Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([NH:5][C:6]([CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([NH2:28])=[C:20]([Cl:29])[CH:19]=1)(C(OCC)=O)[C:7]([O:9]CC)=[O:8])(=O)C>CC(O)=O.O>[ClH:29].[NH2:5][CH:6]([CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:26])([F:27])[F:25])[C:21]([NH2:28])=[C:20]([Cl:29])[CH:19]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)(NC(C)=O)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(Cl)cc(CC(N)C(=O)O)cc1C(F)(F)F
Temperature: 140 °C
Reaction time: 0.25 h

Procedure:
50 mL conc. HCl were added to a solution of 40.0 g (94.16 mmol) of diethyl 2-acetylamino-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-malonate in 110 mL AcOH and 150 mL of water and the reaction mixture was heated to 140° C. for 4 h. The precipitate formed was filtered off and discarded. The filtrate was evaporated down i. vac., combined with 100 mL of EtOH and stirred for 15 min at RT. The precipitate formed was filtered off, washed with EtOH and dried i. vac. The crude product was used in the next reaction step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][NH2:14]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:14][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CN
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
4-Methoxybenzene-1-sulfonyl chloride (1 g, 4.84 mmol) was dissolved in dichloromethane (15 mL) and was treated with methanamine (9.7 ml, 19.40 mmol). The reaction mixture was stirred at room temperature for two hours. The crude was filtered and washed with dichloromethane to give 1.02 g (100% yield) of the title compound as a white solid. Purity 95%.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([N:6]2[CH:10]=[CH:9][CH:8]=[CH:7]2)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCCl>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([C:7]1[N:6]([N:5]2[C:4](=[O:11])[C:3]3=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]3[C:1]2=[O:16])[CH:10]=[CH:9][CH:8]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Solvent: ClCCCl
Product: O=C(c1ccccc1Cl)c1cccn1N1C(=O)c2ccccc2C1=O
Yield: 123.7 %

Procedure:
To a vigorously stirred mixture of 1-phthalimidopyrrole (45 g, 0.212 mol) and o-chlorobenzoyl chloride (37 g, 0.212 mol) in 500 ml of 1,2-dichloroethane was added freshly pulverized, fused zinc chloride (43.3 g, 0.318 mol) in one portion. The reaction mixture was heated at gentle reflux for 4.5 hours and then quenched with 700 ml of crushed ice and 500 ml of dichloromethane. The organic layer was separated and washed with water (2x 500 ml), dried over anhydrous MgSO4, filtered, and evaporated to give 92 g of an oil. This oil was purified by column chromatography (silica gel/dichloromethane) to give 33.8 g (45%) of needles, m.p. 158°-160° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[C@@H:19]3[CH2:23][C@H:22]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])[C@@H:21]([OH:29])[C@H:20]3[OH:30])=[C:12]([NH:31][CH2:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:11]=2)[CH:9]=1)=[O:4].[CH3:46][NH2:47]>>[N:47]1[CH:21]=[CH:20][CH:19]=[CH:23][C:46]=1[CH2:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[C@@H:19]3[CH2:23][C@H:22]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])[C@@H:21]([OH:29])[C@H:20]3[OH:30])=[C:12]([NH:31][CH2:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:11]=2)[CH:9]=1)=[O:4]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)NC)cn4)nc32)[C@H](O)[C@@H]1O
Reactant: CN
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)NCc5ccccn5)cn4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to 1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid methylamide (Example 173), by substituting C-pyridin-2-yl-methylamine for methylamine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=O.[Br:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[F:24][C:25]1[C:30]([F:31])=C(O)[CH:28]=[CH:27][C:26]=1[CH2:33][CH2:34][C:35](OCC)=[O:36]>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:13])([F:12])[F:1])=[C:4]2[CH2:8][O:10][C:11]2[CH:28]=[CH:27][C:26]([CH2:33][CH2:34][CH2:35][OH:36])=[C:25]([F:24])[C:30]=2[F:31])=[CH:17][CH:16]=1
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Product: OCCCc1ccc(OCc2c(C(F)(F)F)ccn2-c2ccc(Br)cc2)c(F)c1F

