Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.Cl.[CH3:16][NH:17][O:18][CH3:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([N:17]([O:18][CH3:19])[CH3:16])=[O:14]
Reactant: CNOC
Reactant: O=C(O)c1ccc2ccccc2c1Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
To a mixture of 1-bromo-2-naphthoic acid (1.04 g, 4.14 mmol, TCI America) and N,O-dimethylhydroxylamine hydrochloride (0.465 g, 4.76 mmol) in N,N-dimethylformamide (10 mL,) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.11 g, 4.76 mmol). After stirred at room temperature for 10 minutes, N,N-diisopropylethylamine (2.16 mL, 12.4 mmol) was added to the resulting mixture. The reaction was stirred at room temperature for 2 h, quenched with water, and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was concentrated and the residue was purified on silica gel, eluting with 0% to 50% ethyl acetate in hexane, to give the desired product (1.08 g, 88%). LCMS calculated for C13H13BrNO2(M+H)+: m/z=294.0; found: 294.2.
Reaction SMILES: C([Li])CCC.[CH2:6]=[CH:7][CH2:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12].C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:33]1CCCC1>>[CH2:8]([C@@H:9]([OH:13])[CH2:10][C@@H:11]1[CH2:12][O:33]1)[CH:7]=[CH2:6]
Reactant: C=CCC(O)CC=C
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Product: C=CC[C@@H](O)C[C@@H]1CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium, 129 mL (200 mmol), is added dropwise to a 0° C. solution of 1,6-heptadien-4-ol, 22.4 g (0.2 mol), in 200 mL of anhydrous tetrahydrofuran until the triphenylmethane indicator turned red. Carbon dioxide is then bubbled in for 30 minutes (lecture bottle carbon dioxide passed through drierite) and the light yellow solution is stirred for 30 minutes under a balloon of carbon dioxide. To this solution is added iodine, 101.4 g (0.4 mol), dissolved in ~200 mL of anhydrous tetrahydrofuran over 60 minutes. The mixture is allowed to warm to room temperature overnight, diluted with ethyl acetate, washed with 10% sodium bisulfite solution, saturated solution of sodium bicarbonate, brine, and dried (magnesium sulfate). The crude product is dissolved in 200 mL of methanol and 20 mL of water, cooled to 0° C. and 0.5 g of solid potassium carbonate is added. The mixture is vigorously stirred for six hours, filtered, concentrated, and partitioned between ethyl acetate and brine. After extracting the aqueous layer 2× with ethyl acetate, the combined organics are washed with brine and dried (magnesium sulfate). Flash chromatography (4:1 hexane-ethyl acetate) provides, after concentration in vacuo, 18 g of (R*,R*)-α-b 2-propenyloxiraneethanol.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9])=[CH:4][CH:3]=1.O=S(Cl)[Cl:17]>CN(C=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([Cl:17])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(Oc1ccc(Br)cc1)C(=O)Cl
Yield: 78 %

Procedure:
A mixture of 2-(4-bromophenoxy)-2-methylpropanoic acid (10.0 g, 38.6 mmol). DMF (0.5 mL) and SOCl2 (40 mL) was heated for 3 h, allowed to cool and distilled to yield the sub-title compound (8.4 g, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:16]1([CH:23]=[CH:22][CH:21]=[C:19]([OH:20])[CH:18]=1)[OH:17].C([O-])([O-])=O.[Na+].[Na+]>B(F)(F)F.CCOCC>[OH:17][C:16]1[CH:18]=[C:19]([OH:20])[CH:21]=[CH:22][C:23]=1[C:13](=[O:15])[CH2:12][CH:9]1[CH2:8][CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CCC(CC(=O)O)CC1
Reactant: Oc1cccc(O)c1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C1CCC(CC(=O)c2ccc(O)cc2O)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of 2-(4-(ethoxycarbonyl)cyclohexyl)acetic acid (700 mg, 11.6 mmol) in BF3-Et2O (10 ml) was added resorcinol (1.5 g, 14.0 mmol). The solution was stirred at 85° C. overnight, poured into Na2CO3 solution (2N, 20 ml), extracted with EtOAc (30 ml×3), washed with brine, dried over Na2SO4, filtrated and concentrated to afford 3 g of yellow oil, which was purified by silica gel column (PE/EtOAc=3/1) to afford 400 mg of Intermediate C. MS (ESI): m/z 307.1[M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH:16]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:17][C:18]#[N:19]>C(O)(=O)C.C(Cl)Cl>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([CH:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=3)[CH2:17][C:18]#[N:19])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: CCOc1cc(C(N)CC#N)ccc1OC
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOc1cc(C(CC#N)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 56 %

