+) m/z 272.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]([C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)#[N:16].[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:20]3[CH2:21][CH2:22][C:17]([C:15]#[N:16])([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CC1(c2ccccc2)CCN(C[C@H](O)COc2cccc3[nH]ccc23)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-cyano-4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 57% overall yield. FDMS m/e=375 (M+ of free base). α[D]589 =-12.76 (c=0.48, methanol).
Reaction SMILES: [C:1]1([Li])C=CC=CC=1.[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:29]([O:31][C:32](=[O:54])[C:33]([CH3:53])([CH3:52])[CH2:34][CH2:35][CH2:36][CH2:37][C:38](=O)[CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:50])([CH3:49])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:30]>C1COCC1>[CH2:29]([O:31][C:32](=[O:54])[C:33]([CH3:53])([CH3:52])[CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[CH2:1])[CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:50])([CH3:49])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:30]
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC(C)(C)C(=O)OCC
Reactant: [Li]c1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Product: C=C(CCCCC(C)(C)C(=O)OCC)CCCCC(C)(C)C(=O)OCC
Temperature: 50 °C
Reaction time: 5 h
Yield: 46.7 %

Procedure:
Under nitrogen atmosphere, a solution of phenyllithium (in diethyl ether:cyclohexane=30:70, 7.06 mL, 1.8 M, 12.7 mmol) was added dropwise over 10 min to a solution of methyltriphenylphosphonium iodide (5.52 g, 13.3 mmol) in anhydrous THF (40 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min, before 2,2,12,12-tetramethyl-7-oxo-tridecanedioic acid diethyl ester (4.5 g, 12.2 mmol) was added and the reaction mixture was stirred for 5 h at 50° C. The resulting light-orange mixture was quenched by adding methanol (0.3 mL), and most of the solvent was removed on a rotary evaporator. The residue was purified by chromatography on silica (hexanes:ethyl acetate=95:5) to furnish the product (2.1 g, 47%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.67 (s, 2 H), 4.10 (q, 4 H, J=7.3 Hz), 1.97 (t, 4 H, J=7.6 Hz), 1.6-1.3 (m, 8 H), 1.30-1.15 (m, 10 H), 1.15 (s, 12 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 178.0, 149.6, 108.6, 60.1, 42.1, 40.6, 35.8, 28.2, 25.1, 24.7, 14.2. HRMS (LSIMS, nba): Calcd. for C22H41O4 (MH+): 369.3004, found 369.3009.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][S:10][C:11](=[O:13])[CH3:12])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15].[NH2:25]/[C:26](/[CH3:35])=[CH:27]\[C:28]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[O:29].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[C:11]([S:10][CH2:9][CH2:8][O:7][C:1]([C:2]1[CH:20]([C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=2)[C:27]([C:28]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[O:29])=[C:26]([CH3:35])[NH:25][C:3]=1[CH3:5])=[O:6])(=[O:13])[CH3:12]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCSC(C)=O
Reactant: COCCOC(=O)/C=C(/C)N
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCSC(C)=O)C1c1cccc([N+](=O)[O-])c1
Yield: 34.4 %

Procedure:
A solution of 2.04 g of 2-acetylthioethyl acetoacetate, 1.51 g of 3-nitrobenzaldehyde, 1.49 g of methoxyethyl 3-aminocrotonate and 0.15 g of piperidinium acetate in 20 ml of 2-propanol was refluxed for 4 hours. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel column chromatography [eluent: ethyl acetate - hexane (1 : 3)]to give 1.54 g of the title compound. m.p. 136-138° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][N:23]3[CH:26]=[CH:27][N:28]=[C:22]3[CH:21]=2)O1>>[N:28]1[CH:27]=[CH:26][N:23]2[CH:24]=[CH:25][C:20]([C:2]3[N:7]=[C:6]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][CH:3]=3)=[CH:21][C:22]=12
Reactant: CC(=O)Cc1cccc(Cl)n1
Reactant: CC1(C)OB(c2ccn3ccnc3c2)OC1(C)C
Product: CC(=O)Cc1cccc(-c2ccn3ccnc3c2)n1

Procedure:
Prepare from 1-(6-chloro-pyridin-2-yl)-propan-2-one and 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazo[1,2-a]pyridine using conditions similar to Preparation 21 step A. MS(ES), m/z 170 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18]Br)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[CH2:23]([N:25]([CH2:29][CH3:30])[C:26](=[S:28])[S-:27])[CH3:24].[Na+]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][S:28][C:26]([N:25]([CH2:29][CH3:30])[CH2:23][CH3:24])=[S:27])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCNC(=O)OCc1ccccc1)NCCBr
Reactant: CCN(CC)C(=S)[S-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCN(CC)C(=S)SCCNC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89.2 %

Procedure:
To the solution of 3-(benzyloxycarbonylamino)-N-(2-bromoethyl)propionamide (10 g) in acetone (250 ml), sodium diethyldithiocarbamate trihydrate (6.8 g) in acetone (150 ml) is added and the mixture is stirred for 40 minutes at room temperature. The reaction mixture is filterd and the filtrate is concentrated in vacuo. The residue is dissolved in ethyl acetate (150 ml) and the solution is washed with N hydrochloric acid, N sodium hydroxide, water and saturated sodium chloride solution in the named order. The ethyl acetate solution is dried over anhydrous magnesium sulfate and concentrated in vacuo to give 10.7 g (89%) of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][N:16]1[CH:20]=[CH:19][NH:18][C:17]1=[O:21]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:18]1[CH:19]=[CH:20][N:16]([CH3:15])[C:17]1=[O:21])[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: Cn1cc[nH]c1=O
Product: C[C@@H](n1ccn(C)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 17.2 %