Procedure:
The title compound was prepared by (a) reacting the product prepared in Step B of Example 1 and 4-bromophenylboronic acid according to the procedure described in Example 1, Step C, (b) then reacting the resulting product according to the procedure in Example 1, Step D, (c) then reacting the resulting product with ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate according to the procedure described in Example 1, Step E, and Example 2.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[C:7]([O:10][CH2:11][C:12]1[N:13]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)=[CH:16][CH:15]=2)(=[O:9])[CH3:8].C1C[O:43]CC1>>[C:7]([O:10][CH2:11][C:12]1[N:13]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[C:14]2[C:19]([C:20]=1[C:1](=[O:5])[C:2]([OH:43])=[O:3])=[CH:18][C:17]([C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=1)=[CH:16][CH:15]=2)(=[O:9])[CH3:8]
Reactant: CC(=O)OCc1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccc(C)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C1CCOC1
Product: CC(=O)OCc1c(C(=O)C(=O)O)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (1.05 mL) was added dropwise to a stirring solution of {1-(4-methylbenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indol-2-yl}methyl acetate (0.515 g) in THF (17 mL) at room temperature over a period of 5 minutes under a nitrogen atmosphere. After the reaction mixture was stirred at room temperature for 4 hours, the reaction was quenched carefully with water. The aqueous mixture was extracted with ethyl acetate. The extract was washed with water, and brine, dried over anhydrous magnesium sulfate, and concentrated to give the title compound as a light brown solid, mp: 79–80° C. Mass spectrum (ESI, [M−H]−) m/z 524. 1HNMR (400 MHz, DMSO-d6): δ 14.50 (br s, 1H), 8.20 (s, 1H), 7.74 (d, 2H, J=8.55 Hz), 7.70 (d, 1H, J=8.69 Hz), 7.62 (d, 1H, J=8.55 Hz), 7.47 (d, 2H, J=8.25 Hz), 7.15 (d, 2H, J=7.88 Hz), 6.99 (d, 2H, J=7.78 Hz), 5.64 (s, 2H), 5.53 (s, 2H), 2.25 (s, 3H), and 1.83 ppm (s, 3H).
Reaction SMILES: [C:1]1([N:7]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27](B4OC(C)(C)C(C)(C)O4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:39][C:40]1[CH:45]=[CH:44][C:43](I)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:39][C:40]1[CH:45]=[CH:44][C:43]([C:27]2[CH:26]=[CH:25][C:24]([C:21]3[CH:20]=[CH:19][C:18]([N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH:11]=[CH:10][CH:9]=4)=[CH:23][CH:22]=3)=[CH:29][CH:28]=2)=[CH:42][CH:41]=1
Reactant: CC1(C)OB(c2ccc(-c3ccc(N(c4ccccc4)c4cccc5ccccc45)cc3)cc2)OC1(C)C
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc(-c2ccc(-c3ccc(N(c4ccccc4)c4cccc5ccccc45)cc3)cc2)cc1
Temperature: 95 °C
Yield: 90.8 %

Procedure:
A mixture of compound 7 (4.5 g, 9.0 mmol), 1-bromo-4-iodobenzene (5.12 g, 18 mmol), Pd(PPh3)4 (0.52 g, 0.45 mmol) and potassium carbonate (4.436 g, 32 mmol) in dioxane/water (150 ml/30 ml) was degassed and heated at 95° C. overnight. After being cooled to RT, the mixture was poured into dichloromethane (300 ml), washed with brine, dried over Na2SO4, then loaded on silica gel, purified by flash column (hexanes to hexanes/ethyl acetate 20:1) to give a light yellow solid 8 (4.30 g, in 90.7 yield).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([CH:18]([C:21]1[NH:22][CH:23]=[CH:24][N:25]=1)[CH2:19][CH3:20])[CH3:17].C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:16]([CH:18]([C:21]1[N:22]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH:23]=[CH:24][N:25]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCC(CC)c1ncc[nH]1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(-n2ccnc2C(CC)CC)c([N+](=O)[O-])c1

