Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:26])=[CH:16][C:17](OS(C(F)(F)F)(=O)=O)=[C:12]3[C:11]([CH3:27])=[CH:10]2)=[C:4]([CH3:28])[CH:3]=1.[NH:29]1[CH2:39][CH2:38][CH:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:30]1.C(N(CC)C(C)C)(C)C>O>[CH2:36]([O:35][C:33]([CH:32]1[CH2:38][CH2:39][N:29]([C:17]2[CH:16]=[C:15]([CH3:26])[N:14]=[C:13]3[N:9]([C:5]4[C:4]([CH3:28])=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=4[CH3:8])[CH:10]=[C:11]([CH3:27])[C:12]=23)[CH2:30][CH2:31]1)=[O:34])[CH3:37]
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c2c(C)cn(-c3c(C)cc(Cl)cc3C)c2n1
Reactant: CCOC(=O)C1CCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2cc(C)nc3c2c(C)cn3-c2c(C)cc(Cl)cc2C)CC1
Temperature: 160 °C
Yield: 79.7 %

Procedure:
A mixture of the crude trifluoromethanesulfonic acid 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl ester (20.5 g), ethyl isonipecotate (74.4 g) and N,N-diisopropylethylamine (12.2 g) was heated at 150-170° C. for 1 hour. To the reaction mixture, water was added and extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=5:1) to give 1-[1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidine-4-carboxylic acid ethyl ester (16.6 g) as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][NH:6][C:7](=[O:10])[CH2:8][CH3:9].Cl[C:12]1[N:17]=[CH:16][C:15]([C:18]([N:20]2[C@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][O:22][C:21]2([CH3:30])[CH3:29])=[O:19])=[CH:14][C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.O>C1COCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:13]2[C:12]([O:3][CH2:4][CH2:5][NH:6][C:7](=[O:10])[CH2:8][CH3:9])=[N:17][CH:16]=[C:15]([C:18]([N:20]3[C@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][O:22][C:21]3([CH3:30])[CH3:29])=[O:19])[CH:14]=2)=[CH:32][CH:33]=1
Reactant: CC(C)C[C@@H]1COC(C)(C)N1C(=O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: CCC(=O)NCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)NCCOc1ncc(C(=O)N2[C@H](CC(C)C)COC2(C)C)cc1-c1ccc(Cl)cc1
Reaction time: 6 h
Yield: 33.2 %

Procedure:
Sodium hydride dispersion in oil (˜55%, 72 mg) was added in portions to a well stirred solution of N-(2-hydroxyethyl)propionamide (71 mg, 0.6 mmol) in THF (13 mL). After stirring the mixture for 15 min at RT [6-Chloro-5-(4-chloro-phenyl)-pyridin-3-yl]-((R)-4-isobutyl-2,2-dimethyl-oxazolidin-3-yl)-methanone (225 mg, 0.55 mmol) was added and stirring continued for 6 h at RT. The mixture was poured into water and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (cyclohexane/ethyl acetate 8:1) to yield 89 mg of the title compound as a white solid, MS (ISP) 488.2 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[CH:6]=1.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCCC1>[C:9]([C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[CH:6]=1)#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1csc(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1cc(C=O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromo-4-thiophenecarboxaldehyde (45.3 g), 1-dodecyne (43.4 g), and triethylamine (99 ml), in dry tetrahydrofuran (250 ml) was chilled to 5° C. and degassed under nitrogen. bis(Triphenylphosphine)palladium(II)chloride (1.66 g) and copper(I)iodide (0.23 g) were added to the reaction mixture. The mixture was degassed and stirred overnight, under nitrogen, as it was allowed to warm to room temperature. The precipitate was filtered off, washed with ethyl acetate, and the filtrate was evaporated. Ethyl acetate was added to the residue. The solution was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed through a silica gel pad eluting with heptane/1% ethyl acetate. The appropriate fractions were collected and evaporated. The residue and that from a similar reaction on a 0.05 mole scale were combined and distilled to give 30.7 g (79.5%), bp 181°-185° C. @0.35 mm Hg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:27])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[NH:25][CH:24]=[N:23][C:22]=3[Cl:26])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:28][C@H:29]([OH:32])[C:30]#[CH:31]>C1COCC1.CCOC(C)=O.[Cu]I>[Cl:26][C:22]1[N:23]=[CH:24][NH:25][C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([C:31]#[C:30][C@@H:29]([OH:32])[CH3:28])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:27])=[O:20]
Reactant: C#C[C@H](C)O
Reactant: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F)c1[nH]cnc1Cl
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](O)C#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 44.3 %

