Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:26]=[C:25]2[C:18]([NH:19][CH:20]=[C:21]2[CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1.C(Cl)CCl.C(OCC)(=O)C>CCCCCC>[OH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([NH:24][CH2:23][CH2:22][C:21]2[C:25]3[C:18](=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:26]=3)[NH:19][CH:20]=2)=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Solvent: CCCCCC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]cc(CCNC(=O)/C=C/c3ccc(O)cc3)c2c1

Procedure:
(E)-3-(4-hydroxyphenyl)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl) acrylamide (2h) was synthesized by the condensation of 4-hydroxy cinnamic acid (150 mg, 0.914 mmol) and 5-methoxy tryptamine (207 mg, 1.09 mmol) using standard EDC coupling method. 2h was isolated as yellowish solid (181 mg, 59%) by elution with 25% ethyl acetate in hexane.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)S[CH2:16][CH2:15][C:14]3=[O:21])=[O:10])[CH:5]=[N:4]1)[CH3:2].OO.C(O)(=O)C.[S:28]([O-:31])(O)=[O:29].[Na+]>O>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[S:28](=[O:31])(=[O:29])[CH2:16][CH2:15][C:14]3=[O:21])=[O:10])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C(=O)c2ccc3c(c2)C(=O)CCS3)c1O
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCn1ncc(C(=O)c2ccc3c(c2)C(=O)CCS3(=O)=O)c1O
Temperature: 60 °C

Procedure:
1.0 Gram (3.31 mmol) of 6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-4-one and 0.83 g (7.28 mmol) of a 30 wt % hydrogen peroxide aqueous solution were added to 3 ml of glacial acetic acid, and then stirred under heat of 60° C. for 2.5 hours. While the reaction mixture was cooled in an ice bath after allowed to cool, a 1 wt % sodium hydrogensulfite aqueous solution was added to decompose excess hydrogen peroxide, and then the reaction mixture was diluted with water. A precipitated solid was extracted with ethyl acetate. An organic layer was washed with water and then with a saturated sodium chloride aqueous solution once, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1.11 g (yield: quantitative) of the titled compound. Table 24 shows the physical property data of the titled compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)[C:19]=1[S:20][CH2:21][CH2:22][CH3:23])=[O:14])(C)(C)C>C(Cl)Cl>[CH3:34][O:33][C:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:18]2[C:19]([S:20][CH2:21][CH2:22][CH3:23])=[C:15]([C:13]([OH:14])=[O:12])[CH:16]=[N:17]2)=[CH:26][CH:27]=1)=[O:32]
Reactant: CCCSc1c(C(=O)OC(C)(C)C)cnn1Cc1ccc(C(=O)OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCSc1c(C(=O)O)cnn1Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
TFA (1.5 ml) was added to a stirred solution of 1-(4-Methoxycarbonyl-benzyl)-5-propylsulfanyl-1H-pyrazole-4-carboxylic acid tert-butyl ester (Intermediate #46) (274 mg, 0.70 mmol) in DCM (6 ml). The reaction was stirred at ambient temperature for 3 hours then evaporated in vacuo. The resulting gum was sonicated with isohexane to yield a solid. The solvent was removed then the white solid was dissolved in EtOAc and evaporated in vacuo to yield the title compound as an off white solid (236 mg, 100%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14](O)=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2[CH:38]=[CH:39][CH:40]=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N1CCCC1.Cl>CN(C=O)C.C(OCC)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([N:41]4[CH2:40][CH2:39][CH2:38][CH2:36]4)=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH2:2][CH2:3]1
Reactant: CCOc1ccc(Cc2nc3cc(C(=O)O)ccc3n2CC2CC2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Solvent: CCOCC
Product: CCOc1ccc(Cc2nc3cc(C(=O)N4CCCC4)ccc3n2CC2CC2)cc1
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
Following the general procedure 20E, 1-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-1H-benzimidazole-5-carboxylic acid (80 mg, 0.228 mmol) was dissolved in DMF (2 mL) and then HATU (104 mg, 0.274 mmol) was added followed by DIPEA (48 μL, 0.274 mmol), After being stirred for 10 min, pyrrolidine (0.456 mmol) was added and the resulting mixture was stirred overnight. The crude residue after work-up was purified by silica gel column chromatography to give pure product which was treated with 1 M HCl solution in diethyl ether to form a HCl salt as white solids (82 mg, 79%). 1H N (400 MHz, CD3OD): δ 7.85 (s, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.48 (d, J=8.6 Hz, 1H), 7.18 (d, J=8.1 Hz, 2H), 6.87 (d, J=8.1 Hz, 2H), 4.32 (s, 2H), 4.07 (d, J=6.8 Hz, 2H), 4.00 (q, J=7.6 Hz, 2H), 3.64 (t, J=. 7.2 Hz, 2H), 3.53 (t, J=7.2 Hz, 2H), 2.06–1.96 (m, 2H), 1.96–1.85 (m, 2H), 1.36 (t, J=7.6 Hz, 3H), 1.10–1.04 (m, 1H), 0.52–0.46 (m, 2H), 0.34–0.28 (m, 2H). MS (ESI) (M+H)+=404. Anal. Calcd for C25H29N3O2.1.5HCl: C, 65.53; H, 6.71; N, 9.17. Found: C, 65.48; H, 6.77; N, 8.75.
Reaction SMILES: [NH2:1][C:2]1[C:19]([Br:20])=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Br:21].ClC(OCC)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Br:21])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:10])=[CH:18][C:19]=1[Br:20]
Reactant: C1COCCN1
Reactant: Nc1c(Br)cc(C(=CC(=O)O)c2ccc(F)cc2)cc1Br
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: Nc1c(Br)cc(C(=CC(=O)N2CCOCC2)c2ccc(F)cc2)cc1Br