Procedure:
Ethyl 4-fluoro-3-nitrobenzoate 9.16 g, 2-(1-ethylpropyl)-1H-imidazole 5.94 g, N,N-diisopropylethylamine 11.2 mL and acetonitrile 86 mL were mixed and heated under reflux for 15 hours in nitrogen atmosphere. From the reaction liquid the solvent was distilled off, and the residue was dissolved in ethyl acetate and rendered weakly alkaline with saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with water and dried over magnesium sulfate. Distilling the solvent off, 13.16 g of the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.O.[CH3:13][N:14]1CCCC1=O>S([O-])([O-])(=O)=O.[Cu+2]>[CH3:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([C:13]#[N:14])=[CH:11][C:6]=2[N:7]=1
Reactant: Cc1nc2cc(Br)ccc2s1
Reactant: CN1CCCC1=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Cc1nc2cc(C#N)ccc2s1
Temperature: 185 °C

Procedure:
28.0 g of 5-bromo-2-methylbenzothiazole was dissolved in 200 ml of N-methyl-2-pyrrolidone, the solution thus prepared was mixed with 13.8 g of cuprous cyanide and a catalytically effective amount of copper sulfate, and the mixture was stirred for 4 hours with heating at a temperature of 180 to 190° C. in a stream of nitrogen. The resulting reaction solution was poured into water, and insoluble materials thus formed were collected by filtration. The thus collected insoluble materials were mixed with a mixture consisting of 22 ml of ethylenediamine and 50 ml of water, and the resulting mixture was stirred thoroughly. After extraction with benzene, the resulting organic layer was washed with water, and dried to distill of benzene. Thereafter, the residue thus formed was washed with ethanol to obtain 10.22 g of 2-methyl-5-benzothiazolecarbonitrile in the form of light brown crystals.
Reaction SMILES: [CH:1]([C@@H:14]1[O:19][CH2:18][C@@H:17](OS(C)(=O)=O)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([C@H:17]1[CH2:16][CH2:15][C@@H:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:19][CH2:18]1)=[N+:26]=[N-:27]
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Yield: 91.3 %

Procedure:
Trans-2-diphenylmethyl-tetrahydropyran-5-yl methanesulfonate 13 (0.39 g, 1.12 mmol) in dry DMF (50 ml) was reacted with sodium azide (0.22 g, 3.35 mmol) to yield cis-5-azido-2-diphenylmethyl-tetrahydropyran 14 (0.3 g, 92%) as an oil (Procedure B).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[C:28]([F:39])[CH:27]=2)[CH:19]=1.[OH-].[Na+].[ClH:42].C(OCC)(=O)C.Cl>C(OCC)(=O)C.O1CCCC1.CO>[ClH:42].[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[C:28]([F:39])[CH:27]=2)[CH:19]=1
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OCc4cccc(C)n4)cc3C)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(COc2cc(C)c(-c3cccc(COc4ccc(CCC(=O)O)c(F)c4)c3)c(C)c2)n1
Yield: 86 %

Procedure:
To a mixture of ethyl 3-[4-({2′,6′-dimethyl-4′-[(6-methylpyridin-2-yl)methoxy]biphenyl-3-yl}methoxy)-2-fluorophenyl]propanoate (1.30 g, 2.46 mmol), methanol (6 mL) and tetrahydrofuran (10 mL) was added 1 N sodium hydroxide aqueous solution (4.9 mL) at room temperature with stirring, and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was neutralized with 1 N hydrochloric acid, diluted with ethyl acetate, washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-ethyl acetate) to give an oil. The oil was dissolved in ethyl acetate and 4 N hydrogen chloride-ethyl acetate solution was added. The precipitated crystals were collected by filtration, washed and dried to give the title compound (1.14 g, yield 86%) as colorless crystals.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:16]4[C:21]([CH:22]=3)=[CH:20][C:19](I)=[CH:18][CH:17]=4)=[O:13])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:32]1([CH:38]([SiH3:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+]>CN1CCCC1=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:1]1([C:5]2[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([SiH2:45][CH:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:18][CH:17]=4)=[O:13])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(N2CCC2)nc1)c1cc2cc(I)ccc2n1Cc1cccc(F)c1
Reactant: [SiH3]C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(N2CCC2)nc1)c1cc2cc([SiH2]C(c3ccccc3)c3ccccc3)ccc2n1Cc1cccc(F)c1
Yield: 11.4 %