Procedure:
In the same manner as in Reference Example 5, starting from 423 mg of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2oxiranyl]ethanol and 207 mg of 1-methyl-2(1H,3H)-imidazolone prepared by a method described in Journal of American Chemical Society vol. 98, page 8218 (1976), 102 mg of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-methyl-2(1H,3H)-imidazolone was obtained as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:6]([Br:18])[CH:5]=1.[OH-].[Na+].Cl>CO.O>[Br:18][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]([OH:19])=[O:2]
Reactant: COC(=O)c1ccc(Oc2ccc(Cl)cc2)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Oc2ccc(Cl)cc2)c(Br)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
To a solution of methyl-3-bromo-4-(4-chlorophenoxy)-benzoate (Preparation 28, 2 g, 6 mmol) in 40 mL methanol was added sodium hydroxide (0.486 g, 11.7 mmol) in 10 mL water. The reaction mixture was stirred at 50° C. for 16 hours and then acidified to pH 4 with 1M hydrochloric acid, stirred for 1 hour, filtered and dried in vacuo to afford the title compound (1.53 g, 78%).
Reaction SMILES: C.C1C(Br)=C(Br)[NH:4]C=1C(O)=[O:10].[S:12]([OH:22])(=[O:21])([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)=[O:13].[N+]([O-])=O>O>[OH-:10].[S:12]([C:14]1[CH:15]=[CH:16][C:17]([N+:20]#[N:4])=[CH:18][CH:19]=1)([OH:22])(=[O:21])=[O:13]
Reactant: O=C(O)c1cc(Br)c(Br)[nH]1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: C
Agent: O=[N+][O-]
Solvent: O
Product: N#[N+]c1ccc(S(=O)(=O)O)cc1
Product: [OH-]

Procedure:
This example illustrates the preparation of a carbon black product of the present invention and the use of this carbon black product in an aqueous coating. A carbon black (200 g) with a CTAB surface area of 350 m2 /g and a DBPA of 120 ml/100 g was added to a stirred solution of 42.4 g sulfanilic acid in 2800 g of water. Nitrogen dioxide (25.5 g) was dissolved in 100 g of cold water and added to the carbon black product suspension. Bubbles were released. 4-Sulfobenzenediazonium hydroxide inner salt was formed in situ, which reacted with the carbon black. After stirring for one hour, 5 g of additional NO2 was added directly to the carbon black dispersion. The dispersion was stirred for an additional 15 minutes, and left overnight. The resulting carbon black product was recovered by drying the dispersion in an oven at 130° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:28][CH3:29])=[CH:20][C:16]=2[C:17]([OH:19])=O)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)#N.C1C=CC2N(O)N=[N:44][C:42]=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:28][CH3:29])=[CH:20][C:16]=2[C:17]([N:32]2[CH2:33][CH2:34][CH:35]([C:42]#[N:44])[CH2:36][CH2:37]2)=[O:19])=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CN1CCCCC1
Reactant: On1nnc2ccccc21
Reactant: COc1cc(C(=O)O)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCC(C#N)CC2)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
step 4—To a solution of 68 (100 mg, 0.26 mmol) in DMF (3 mL) were added 4 cyano-piperidine (32 mg, 0.29 mmol), HOBt (39 mg, 0.29 mmol), EDCI (56 mg, 0.29 mmol) and DIPEA. The reaction mixture was stirred at RT overnight then quenched with H2O and thrice extracted with EtOAc. The combined extracts were sequentially washed with H2O (3 times) and brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford 126 mg (99%) of 1-[2-(2-benzyloxypyridin-3-yl)-4-tert-butyl-5-methoxybenzoyl]piperidine-4-carbonitrile (70) as a pale yellow foam.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:12][CH2:11]2)=[CH:6][C:5]=1[Cl:13])=[N+:2]=[N-:3].O=[C:15]([CH3:21])[CH2:16][C:17]([O:19]C)=[O:18].C[O-].[Na+]>O>[Cl:13][C:5]1[CH:6]=[C:7]([CH:10]2[CH2:11][CH2:12]2)[CH:8]=[CH:9][C:4]=1[N:1]1[C:15]([CH3:21])=[C:16]([C:17]([OH:19])=[O:18])[N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1ccc(C2CC2)cc1Cl
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(C(=O)O)nnn1-c1ccc(C2CC2)cc1Cl
Temperature: 5 °C
Reaction time: 64 h

Procedure:
To crude 1-azido-2-chloro-4-cyclopropylbenzene (0.2 M solution in THF) was added methyl 3-oxobutanoate (146 g, 1254 mmol) and the resulting mixture was cooled to 5° C. NaOMe (232 mL, 1254 mmol) was added slowly forming a precipitate and the mixture was stirred at RT for 64 hrs. The resulting suspension was cooled in an ice bath and water (2 L) was added. The mixture was transferred to a separating funnel and the aqueous layer was extracted with Me-THF (500 mL). The aqueous layer was acidified with 2M HCl (aq) and extracted with EtOAc (2 L) (1×) and (1 L) (2×). The combined organic extracts were washed with water (1 L) and brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give an orange oily residue. Water (300 mL) was added and the mixture was stirred for 30 min, filtered, washed with water and dried under reduced pressure to give the title compound as orange crystals.