Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9](Cl)(=[O:11])=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([Cl:19])[CH:21]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=S(=O)(Cl)Cc1ccc(Br)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Cc1ccc(Br)cc1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
To a solution of (4-bromo-phenyl)-methanesulfonyl chloride (1.4 g, 5.2 mmol) in DCM (20 mL) at room temperature was added pyridine (1.26 mL, 15.6 mmol) followed by 3-chloroaniline (1.1 mL, 10.4 mmol) and the reaction was stirred at room temperature for 3 hours. 1 M aqueous HCl was added and then extracted with DCM, filtered through a separator, concentrated, dry loaded onto silica and purified by silica gel column chromatography (0-100% DCM in cyclohexane) to give C-(4-bromo-phenyl)-N-(3-chloro-phenyl)-methanesulfonamide (0.61 g, 1.68 mmol). 1H NMR (300 MHz, CDCl3): δ 7.49 (d, 2H), 7.26 (m, 1H), 7.13-7.15 (m, 4H), 6.96-6.98 (m, 1H), 6.31 (s, 1H), 4.31 (s, 2H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:9]=[C:8]([CH3:18])[C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)[CH:20]=1)(=O)C.[OH-].[Li+].O.[OH-].[Na+]>CO.O1CCCC1>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:9]=[C:8]([CH3:18])[C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)[CH:20]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@@H]5CCOC5)cc4COC(C)=O)c3)ccc21
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(O[C@@H]2CCOC2)cc(CO)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 3 h
Yield: 8.5 %

Procedure:
The crude methyl 2-((S)-6-((2′-(acetoxymethyl)-6′-methyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 35e (189 mg, 0.36 mmol) was dissolved in 10 mL of a mixture of the solvents of methanol and tetrahydrofuran (V/V=1:4), followed by addition of 1M aqueous lithium hydroxide solution (4 mL, 4 mmol). The reaction solution was stirred for 3 hours. The resulting solution was added with 50 mL of water and 5 mL of 2M aqueous sodium hydroxide solution. The aqueous phase was washed with ethyl acetate (30 mL), then 1M hydrochloric acid was added dropwise to adjust the pH to 2-3, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by TLC with elution system A to obtain the title compound 2-((S)-6-((2′-(hydroxymethyl)-6′-methyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 35 (15 mg, yield 8.6%) as a white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)=[O:4].[N:10]12[CH2:17][CH2:16][CH:13]([CH2:14][CH2:15]1)[C@@H:12]([NH:18][C:19](=[O:36])[O:20][CH:21]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[CH2:11]2.CCOCC>C(OCC)(=O)C>[Br-:1].[F:35][C:31]1[CH:30]=[C:29]([CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[O:20][C:19]([NH:18][C@@H:12]2[CH:13]3[CH2:14][CH2:15][N+:10]([CH2:2][C:3](=[O:4])[C:5]4[CH:9]=[CH:8][S:7][CH:6]=4)([CH2:17][CH2:16]3)[CH2:11]2)=[O:36])[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(CBr)c1ccsc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)OC(c1cccc(F)c1)c1cccc(F)c1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(N[C@H]1C[N+]2(CC(=O)c3ccsc3)CCC1CC2)OC(c1cccc(F)c1)c1cccc(F)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
2-Bromo-1-(thiophen-3-yl)ethanone (27.5 mg, 0.13 mmol) was added to a solution of (R)-bis(3-fluorophenyl)methyl quinuclidin-3-ylcarbamate (50 mg, 0.13 mmol, prepared as in example 1) in ethyl acetate (2 ml). The reaction was stirred at room temperature overnight. Et2O (2 ml) was added, and the precipitate was collected by suction filtration and dried under vacuum at 40° C. over a week-end to obtain (R)-3-((bis(3-fluorophenyl)methoxy)-carbonylamino)-1-(2-oxo-2-(thiophen-3-yl)ethyl)-1-azoniabicyclo[2.2.2]-octane bromide (66.3 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[F:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43](O)=[O:44])[CH:38]=[CH:39][C:40]=1[CH3:41].Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:43](=[O:44])[CH2:42][C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[C:35]([F:34])[CH:36]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: Cc1ccc(CC(=O)O)cc1F