Procedure:
A solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (86 mg, 0.174 mmol), (2S)-3-butyn-2-ol (30.5 mg, 0.436 mmol), palladiumbisdichlorobistriphenylphosphine (12.23 mg, 0.017 mmol), copper(I) iodide (1.659 mg, 8.71 μmol) and TEA (0.121 ml, 0.871 mmol) in THF (3 ml) was irradiated in the microwave for 10 minutes at 120° C. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(3S)-3-hydroxy-1-butyn-1-yl]phenyl}oxy)-2-fluorophenyl]methyl}-1H-imidazole-5-carboxamide (37 mg, 0.077 mmol, 44% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.54-7.94 (m, 1H), 7.26-7.47 (m, 2 H), 7.11 (s, 1H), 6.89 (s, 1H), 6.74 (s, 1H), 4.24-4.71 (m, 3H), 1.41 (d, 3H). LC-MS (ES+) m/z 481.95, [M+H].
Reaction SMILES: C(OC([N:8]1C(C(O)=O)C[C:15]2[CH:14]=[C:13]3OC[C@H](C4C=CC(OCC5C=CC(Cl)=C(Cl)C=5)=CC=4)O[C:12]3=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.[C:41]([O:45][C:46]([N:48]1[CH:57]([C:58](=[O:68])[NH:59][C@H:60]([C:64]([O:66][CH3:67])=[O:65])[CH2:61][C:62]#[CH:63])[CH2:56][C:55]2[CH:54]=[C:53]3[O:69][CH2:70][C@H:71]([C:73]4[CH:78]=[CH:77][C:76]([O:79][CH2:80][C:81]5[CH:86]=[CH:85][C:84]([Cl:87])=[C:83]([Cl:88])[CH:82]=5)=[CH:75][CH:74]=4)[O:72][C:52]3=[CH:51][C:50]=2[CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42].IC1C=CC(C#N)=CC=1>>[C:41]([O:45][C:46]([N:48]1[CH:57]([C:58](=[O:68])[NH:59][C@H:60]([C:64]([O:66][CH3:67])=[O:65])[CH2:61][C:62]#[C:63][C:13]2[CH:12]=[CH:11][C:10]([C:9]#[N:8])=[CH:15][CH:14]=2)[CH2:56][C:55]2[CH:54]=[C:53]3[O:69][CH2:70][C@H:71]([C:73]4[CH:74]=[CH:75][C:76]([O:79][CH2:80][C:81]5[CH:86]=[CH:85][C:84]([Cl:87])=[C:83]([Cl:88])[CH:82]=5)=[CH:77][CH:78]=4)[O:72][C:52]3=[CH:51][C:50]=2[CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: C#CC[C@H](NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3)C(=O)OC
Agent: N#Cc1ccc(I)cc1
Product: COC(=O)[C@H](CC#Cc1ccc(C#N)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 40.3 %