Procedure:
This compound was prepared from 4-amino-3,5-dibromo-β-(4'-fluorophenyl)-cinnamic acid (isomer ratio A:B=2.5:1), ethyl chloroformate, triethylamine and morpholine analogous to Example 1(c).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C@@H:11]([CH2:13][O:14][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[O:10][C:9]2=[O:32])=[N:6][CH:7]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:32])=[N:6][CH:7]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1CN(c2ccc(Br)cn2)C(=O)O1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1O[C@H](CO)CN1c1ccc(Br)cn1
Temperature: 0 °C
Yield: 83.5 %

Procedure:
Compound 25b (1.4 g, 2.83 mmol) was dissolved in tetrahydrofuran, cooled to 0° C., and nBu4NF (4.2 mL, 4.2 mmol, 4.2 M solution in tetrahydrofuran) was added. The mixture was allowed to react for 5 hrs and monitored by TLC. After the reaction completed, the mixture was diluted with water, and extracted with ethyl acetate. The organic phase was wash with saturated saline solution, dried over anhydrous sodium sulfate. Column chromatography afforded 645 mg of white solid, yield 83%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C[Mg]Br>[Cl-].[NH4+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: OCc1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
5-Bromo-2-fluorobenzaldehyde (commercially available from Aldrich) (150.0 g, 739 mmol) was charged into a 2 liter round bottom flask. The reaction mixture in the flask was immersed in an ice-water bath. Methylmagnesium bromide (270 mL, 812 mmol) was added dropwise via an addition funnel. The reaction mixture was stirred for one hour following completion of the addition. After the reaction was completed, the mixture was slowly poured into 500 mL ice water and 250 mL saturated ammonium chloride. The resulting aqueous solution was extracted with ether (800 mL×2) in a separation funnel. The combined ether layer was washed with brine and dried over sodium sulfate. Removal of the solvent gave the product (150 g, yield=93%). The product was used directly in the next step without further purification.
Reaction SMILES: [Cl].[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCOCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([Br:2])=[CH:4][CH:5]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Oc1ccc(F)cc1
Agent: [Cl]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ten ml of dioxane, 5 mmol (1.1 g) of 4-bromo-benzoic acid chlorine, and 5 mmol (0.56 g) of 4-fluoro-phenol were added to 50 ml four-mouth-flask sequentially and dissolved at room temperature. Triethylamine dissolved in dioxane was slowly dripped into this solution and the solution was stirred for three hours at room temperature. The precipitated crystals were filtered and extracted with benzene. The extracted solution was washed with sodium hydrocarbonate several times, magnesium anhydrate was added, and the resulting solution was dried and filtered. The solution was distilled under low pressure and crystallized. The row crystals were yellowish-white, weighing 1.37 g. A portion of this crystal (0.5 g) was dissolved in benzene and purified with 100 g of silica gel (Wako gel C-300, Japan). The purified product was white, and the purity was confirmed to 99.93% by liquid chromatography (LC). The structure was confirmed by NMR as follows. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (2H, d, J=8.8 Hz), 7.83 (2H, d, J=8.8 Hz), 7.38-7.29 (4H, m) 13C NMR (100 MHz, DMSO-d6) δ 159.72 (C—F, d, J=240 Hz) 163.95 (C═O)
Reaction SMILES: Br[CH:2]([C:4]1[CH:35]=[CH:34][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([NH:28][C:29]([CH:31]5[CH2:33][CH2:32]5)=[O:30])[N:24]=[CH:25]4)=[CH:20][CH:19]=3)[CH:12]=2)=[O:9])=[CH:6][CH:5]=1)[CH3:3].[CH3:36][NH:37][CH3:38].C(N(CC)CC)C.CN(C)C=O>O1CCCC1.ClCCl>[CH:31]1([C:29]([NH:28][C:23]2[N:24]=[CH:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([C:13]2[CH:12]=[C:11]([NH:10][C:8](=[O:9])[C:7]4[CH:34]=[CH:35][C:4]([CH:2]([N:37]([CH3:38])[CH3:36])[CH3:3])=[CH:5][CH:6]=4)[CH:16]=[CH:15][C:14]=2[CH3:17])[CH:27]=3)=[O:30])[CH2:33][CH2:32]1
Reactant: CNC
Reactant: Cc1ccc(NC(=O)c2ccc(C(C)Br)cc2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(C(C)N(C)C)cc2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 22 %