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1F
Reaction time: 0.17 h
Yield: 72.7 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotraiazole (0.4 g, 2.6 mmol) and 3-fluoro-4-methylphenylacetic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-fluoro-4-methyl-phenyl)-acetamide (0.7 g, 70%) as a white solid: mp 148-150° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.06 min. (98%); 1H NMR (DMSO-d6) δ 2.04-2.07 (m, 1H), 2.20 (s, 3H), 2.52-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.52 (s, 2H), 4.70 (d, J=5.7 Hz, 2H), 5.12-5.18 (dd, J=5.1 and 12.7 Hz, 1H), 6.99-7.07 (dd, J=11.2 and 14.7 hz, 2H), 7.21 (t, J=8.0 Hz, 1H), 7.63-7.76 (dd, J=3.3 and 7.5 Hz, 1H), 7.77-7.83 (dd, J=7.6 and 11.9 Hz, 2H), 8.65 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 13.74 (13.78), 21.95, 30.90, 37.84, 41.41, 48.83, 115.31, 115.60, 121.89, 124.84 (124.87), 127.12, 131.02 (131.28), 131.51, 133.20, 134.66, 135.87 (135.97), 139.09, 158.77 (161.98), 166.90, 167.42, 169.78, 170.26, 172.73; Anal. Calcd. for C23H20N3O5F: C, 63.15; H, 4.61; N, 9.61; F, 4.34. Found: C, 62.78; H, 4.45; N, 9.32; F, 4.47.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11][NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(CN)cc1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(CNCc2cc(Br)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Benzyloxy-5-bromobenzaldehyde and ethyl 4-aminomethylbenzoate were heated together at 100° C. for 1 hour. The mixture was cooled, dissolved in ethanol (100 ml) and sodium borohydride (1.3 g) was added. The mixture was stirred for 18 hours at ambient temperature, acidified with acetic acid and water (200 ml) was added. The mixture was extracted with diethyl ether (4×100 ml), the extracts washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and evaporated to give ethyl 4-[N-(2-benzyloxy-5-bromobenzyl)aminomethyl]benzoate which was purified by chromatography on silica gel eluting with CH2Cl2 then 5% ethyl acetate/CH2Cl2 (yield 11.4 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@H:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]3=[O:31])[C:20]=2[O:32][CH:33]([F:35])[F:34])(=[O:18])=[O:17])[C:12](O)=[O:13])=[O:8])=[CH:4][CH:3]=1.[CH2:36]([O:38][C:39]([CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])[CH3:37]>CN(C=O)C>[CH2:36]([O:38][C:39]([CH:41]1[CH2:46][CH2:45][N:44]([C:12](=[O:13])[C@@H:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]3=[O:31])[C:20]=2[O:32][CH:33]([F:34])[F:35])(=[O:18])=[O:17])[CH2:10][NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:43][CH2:42]1)=[O:40])[CH3:37]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(NC[C@H](NS(=O)(=O)c1cccc(N2CCCCC2=O)c1OC(F)F)C(=O)O)c1ccc(Cl)s1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)[C@H](CNC(=O)c2ccc(Cl)s2)NS(=O)(=O)c2cccc(N3CCCCC3=O)c2OC(F)F)CC1

Procedure:
Intermediate 34 (258 mg, 0.467 mmol) and Piperidine-4-carboxylic acid ethyl ester (81 mg, 0.514 mmol) were coupled in close analogy to the procedure described in 3.5) using DMF as solvent. The mixture was purified by prep. HPLC. Yield after lyophilization: 253 mg, 78%, colorless, amorphous solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6].C(N(C(C)C)CC)(C)C.[CH:19]1[C:31]2[CH:30]([CH2:32][O:33][C:34](Cl)=[O:35])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1>ClCCl>[CH:19]1[C:31]2[CH:30]([CH2:32][O:33][C:34]([NH:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6])=[O:35])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(CN)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 18 h
Yield: 45.2 %

Procedure:
To 3-amino-2,2-dimethylpropanoic acid, hydrochloride salt (250 mg, 1.63 mmol, 1 eq.) in dichloromethane (4 mL, 0.4 M) was added diisopropylethylamine (859 μL, 4.88 mmol, 3 eq.) followed by (9H-fluoren-9-ylmethoxy)carbonyl chloride (473 mg, 1.79 mmol, 1.1 eq.) The reaction was stirred for 18 hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (3 mL) and washed with 1 M aqueous hydrochloric acid solution (2×1 mL) and with brine. The organic layer was dried over sodium sulfate, filtered, and purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to give #93 (250 mg, 45%) as an oil. 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 7.89 (d, J=7.4 Hz, 2H), 7.72 (d, J=7.4 Hz, 2H), 7.38-7.44 (m, 2H), 7.27-7.35 (m, 3H), 4.18-4.30 (m, 3H), 3.16 (d, J=6.2 Hz, 2H), 1.05 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:14](=[O:19])[C:15]=2[C:16](O)=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:31])=O>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:14](=[O:19])[C:15]=2[C:16]([Cl:31])=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(-c2ccc(C(C)(C)C)cc2)c(C(=O)O)c(=O)n1-c1ccc(C#N)cc1
Reactant: O=S(Cl)Cl
Product: Cn1c(-c2ccc(C(C)(C)C)cc2)c(C(=O)Cl)c(=O)n1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 12.1 g of 3-(4-t-butylphenyl)-1-(4-cyanophenyl)-4-hydroxycarbonyl-2-methyl-2H-pyrazol-5-one and 100 ml of thionyl chloride was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized in a liquid mixture of n-hexane-toluene to give 14.0 g of the title compound as pale yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH3:18].[Cl:19]Cl>Cl.C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:18])[Cl:19]
Reactant: ClCl
Reactant: CC1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: CC1(Cl)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
By following substantially the procedure described in Example 12, Step B, and using as the reactants (1-oxo-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid (2.89 g., 0.01 mole), glacial acetic acid (50 ml.), chlorine (710 mg., 0.01 mole) and concentrated hydrochloric acid (1 drop) there is obtained (1-oxo-2-methyl-2,6,7-trichloro-5-indanyloxy)acetic acid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C@H:6]1[C@@H:11]2[C@@H:9]([C@H:10]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@:8]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:7]1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1.C(N(CC)CC)C>ClCCl.O>[C:1]([NH:5][C@H:6]1[C@@H:11]2[C@@H:9]([C@H:10]2[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C@:8]([NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@@H:7]1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](N)[C@H]1OCc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)N[C@H]1[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@@H]1OCc1ccc(Cl)c(Cl)c1
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
Acetyl chloride (334.31 μL, 368.75 mg, 4.70 mmol) in dichloromethane (5 mL) is added to a stirring, cooled solution of di-tert-butyl (1S,2R,3R,4S,5R,6S)-4-amino-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.30 g, 3.91 mmol) and triethylamine (709.32 μL, 514.97 mg, 5.09 mmol) in dichloromethane (19.57 mL) at 0° C. then stirred. After 90 minutes, dilute with water and extract with dichloromethane (3×25 mL). The combined organic extracts are dried over magnesium sulfate, filtered, and concentrated under reduced pressure giving the title compound (2.40 g, 3.81 mmol, 97%): MS (m/z): 653 (M+1).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)[C:9]([C:23]([OH:25])=O)=[CH:8][N:7]=1)=[O:5].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.[CH:57]([N:60]1[CH2:65][CH2:64][CH:63]([NH2:66])[CH2:62][CH2:61]1)([CH3:59])[CH3:58]>CN(C=O)C.C(Cl)Cl>[CH2:2]([O:3][C:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)[C:9]([C:23](=[O:25])[NH:66][CH:63]2[CH2:64][CH2:65][N:60]([CH:57]([CH3:59])[CH3:58])[CH2:61][CH2:62]2)=[CH:8][N:7]=1)=[O:5])[CH3:1]
Reactant: CC(C)N1CCC(N)CC1