Procedure:
A stirred suspension of 3-nitrophthalic anhydride (0.24 g, 1.13 mmol) and 3-amino-3-(3-ethoxy-4-methoxyphenyl)propanenitrile (0.25 g, 1.13 mmol) in 6 mL of acetic acid was heated to reflux under nitrogen for 12 hours. The acetic acid was removed in vacuo to afford an orange gum which was dissolved in methylene chloride (10 mL) and was washed with a saturated aqueous solution of sodium bicarbonate (2×10 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride (10 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil. The crude product was purified by flash column chromatography (silica gel, 5% ethyl acetate/methylene chloride) and the resulting solid was dried in vacuo (60° C., <1 mm) to afford 0.25 g (56%) of 3-(3-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile as a yellow solid: mp 155.5°-157° C.; 1H NMR (CDCl3) δ 8.20-8.09 (m, 2 H), 8.02-7.86 (m, 1 H), 7.15-7.02 (m, 2 H), 6.88-6.76 (m, 1 H), 5.64 (dd, J=6.3, 10.6 Hz, 1 H), 4.09 (q, J=7 Hz, 2 H), 3.85 (s, 3 H), 3.84 (dd, J=10.6, 16.7 Hz, 1 H), 3.26 (dd, J=6.3, 16.7 Hz, 1 H), 1.46 (t, J=7 Hz, 3 H); 13C NMR (CDCl3) δ 165.3, 162.3, 150.1, 148.7, 144.9, 135.7, 133.5, 129.0, 128.1, 127.4, 123.2, 120.3, 116.6, 112.1, 111.5, 64.6, 55.9, 51.9, 20.9, 14.7; Anal. calcd for C20H17N3O6. Theoretical: C, 60.76; H, 4.33; N, 10.63. Found: C, 60.59; H, 4.22; N, 10.65.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Mg]Cl)(C)C.[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[C:24]2=[O:33])=[CH:20][CH:19]=1.Cl>ClCCCl.O1CCCC1>[F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([C:25]2([OH:32])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]([CH2:22][C:21]3[CH:34]=[CH:35][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[C:24]2=[O:33])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: COc1ccc(CN2C(=O)C(=O)c3ccccc32)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COc1ccc(CN2C(=O)C(O)(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a stirred solution of 2-fluoro-4-hydroxybenzonitrile (8.00 g, 58.3 mmol) in 1,2-dichloroethane (500 mL) and tetrahydrofuran (50 mL) was added isopropylmagnesium chloride (29.2 mL, 2.0 M solution in tetrahydrofuran, 58.4 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and at ambient temperature for 2 h. 1-(4-methoxybenzyl)-1H-indole-2,3-dione (15.0 g, 56.1 mmol) was added and the reaction mixture was stirred at reflux for 156 h. The mixture was cooled to 0° C. and 10% w/v hydrochloric acid was added. The phases were separated and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate/hexanes (1/1) to afford 2-fluoro-4-hydroxy-5-[3-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (12.30 g, 54%): 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, J=9.0 Hz, 1H), 7.34-7.32 (m, 2H), 7.17-7.11 (m, 1H), 6.91-6.76 (m, 7H), 4.78 (ABq, 2H), 3.72 (s, 3H); MS (ES+) m/z 404.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[C:14]2=O)[C:5]([O:7][CH3:8])=[O:6].[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[CH2:14]2)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C(=O)OC)c1cccc2c1NC(=O)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C(C(=O)OC)c1cccc2c1NC(=O)C2