Procedure:
Compound No. 12 was prepared according to a process similar to that described in stage 8.4, by reacting 0.15 g (0.28 mmol) of N-[6-(azetidin-1-yl)pyridin-3-yl]-5-iodo-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in stage 8.3, with 167 mg (0.84 mmol) of diphenylmethylsilane in the presence of 0.18 g (0.84 mmol) of potassium triphosphate and of 15 mg (0.03 mmol) of bis(tri-tert-butylphosphine)palladium in 2 ml of dry 1-methyl-2-pyrrolidinone (NMP). 19 mg of the expected product are obtained.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH:13]1[CH2:16][CH:15]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1.CCN(CC)CC>C(Cl)Cl>[CH2:19]([O:18][CH2:17][C@@H:15]1[CH2:16][C@H:13]([CH:12]=[O:11])[CH2:14]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCC1CC(COCc2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C[C@H]1C[C@@H](COCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 25 mL flask, a solution of dry DMSO (0.2 mL, 2.76 mmol) in 7 mL dry CH2Cl2 was cooled to −78° C., after which oxalyl chloride (0.12 mL, 1.37 mmol) was added drop by drop under argon. After stirring at −78° C. for 30 min, a CH2Cl2 solution of 1-hydroxymethyl-3-benzyloxymethyl-cyclobutane (cisl trans=211, 0.2 g, 0.97 mmol) was added drop by drop. After stirring for 1 hr, Et3N (0.7 mL, 4.9 mmol) was added dropwisely. After 15 min, the reaction was warmed to ambient temperature. After 4 hr, TLC showed no starting material. Then the reaction mixture was diluted with 30 mL CH2Cl2, washed with 30% aqueous NH4Cl (2×10 mL), H2O (1×10 mL) and brine (1×10 mL). The organic phase was dried over MgSO4 and the solvents were removed to give an oily product, which was purified by silica gel chromatography ((Hexane: EtOAc=9:1) to give the cis-diastereomer (74 mg, 37.4%, Rf=0.43 (Hexane: EtOAc=12:1)) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 2.01-2.08 (m, 2H), 2.21-2.28 (m, 2H), 2.58-2.70 (m, 1H), 3.03-3.12 (m, 1H), 3.37-3.39 (d, J=8.0, 2H), 4.49 (s, 2H), 7.25-7.36 (m, 5H), 9.66-9.67 (d, J=4.0, 1H). MS (FAB): expected for C13H16O2 (M−H)+ 203.26. Found 203.10658. IR (neat) νmax 3054, 2935, 2858, 1704, 1454, 1266, 1092, 738, 704.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[ClH:13]>C1C=CC=CC=1.O.[Cd].ClC1C=CC=CC=1.ClC1C=CC=CC=1>[Cl:13][C:3]1[CH:4]=[CH:5][C:9]([C:6]([C:5]2[C:4]([CH3:12])=[C:3]([CH:11]=[CH:10][CH:9]=2)[C:1]#[N:2])=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1c(C#N)cccc1C(=O)Cl
Reactant: Cl
Agent: [Cd]
Solvent: Clc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: Cc1c(C#N)cccc1C(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
The said benzene solution was cooled to 5° C. and then a solution of 27.4 g of 3-cyano-2-methyl-benzoyl chloride in 85 cc of benzene was added thereto. The mixture was allowed to return to room temperature and was stirred overnight. The mixture was refluxed for 31/2 hours and after cooling, the mixture was added to a solution of 30 cc of hydrochloric acid in 600 cc of water. The mixture was extracted with ether and the combined ether phases were washed successively with 1 N hydrochloric acid, water, 1 N sodium hydroxide and water until the wash waters were neutral. The organic phase was dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was empasted with 40 cc of petroleum ether, vacuum filtered, washed with petroleum ether and dried at room temperature under reduced pressure to obtain 30.6 g of 3-p-chlorobenzoyl-2-methyl-benzonitrile. For analysis, the product was crystallized from methanol and melted at 84° C. The compound occurred in the form of beige crystals soluble in methylene chloride and chloroform.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]=O.Cl.[CH2:11]([CH2:18][NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)(=O)C>[CH2:11]([CH2:18][NH:19][CH2:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCCCC1
Reactant: NCCc1ccccc1
Reactant: C=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CCCCC1CNCCc1ccccc1
Temperature: 25 °C