Procedure:
To the crude reaction mixture from Step 2 was added 2.0 M of dimethylamine in tetrahydrofuran (0.15 mL). The resulting mixture was then stirred at 40° C. After 1.5 hours, 2.0 M of dimethylamine in tetrahydrofuran (0.20 mL), triethylamine (0.05 mL, 0.4 mmol), and 1 mL N,N-dimethylformamide were added and the reaction mixture was heated at 50° C. After an additional hour, the reaction was poured into dichloromethane and washed once with saturated aqueous NaHCO3, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 17.6 mg (22%) of N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-4-(1-(dimethylamino)ethyl)benzamide. LCMS (ESI): RT (min)=4.090, M+H=493.2, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.20 (s, 1H), 9.19 (s, 1H), 8.50 (s, 1H), 8.02 (s, 1H), 7.92 (overlapping, 3H), 7.79 (d, J=1.9 Hz, 1H), 7.77-7.67 (m, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.4 Hz, 1H), 3.35 (q, J=6.8 Hz, 1H), 2.26 (s, 3H), 2.11 (s, 7H), 1.29 (d, J=6.7 Hz, 3H), 0.85 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([CH:23]4[CH2:26][N:25]([C:27]5[N:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=5)[CH2:24]4)=[O:22])=[CH:16][CH:15]=3)[CH:11]=[N:10]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:34]1[CH2:37][C:36](=O)[CH2:35]1.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]([CH:23]4[CH2:26][N:25]([C:27]5[N:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=5)[CH2:24]4)=[O:22])=[CH:18][CH:19]=3)[CH:11]=[N:10]2)[CH2:7][CH2:6][N:5]([CH:36]2[CH2:37][O:34][CH2:35]2)[CH2:4][CH2:3]1
Reactant: O=C1COC1
Reactant: Cc1ccc(N2CC(C(=O)Nc3ccc(-c4cnn(CC5(C)CCNCC5)c4)cc3)C2)nn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(N2CC(C(=O)Nc3ccc(-c4cnn(CC5(C)CCN(C6COC6)CC5)c4)cc3)C2)nn1