Reactant: CCOC(=O)c1ncc(C(=O)O)n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ncc(C(=O)NC2CCN(C(C)C)CC2)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
To a solution of 12 mg of 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazole-2,4-dicarboxylic acid 2-ethyl ester (ii) in DMF (0.5 mL) and DCM (0.5 mL) was added successively 1-Hydroxy-7-azabenzotriazole (5 mg), N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (7 mg) and diisopropyl ethylamine (26 μL). The mixture was stirred for 15 min at RT. 7 mg of 1-Isopropyl-piperidin-4-ylamine (dihydrochloride) were added and stirring was continued at RT. After 2 h the mixture was concentrated in vacuo and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated to provide 8.5 mg of the title compound as its trifluoroacetate salt. Yield: 8.5 mg; MS (ESI+): m/e=505, chloro pattern.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].[CH2:18]([N:30]1[C:34](=[O:35])[CH:33]=[CH:32][C:31]1=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(O)(C)(C)C>[C:13]([C:9]1[CH:10]=[C:11]([CH:33]2[CH2:32][C:31](=[O:36])[N:30]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:34]2=[O:35])[CH:12]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]=1[OH:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCCCCCCCCCCN1C(=O)C=CC1=O
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCN1C(=O)CC(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 17.3 %

Procedure:
This compound is prepared by the procedure of Example 1 from 2.40 g (0.1 mol) of sodium hydride, 20.63 g (0.1 mol) of 2,6-di-tert-butylphenol, and 26.54 g (0.1 mol) of N-n-dodecylmaleimide in tert-butyl alcohol. The reaction mixture is concentrated in vacuo and the residue is dissolved in 800 ml of toluene. The toluene solution is extracted sequentially with 1M sodium hydroxide (2×100 ml) and water (6×200 ml). The organic phase is dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the residue purified by flash chromatography (8:2 heptane: ethyl acetate eluent) followed by recrystallization from petroleum ether to give 8.15 g (17%) of a white solid: mp 66°-70° C.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH3:15])[C:11]2=O)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[O:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.Cl>C1COCC1.O>[C:1]([C:5]1[CH:13]=[C:12]2[C:8](=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=1[O:22][CH3:23])[CH2:9][C:10]([CH3:15])=[CH:11]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(C)C2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(C)=C2
Temperature: 5 °C
Reaction time: 7 h
Yield: 98921.8 %

Procedure:
To a solution of 45.9 g (0.149 mmol) of 6-tert-butyl-5-methoxy-2-methyl-4-phenylindan-1-one in 300 ml of THF cooled to 5° C. 8.51 g (0.225 mol) of NaBH4 was added. Further on, 150 ml of methanol was added dropwise to this mixture by vigorous stirring for ca. 7 h at 5° C. The resulting mixture was stirred overnight at room temperature, and then 1 liter of cold water and 12 M HCl to pH˜1 were added. The crude product was extracted with 3×200 ml of dichloromethane, the combined organic extract was dried over K2CO3 and then evaporated to dryness. To a solution of the residue in 800 ml of toluene 1.0 g of TsOH was added, this mixture was refluxed with Dean-Stark head for 10 min and then cooled to room temperature using water bath. The resulting solution was washed by 10% aqueous Na2CO3, the organic layer was separated, the aqueous layer was extracted with 2×50 ml of dichloromethane. The combined organic solution was dried over K2CO3 and then passed through short layer of silica gel 60 (40-63 um). The silica gel layer was additionally washed by 100 ml of dichloromethane. The combined organic elute was evaporated to dryness. This procedure gave 43.1 g (99%) of yellowish oil which was further used without an additional purification.