Procedure:
A solution of 2,3-dihydro-2,3-dioxo-1H-indole-7-propandioic acid dimethyl ester (1.4 g, 0.0048 mole) is dissolved in acetic acid (100 ml) and in the presence of 20% Pd/C is treated with hydrogen gas at 50 psi. The solution is filtered and concentrated to yield 2,3-dihydro-2-oxo-1H-indole-7-propandioic acid dimethyl ester. This is purified by flash chromatography on silica (elution with 7:3 hexane: ethyl acetate) to give after concentration pure 2,3-dihydro-2-oxo-1H-indole-7-propandioic acid dimethyl ester, mp 161°-161.5° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](Cl)(=[O:19])[C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12](Cl)=[O:13]>CCO>[OH:2][C:1]1[C:8]2[C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9](=[O:19])[C:7]=2[C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: Oc1ccc(O)cc1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Yield: 64.9 %

Procedure:
The method was the same as in Example 1, but using 11.0 g (0.1 mols) of hydroquinone and 20.1 g (0.1 mols) of phthalic acid dichloride. The product was 15.6 g (65% yield) of 1,4-dihydroxy-9,10-anthraquinone (2), m.p.=199° C. (literature 200°-202° C. EtOH).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CN(C=O)C.C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:32][CH2:33][N:34]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:35][CH2:36]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Nc3cc(Cl)cc(Cl)c3)c1)cn2C1CCNCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(n2cc(C(=O)c3cccc(NC(=O)Nc4cc(Cl)cc(Cl)c4)c3)c3c(N)ncnc32)CC1
Yield: 19 %

Procedure:
A solution of 1-[3-(4-Amino-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-3-(3,5-dichloro-phenyl)-urea (100 mg, 0.19 mmol) and methanesulfonylchloride (22 mg, 0.19 mmol) in DMF/CH2Cl2 (2/3, 5 mL) was stirred in a sealed tube for 1.5 hours at room temperature. The reaction mixture concentrated in vacuo. Purification by reverse phase preparative HPLC (HPLC method 2) provided the title compound as a white solid (21.8 mg, 19%). MS: 603.5 (MH+); HPLC Rf: 2.3 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:28][O:29]C1C=CC=CC=1B(O)O.O1C2C=CC(C3(C(NC4C=NC(Br)=CC=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[O:29][CH3:28])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Nc1ccc(-c2ccccc2)nc1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: COc1ccccc1B(O)O
Agent: O=C(Nc1ccc(Br)nc1)C1(c2ccc3c(c2)OCO3)CC1
Product: COc1ccccc1-c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cn1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-(2-methoxyphenyl)pyridin-3-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-phenylpyridin-3-yl)cyclopropanecarboxamide from 2-methoxyphenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[S:27]([NH2:30])(=[O:29])=[O:28]>CN(C)C1C=CN=CC=1.C(O)(C)(C)C.ClCCl>[Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([NH:30][S:27]([C:20]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=3[Cl:18])(=[O:29])=[O:28])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: COc1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: O=C(O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Agent: CN(C)c1ccncc1
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: COc1ccc(Cl)c(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Cl)c3n2)c1
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
To the carboxylic acid from Step C (243 mg, 0.92 mmol) was added a solution of 4-(dimethylamino)pyridine (340 mg, 2.76 mmol) and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (232 mg, 2.3 mmol) in t-butanol (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred for 15 min, 2-chloro-5-methoxybenzenesulfonamide (190 mg, 0.86 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Dichloromethane (200 mL) was then added, the mixture was extracted with 1 N hydrochloric acid (3×100 mL), and the separated organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford a solid. The solid was rinsed with diethyl ether to afford 240 mg of the title compound, a compound of the present invention, as a white solid, m.p. 211-212° C. 1H NMR (CDCl3) δ 10.10 (br s, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 7.86 (d, 1H), 7.54 (s, 1H), 7.38 (d, 1H), 7.09 (dd, 1H) 3.91 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)C1C=CC=CC=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1>>[OH:8][C:9]1[CH:14]=[C:13]([C:26]2[CH:27]=[CH:28][S:24][CH:25]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:23])[CH2:17]1
Reactant: OB(O)c1ccsc1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-c3ccsc3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared using 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and thiophene-3-boronic acid analogous to Example 272: 1H NMR (DMSO-d6δ9.68 (br s, 1H), 7.75 (m, 1H), 7.61 (m, 1H), 7.43 (m, 1H), 7.38 (m, 1H), 7.15 (m, 2H), 4.32 (s, 2H); (M−1)−=309.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[N:57]=[CH:58][O:59][C:60]=1[C:61](Cl)=[O:62]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:61]([C:60]2[O:59][CH:58]=[N:57][C:56]=2[CH3:55])=[O:62])[CH2:49][CH2:48]1
Reactant: Cc1ncoc1C(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncoc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 37 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-methyl-1,3-oxazole-5-carbonyl chloride as starting materials in 37% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.41 (m, 2H), 9.02 (s, 1H), 8.40 (s, 1H), 8.30 (s, 2H), 8.20 (s, 1H), 7.65 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 4.52 (m, 2H), 3.12 (m, 1H), 2.98 (m, 4H), 2.32 (m, 2H), 2.21 (s, 3H), 2.12 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C29H30ClN8O3 (M+H)+: m/z=573.2.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[C:11]([O:15][C:16](=[O:29])[N:17]([C:19]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[CH3:18])([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16](=[O:29])[N:17]([C:19]1[CH:24]=[C:23]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=2)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[CH3:18])([CH3:14])([CH3:12])[CH3:13]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(Br)c2)ccc1[N+](=O)[O-]
Yield: 82.6 %