Procedure:
N-(4-(1-((4-Methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)phenyl)-1-(6-methylpyridazin-3-yl)azetidine-3-carboxamide was dissolved in methanol (3 ml) and treated with oxetan-3-one (0.022 ml, 0.338 mmol) and sodium cyanoborohydride (0.021 g, 0.338 mmol) and stiffed overnight. The mixture was concentrated, purified by normal phase chromatography, triturated with ether and concentrated to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.09 (s, 1H), 8.05 (s, 1H), 7.82 (s, 1H), 7.64-7.58 (m, 2H), 7.56-7.49 (m, 2H), 7.29 (d, J=9.1 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 4.51 (t, J=6.4 Hz, 2H), 4.40 (t, J=5.8 Hz, 2H), 4.20 (t, J=8.3 Hz, 2 H), 4.12 (dd, J=7.9, 6.1 Hz, 2H), 3.98 (s, 2H), 3.73 (tt, J=8.5, 6.1 Hz, 1H), 3.48-3.39 (m, 1H), 2.44 (s, 3 H), 2.42-2.33 (m, 2H), 2.16-1.99 (m, 2H), 1.58-1.46 (m, 2H), 1.30 (d, J=12.6 Hz, 2H), 0.89 (s, 3 H); MS (ESI(+)) m/e 502 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][C:3]=1[S:11]([CH3:14])(=[O:13])=[O:12].C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:29]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:4]=1)[CH3:9])=[N+:30]=[N-:31]
Reactant: CC(O)c1ccc(Cl)c(S(C)(=O)=O)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(N=[N+]=[N-])c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
A round bottom flask was charged with 1-(4-chloro-3-(methylsulfonyl)phenyl)ethanol (8.5 g, 32.44 mmol) and toluene (100 mL). Diphenyl phosphoryl azide (8.4 mL, 38.93 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.8 mL, 38.93 mmol) were added at 0° C. and the mixture was stirred over night at room temperature. The volatiles were removed under reduced pressure and the residue was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography to get the product (2.4 g, 28% yield).
Reaction SMILES: [CH3:1][CH:2]1[S:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[OH:9]O>C(O)=O.C(OC(=O)C)(=O)C>[CH3:1][CH:2]1[S:7](=[O:9])[CH2:6][CH2:5][NH:4][C:3]1=[O:8]
Reactant: OO
Reactant: CC1SCCNC1=O
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: CC1C(=O)NCCS1=O
Temperature: 0 °C

Procedure:
To a solution of 9 g of 2-methyl-3-thiamorpholinone in a mixture of 50 cm3 of formic acid and 10 cm3 of acetic anhydride, cooled to 0° C., 7 cm3 of H2O2 at 110 vol. are slowly added. After an 18 hour reaction period, the solution is concentrated under reduced pressure. The resulting product is dissolved in chloroform and the chloroform solution is deposited on a silica gel column.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]([O:17]C)=[O:16])[NH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>CCO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]([OH:17])=[O:16])[NH:12][CH:13]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)C(Cc1ccccc1)c1nc(-c2ccc(C#N)cc2)c[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(-c2c[nH]c(C(Cc3ccccc3)C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
Methyl 2-(4-(4-cyanophenyl)-1H-imidazol-2-yl)-3-phenylpropanoate from Example 56 Part A (60 mg, 0.20 mmol) was dissolved in 4 mL of EtOH. NaOH (1.5 mL of 1N aqueous solution) was added and the mixture was stirred RT for 1.5 h. The mixture was acidified with 1N HCl to pH 5. The precipitate formed was filtered and dried to give 40 mg of the acid (63%). MS 318.3 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.[C:17]([O:21][C:22](=[O:29])[NH:23][C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:5]1([O:4][C:2]([N:26]2[CH2:27][CH2:28][C@@H:24]([NH:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:29])[CH2:25]2)=[O:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)Oc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (1 eq.) is added dropwise to a solution of pyridine in DCM. The reaction mixture is cooled to 0° C. and a solution of (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at RT for 1 hour. The reaction mixture is partitioned between (0.2 M) HCl)(aq) and DCM. The organics are washed with water, (sat)NaHCO3(aq) and brine. The organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound.
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].C1C=CC2N(O)N=NC=2C=1.O.Cl.[NH2:30][C@@H:31]([C:33]([NH:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:38])=[O:34])[CH3:32]>CN(C=O)C.C(Cl)CCl>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:30][C@@H:31]([C:33]([NH:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])=[O:38])=[O:34])[CH3:32])=[O:10])[CH3:7])=[O:4]
Reactant: C[C@@H](N)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of Boc-Gly-Ala prepared as in Example 33B (10.2 g, 41.5 mmol) in anhydrous DMF (300 ml), was added HOBT.circle-solid.H2O (6.21 g, 46.0 mmol), EDC.circle-solid.HCl (8.81 g, 46.0 mmol) and DAla-Gly-Gly-OBzl.circle-solid.HCl (13.7 g, 41.5 mmol). The pH of the resulting solution was adjusted to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the reaction mixture was allowed to stir at room temperature for 12 h thereafter. The solution was concentrated in vacuo and the residue was dissolved in water (40 ml). The resulting solution Was extracted with ethyl acetate (3×150 ml). The combined ethyl acetate layers were washed with 1N sodium bisulfate (100 ml), saturated sodium bicarbonate (100 ml) and brine (100ml). The ethyl acetate solution was dried (magnesium sulfate), filtered and concentrated to half volume. The product crystallized out upon standing at RT for 30 min. Collection of the crystals by filtration and drying at high vacuum afforded 17.4 g (80% yield) of the pure product: 1H NMR (DMSO-d6) δ 1.21 (d, J=7.4 Hz, 3H), 1.23 (d, J=7.3 Hz, 3H), 1.38 (s, 9H), 3.56 (d, J=6.3 Hz, 2H), 3.75 (d, J=5.7 Hz, 2H), 3.93 (d, J=6.0 Hz, 2H), 4.24-4.34 (m, 2H), 5.14 (s, 2H), 6.98 (t, J=5.7 Hz, 1H), 7.34-7.40 (m, 5H), 7.93 (d, J=7.2 Hz, 1H), 8.17-8.24 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:12].[H-].[Na+].[CH3:15]I>CN(C=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][CH3:15]
Reactant: Cc1c([N+](=O)[O-])ccc(O)c1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(C)c1Cl
Yield: 81.2 %