Reaction SMILES: N.[N+:2]([O-:5])([O-:4])=[O:3].[Ca+2:6].[N+:7]([O-])([O-])=[O:8].[C:11](=[O:13])=[O:12]>O>[N+:2]([O-:5])([O-:4])=[O:3].[NH4+:7].[C:11](=[O:8])([O-:13])[O-:12].[Ca+2:6]
Reactant: O=C=O
Agent: N
Agent: O=[N+]([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])[O-]
Product: [NH4+]

Procedure:
U.S. Pat. No. 2,753,252, Barnes, July 3, 1956, it is proposed that a substantially completely citrate soluble phosphatic product may be prepared by reacting phosphate rock with nitric acid, filtering the gangue, evaporating free water from the acidulate by boiling, heating the resulting residue to about 180° C. to about 190° C. to expel all water of hydration, dispersing the residue in anhydrous ammonia to dissolve the calcium nitrate, and finally filtering the mixture to obtain the phosphate product and a filtrate containing anhydrous ammonia and calcium nitrate. The filtrate is further processed with water and carbon dioxide to produce an ammonium nitrate solution and by-product calcium carbonate. Barnes claims a 95.8 percent recovery of the P2O5 initially present in the rock, but makes no provision for the recovery of nitric acid liberated during the heating processes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:19]=[C:13]3CN(C)C[CH2:17][N:12]3[N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.N[C:21]1N=CC=CN=1.BrC1C(=O)N(C)N=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:19]=[CH:13][N:12]=[CH:17][N:11]=2)[C:5](=[O:8])[N:6]([CH3:21])[N:7]=1
Reactant: Nc1ncccn1
Reactant: CN1CCn2nc(Nc3cc(Cl)n[nH]c3=O)cc2C1
Agent: Cn1nc(Cl)cc(Br)c1=O
Product: Cn1nc(Cl)cc(Nc2ccncn2)c1=O
Yield: 69 %

Procedure:
Using the same general procedure as described for the preparation of 101m, reaction of 2-aminopyrimidine (450 mg, 4.74 mmol) with 103a (1.06 g, 4.74 mmol) afforded 103b in 69% yield (745 mg) as an amorphous yellow solid: mp 233-235° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.92 (d, J=1.0 Hz, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.45 (s, 1H), 7.58 (dd, J=6.0, 1.0 Hz, 1H), 3.70 (s, 3H); MS (ESI+) m/z 238.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[N:10]([O-])=O.[Na+].[CH3:14][CH:15](C(C)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][N:10]=[C:15]([CH3:14])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Cc1ccc(N)cc1C
Reactant: O=N[O-]
Agent: [Na+]
Product: CCOC(=O)C(C)=NNc1ccc(C)c(C)c1

Procedure:
In a manner analogous to that described in Example 4, 60.6 g 3,4-dimethylaniline were diazotized with 37.0 g sodium nitrite and reacted with 73.0 g ethyl 2-methyl-acetoacetate to give ethyl pyruvate (3,4-dimethylphenylhydrazone), which does not crystallize. A greater part of the dark brown impurities present can be removed by treatment of a solution of the hydrazone in ligroin with silica gel. After evaporation of the ligroin, the hydrazone (81.1 g; 49% of theory) was dissolved in ethanol and hydrogen chloride was passed in, with ice cooling, until the solution was saturated. While passing in further hydrogen chloride, the solution was heated under reflux for 15 minutes, whereafter the reaction mixture was cooled and filtered with suction. The filtrate was evaporated to dryness and the residue digested several times with warm ligroin. The ligroin was evaporated somewhat and cooled. The ester which thereby crystallized out (31.6 g; 42% of theory) was filtered off with suction and, for saponification, heated under reflux for one hour with 27 g potassium hydroxide in 230 ml methanol. Thereafter, the reaction mixture was cooled and filtered with suction. The filtrate was treated with active charcoal and thereafter evaporated to dryness. The residue was taken up in water, again clarified with active charcoal and acidified with hydrochloric acid. The product was filtered off with suction and recrystallized twice from isopropanol; the 4,5-dimethylindole-2-carboxylic acid obtained (3.6 g; 13% of theory) then has a melting point of 247°-250° C (decomp.).