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (59 mg) was coupled with (S)-propargyl-glycinemethylester hydrochloride (20 mg) according to General Procedure A. The resulting (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-8-((S)-1-methoxycarbonyl-but-3-ynylcarbamoyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (26 mg) was reacted with 4-iodobenzonitrile (7 mg) according to General Procedure S to give (S)-8-[(S)-4-(4-cyano-phenyl)-1 methoxycarbonyl-but-3-ynylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (12 mg).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14](Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]C.C([Li])CCC.FC([I:35])(F)F>>[ClH:1].[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14]([I:35])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)I
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Agent: Cl
Agent: [Li]C
Agent: [Li]CCCC
Product: Cc1csc(Nc2ncc(I)cc2OCc2ccccc2)n1
Yield: 37 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (prepared according to Example 1) (0.250 g, 0.664 mmol), MeLi (0.519 mL, 0.831 mmol), butyllithium (0.332 mL, 0.831 mmol) and trifluoromethyliodide (bubbled in excess) were reacted according to the method of Example 7 to provide 3-(benzyloxy)-5-iodo-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (0.104 g, 37.0% yield). 1H NMR (d6-DMSO) δ 8.14 (d, 1H), 7.82 (m, 1H), 7.58 (m, 2H), 7.40 (m, 3H), 6.79 (s, 1H), 5.31 (s, 2H), 2.28 (s, 3H). Mass spectrum (apci) m/z=424.0 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: COc1cccc(CN)c1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCc3cccc(OC)c3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 3-methoxy-benzylamine to afford the title compound. MS: m/e=378 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)(=O)=O)N=2)CC1.[NH:50]1[CH:54]=[C:53]([CH:55]=[O:56])[N:52]=[CH:51]1>C(O)(C)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4\[NH:19][C:18](=[O:20])[NH:17][C:16]\4=[O:21])=[C:9]3[N:8]=[C:7]([N:50]3[CH:54]=[C:53]([CH:55]=[O:56])[N:52]=[CH:51]3)[N:6]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1c[nH]cn1
Reactant: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Solvent: CC(C)O
Product: O=Cc1cn(-c2nc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)cn1
Temperature: 150 °C

Procedure:
A mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (20 mg, 0.056 mmol) was mixed with 1H-imidazole-4-carbaldehyde (16 mg, 0.168 mmol) in isopropanol (2 mL). The mixture was stirred under microwave heating at 150° C. for 20 minutes. The reaction mixture was cooled to room temperature and the solvent was removed by rotary evaporation to provide (Z)-1-(4-(cyclopropylamino)-8-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a][1,3,5]triazin-2-yl)-1H-imidazole-4-carbaldehyde as a crude mixture which was taken on to the next step without further purification. LCMS (ES): >95% pure, m/z 380 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[C:9]1([CH3:24])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1C1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:13]=[CH:14][C:9]([CH3:24])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccccc1-c1ccc(B(O)O)cc1
Reactant: Clc1cc(I)ccn1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccnc(Cl)c2)cc1
Yield: 44 %

Procedure:
A mixture of 2-chloro-4-iodopyridine (10.0 g, 41.8 mmol), p-tolylphenylboronic acid (5.68 g, 41.8 mmol), Pd(Ph3P)4 (1.45 g 1.25 mmol), sodium carbonate (13.3 g, 125 mmol), DME (300 mL) and water (75 mL) was degassed with nitrogen and then refluxed overnight. The mixture was concentrated and the extracted with ethyl acetate. The the ethyl acetate layer was dried on Na2SO4, vacuum distilled and recrystalized to give 2-chloro-4-(p-tolyl)pyridine (3.75 g, 18.4 mmol, 44% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:25]1C(C)=NC=CC=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[C:18]([CH3:25])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Reactant: Cc1ncccc1Br
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2C)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 3-Bromo-2-methylpyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=340.0 (M+H+).
Reaction SMILES: [Br-:1].O[C@@H]1C2CC[N+](CC(=O)NC3C=CON=3)(CC2)C1.[Br-].[OH:21][C@@H:22]1[CH:27]2[CH2:28][CH2:29][N+:24]([CH2:30][C:31](=[O:39])[NH:32][C:33]3[CH:38]=[N:37][CH:36]=[CH:35][N:34]=3)([CH2:25][CH2:26]2)[CH2:23]1.[CH:40]1([C:45]([OH:55])([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46](O)=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41]1>>[Br-:1].[CH:40]1([C:45]([OH:55])([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:46]([O:21][C@@H:22]2[CH:27]3[CH2:28][CH2:29][N+:24]([CH2:30][C:31](=[O:39])[NH:32][C:33]4[CH:38]=[N:37][CH:36]=[CH:35][N:34]=4)([CH2:25][CH2:26]3)[CH2:23]2)=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCC1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1cnccn1
Agent: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)C1CCCC1)C2)Nc1cnccn1