Procedure:
2-Chloro-3-methyl-4-nitrophenol (9.39 g, 50.0 mmol) was reacted with sodium hydride (50%, 2.64 g, 55.0 mmol) and methyl iodide (7.81 g, 55.0 mmol) in dry DMF (200 ml) by the method described in 1 (a). After treatment with water, the product was extracted with chloroform, and the dried extract evaporated to dryness, leaving an oil which crystallised on cooling, leaving solid 2-chloro-3-methyl-4-nitroanisole (8.19 g).
Reaction SMILES: [CH3:1][CH2:2]/[C:3](/[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[C:4](/[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:15][CH:16]=1)\[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[O:29]=[C:30]([OH:41])[C@@H:31]([C@H:33]([C@@H:35]([C@@H:37]([CH2:39][OH:40])[OH:38])[OH:36])[OH:34])[OH:32]>C(O)C.CC(O)C>[CH3:1][CH2:2]/[C:3](/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[C:4](/[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:15][CH:16]=1)\[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[O:29]=[C:30]([O-:41])[C@@H:31]([C@H:33]([C@@H:35]([C@@H:37]([CH2:39][OH:40])[OH:38])[OH:36])[OH:34])[OH:32]
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CC/C(=C(\c1ccccc1)c1ccc(OCCN(C)C)cc1)c1ccccc1
Solvent: CC(C)O
Solvent: CCO
Product: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A particular emulsion formulation such as a cream or lotion may be obtained for example, by adding a slurry of tamoxifen free base in ethanol or 2-propanol to an aqueous solution of D-gluconic acid to form tamoxifen gluconate in situ, which mixture is then combined with the required components of the disperse phase.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH3:18])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: Cc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OCc2ccccc2C)c1
Temperature: 15 °C
Reaction time: 0.33 h
Yield: 29.8 %

Procedure:
To a solution of methyl 3,5-dihydroxybenzoate (50 g, 0.30 mol) in DMF (500 mL) at 0° C. was added sodium hydride (10.8 g, 0.27 mol) portionwise, maintaining the reaction temperature below 10° C. The reaction was allowed to warm to 15° C., and was stirred for 20 minutes. The mixture was cooled to 0° C. and a solution of 2-methylbenzyl bromide (36 mL, 0.27 mol) in DMF (50 mL) was added over 30 minutes. The reaction was warmed to ambient temperature and concentrated in vacuo, the residual oil partitioned between ethyl acetate (500 mL) and water (250 mL), the ethyl acetate layer separated, washed sequentially with water and brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica eluting with a gradient of 0-100% ethyl acetate in isohexane to give the desired compound (21.9 g). 1H NMR δ (CDCl3) 2.39 (s, 3H), 3.90 (s, 3H), 5.02 (s, 2H), 5.61 (s, 1H), 6.69 (t, 1H), 7.15-7.42 (m, 6H).