Procedure:
37.6 ml cyclohexanone, 5.75 g paraformaldehyde, 38 ml glacial acetic acid and 30.2 g benzylmethylamine hydrochloride were heated at 105° C. (bath temperature) for 25 minutes, while stirring, the mixture was concentrated in vacuo (10 mbar), the residue was taken up in 100 ml 2-butanone and the mixture was concentrated again in vacuo. The residue was heated under reflux with 150 ml 2-butanone. After cooling to room temperature, the mixture was filtered and the residue on the filter was dried in vacuo. 36 g 2-[(benzylmethylamino)methyl]cyclohexanone were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cccc(Br)c3)c2c1

Procedure:
3-Bromoaniline is coupled with 4-chloro-6-nitroquinazoline, to produce 4-[(3-bromophenyl)amino]-6-nitroquinazoline, which is reduced thereafter to the corresponding 6-aminoquinazoline. The 4-[(3-bromophenyl)amino]-6-aminoquinazoline is then reacted with bistributyltin, using tetrakis(triphenylphosphine)palladium in triethylamine solution as the reaction catalyst. The stanylated quinazoline is then reacted with iodine-123, iodine-124 or iodine-131, in the presence of an oxidizing agent, to produce iodine-123 labeled, iodine-124 or iodine-131 labeled 4-[(3-bromophenyl)amino]-6-aminoquinazoline, as is described hereinbelow, which is further reacted with acryloyl chloride as described, to yield the final iodine-123 labeled, iodine-124 labeled or iodine-131 labeled product.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:31]1[N:36]=[C:35]([C:37](OC)=[O:38])[CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+].[CH:47]([OH:50])([CH3:49])[CH3:48]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([C:31]5[N:36]=[C:35]([C:37]([O:50][CH:47]([CH3:49])[CH3:48])=[O:38])[CH:34]=[CH:33][CH:32]=5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)OC1(C)C
Reactant: COC(=O)c1cccc(Br)n1
Reactant: CC(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)OC(=O)c1cccc(-c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)n1
Temperature: 80 °C

Procedure:
A vial containing (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (Example 64A, 31 mg, 0.074 mmol), methyl 6-bromo-2-pyridinecarboxylate (16 mg, 0.074 mmol), K2CO3 (31 mg, 0.22 mmol) and bis(triphenylphosphine)palladium(II) chloride (5 mg, 7 μmol) suspended in isopropanol (1 mL) was heated to 80° C. for 2 hours. The mixture was allowed to stand at room temperature over night. The mixture was partitioned between 1 M NaOH (5 mL) and CH2Cl2 (25 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (25 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated and chromatographed on silica gel eluting with a gradient of 2% to 10% (9:1 methanol:ammonium hydroxide) in CH2Cl2 and then rechromatographed on silica gel eluting with a gradient of 10:1:1 to 7:1:1 ethyl acetate:HCO2H:H2O. The residue was partitioned between 1 M NaOH and CH2Cl2. This CH2Cl2 layer was dried (MgSO4), filtered and concentrated to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.42-1.52 (m, 2H), 1.44 (d, J=6.3 Hz, 6H), 1.59-1.68 (m, 4H), 1.96-2.11 (m, 1H), 2.26-2.36 (m, 1H), 2.41-2.59 (m, 4H), 2.95-3.08 (m, 1H), 3.46 (t, J=9.3 Hz, 1H), 3.53-3.63 (m, 1H), 3.75-3.84 (m, 1H), 3.85-3.94 (m, 1H), 5.29-5.39 (m, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.80-7.99 (m, 4H), 8.50 (d, J=1.2 Hz, 1H); MS (DCI/NH3) m/z 451 (M+H)+.