Procedure:
To a 50 ml of anhydrous N,N-dimethylformamide suspension containing 2.5 g of sodium hydride (55% weight) was added 10.0 g of 3-bromophenol, and the mixture was stirred under ice-cooling for 15 minutes. Subsequently, a solution of 16.6 g of N-(5-chloro-2-nitrophenyl)-N-methylcarbamic acid t-butyl ester dissolved in 70 ml of anhydrous N,N-dimethylformamide was added to the mixture in drops, and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was concentrated, followed by addition of water, neutralization using 3N hydrochloric acid and extraction with ethyl acetate. The extraction solution was washed with saturated saline, and then dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extraction solution, and the insoluble product which deposited was washed with hexane and filtered, followed by drying under reduced pressure, to give the title compound (20.2 g, 83% yield).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3](=O)[CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=1)[C:5](OCC)=[O:6].O.[NH2:25][NH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:20][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18])[CH2:10][CH:4]1[C:3]([C:2]([F:23])([F:22])[F:1])=[N:26][NH:25][C:5]1=[O:6]
Reactant: CCOC(=O)C(Cc1ccc([N+](=O)[O-])c(C)c1)C(=O)C(F)(F)F
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(CC2C(=O)NN=C2C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 55.3 %

Procedure:
Ethyl 4,4,4-trifluoro-2-(3-methyl-4-nitro-benzyl)-3-oxo-butyrate (2.0 g), hydrazine monohydrate (0.5 g) and a small amount of p-toluenesulfonic acid were dissolved in toluene, and the mixture was refluxed for 4 hours. After cooling, the solvent was distilled off under reduced pressure. The residue was suspended in ethyl acetate and washed with 1N aqueous solution of hydrochloric acid. After drying the organic layer with sodium sulfate, the solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain 4-(3-methyl-4-nitro-benzyl)-5-trifluoromethyl-2,4-dihydro-pyrazol-3-one (1.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH2:14][N:15]=[N+:16]=[N-:17]>C1C=CC=CC=1.C1CCCCC1>[CH3:1][O:2][C:3]([C:5]1[N:17]=[N:16][N:15]([CH2:14][C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[Cl:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:4]
Reactant: COC(=O)C#CC(=O)OC
Reactant: [N-]=[N+]=NCc1ccccc1Cl
Solvent: c1ccccc1
Solvent: C1CCCCC1
Product: COC(=O)c1nnn(Cc2ccccc2Cl)c1C(=O)OC

Procedure:
A solution of 8 g (0.054 mol) of acetylene-dicarboxylic acid dimethyl ester in 25 ml of benzene is added dropwise to a solution of 8.4 g (0.05 mol) of o-chlorobenzyl azide in 50 ml of benzene that is boiling under reflux. After a further hour under reflux, the whole is diluted with 75 ml of cyclohexane and, after cooling, the substance that has crystallised out is filtered off with suction. After washing with a mixture of diethyl ether and hexane (1:1), there is obtained 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester having a melting point of 88°-91°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[F:16]C1C=C(C=CC=1)C=O.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:16])[CH:7]=1
Reactant: O=Cc1cccc(F)c1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1cccc(F)c1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methylester but using 3-fluorobenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:19][C:20]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCSCc1cc[nH]n1
Reactant: O=C(N=C=S)c1ccccc1
Product: O=C(NC(=S)NCCSCc1cc[nH]n1)c1ccccc1

Procedure:
By the procedure of Example 18, 3-[(2-aminoethyl)thiomethyl]pyrazole is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(3-pyrazolylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(3-pyrazolylmethylthio)ethyl]thiourea.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[CH3:9][Si:10]([CH3:18])([CH3:17])[CH2:11][CH2:12][O:13][C:14](Cl)=[O:15]>CCOCC>[CH3:9][Si:10]([CH3:18])([CH3:17])[CH2:11][CH2:12][O:13][C:14]([NH:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1)=[O:15]
Reactant: C[Si](C)(C)CCOC(=O)Cl
Reactant: NCCc1c[nH]cn1
Solvent: CCOCC
Product: C[Si](C)(C)CCOC(=O)NCCc1c[nH]cn1

Procedure:
1.84 g (10 mmol) of histamine dihydrochloride is slurried in 50 ml of methylene chloride, and 6.2 ml (44 mmol) of triethylamine is added. The thus resultant mixture is added portionwise to 2-trimethylsilylethylchloroformate in toluene (prepared as described above) at 10°-15° C. The reaction mixture is stirred at room temperature overnight. Undissolved material is filtered off and identified by NMR as being triethylamine hydrochloride. The toluene solution is evaporated, the residue then being slurried in 30 ml of ethyl acetate. 1.0 g of undissolved triethylamine hydrochloride is removed by filtration. The ethyl acetate solution is evaporated, and the residue is slurried twice in petroleum ether. The petroleum ether solutions are evaporated and 1.0 g of a semicrystalline product is obtained; by NMR analysis this product is identified as being histamine in which both the amino group and ring nitrogen have been acylated with 2-trimethylsilylethylchloroformate. The acyl group on the ring nitrogen is removed by treatment of the product for 2 hours with 100 μl of triethylamine in 50 ml of methanol. The solution is evaporated to leave an oil which is transformed into white crystals by treatment with 30 ml of ether. More precipitate is obtained upon addition of 75 ml petroleum ether. 560 mg of I is obtained upon filtration. The structure of the product is established with the aid of its NMR spectrum. 1H NMR spectrum (CDCl3) expressed as values: 2H 7.60 s, 5H 6.82 s, --NH-- 5.20, --CH2CH2 --O-- 4.15 t, --OCONHCH2 -- 3.50 m, 4-CH2 -imidazole 2.82 t, SiCH2CH2 1.00 t, (CH3)3Si 0.03 s.