Procedure:
This compound is prepared using an method analogous to Example 4 by replacing (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) with (R)-3-Hydroxy-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate H) and 2,2′-diphenylpropionic acid with cyclopentyl-hydroxy-phenyl-acetic acid.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1I
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NS(C)(=O)=O)ccc1I
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A solution of 4-iodo-3-methylaniline (4.37 g, 18.75 mmol) in CH2Cl2 (25 ml) was treated with pyridine (6.07 ml, 75 mmol) followed by drop wise addition of methanesulfonyl chloride (1.607 ml, 20.63 mmol) to give a reddish/orange mixture. The mixture was stirred for 2 h, concentrated and diluted with EtOAc. The EtOAc layer was washed with 1M HCl, water, saturated NaCl, dried (Na2SO4) and filtered. The EtOAc filtrate was treated with activated charcoal for 30 min at 50° C. and filtered through a 10 g silica plug and concentrated to give the title compound as a light yellow solid (5.5 g, 94%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[Cl:32])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:33][N:34]([CH3:40])[CH2:35][CH2:36][CH2:37][NH:38][CH3:39]>>[Cl:32][C:12]1[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:21]=2)=[O:19])=[CH:16][C:11]=1[NH:10][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:38]([CH2:37][CH2:36][CH2:35][N:34]([CH3:40])[CH3:33])[CH3:39])[CH:7]=1)=[O:9]
Reactant: CNCCCN(C)C
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(N2CCOCC2)c1
Product: CN(C)CCCN(C)c1cc(C(=O)Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2Cl)ccn1
Yield: 46 %

Procedure:
Using an analogous procedure to that described in Example 21, 2-chloro-N-[2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give the title compound in 46% yield; NMR Spectrum: (DMSOd6) 1.67 (m, 2H), 2.11 (s, 6H), 2.21 (m, 2H), 3.04 (s, 3H), 3.51 (m, 6H), 3.71 (m, 4H), 6.97 (d, 1H), 7.09 (m, 2H), 7.23 (s, 1H), 7.54 (d, 1H), 7.71 (d, 1H), 8.04 (s, 1H), 8.20 (d, 1H), 8.27 (d, 1H), 10.13 (s, 1H), 10.47 (s, 1H); Mass Spectrum: M+H+ 552.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)([CH3:7])[CH3:6].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.CCN(CC)CC>C1C=CC=CC=1>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:5]([C:4]2[N:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[C:27](=[S:28])[NH:2][CH:3]=2)([CH3:7])[CH3:6])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: COc1ccc(C(C)(C)C(=O)CN)cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(C(C)(C)c2c[nH]c(=S)n2-c2ccc(F)cc2)cc1OC
Yield: 90.7 %

Procedure:
A mixture of 1-amino-3-(3,4-dimethoxyphenyl)-3-methylbutan-2-one hydrochloride (210 mg, 0.77 mmol), 4-fluorophenyl isothiocyanate (141 mg, 0.92 mmol), and Et3N (0.16 mL, 1.15 mmol) in benzene (7 mL, anhyd) was refluxed for 8 h. The volatiles were removed under reduced pressure. The residue was combined with acetic acid (5 mL) and heated at reflux 4 h. After concentration, the crude product was purified by flash chromatography to provide 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione (260 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 6.87 (t, 2H), 6.80 (d, 1H), 6.67 (d, 1H), 6.62-6.59 (m, 2H), 6.48 (d, 1H), 6.46 (s, 1H), 3.87 (s, 3H), 3.75 (s, 3H), 1.44 (s, 6H).
Reaction SMILES: [N:1]1([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[OH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>O1CCCC1>[CH3:23][N:24]([CH3:28])[C:25]([O:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[N:8]=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:26]
Reactant: Oc1cnccc1N=CN1CCCCC1
Reactant: CN(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cnccc1N=CN1CCCCC1

Procedure:
A mixture prepared from 4-[[(1-piperidinyl)methylene]amino]-3-pyridinol (3.5 g), triethylamine (3.69 mL), dimethylcarbamyl chloride (2.3 mL) and tetrahydrofuran (130 mL) was refluxed for 2 hours, filtered, poured directly onto a silica column and eluted successively with ethyl acetate and 5% Et3N/ethyl acetate to yield 4.49 g of product. Recrystallization from ethyl acetate and drying under high vacuum yielded 3.94 g of crystals, m.p. 88°-89° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[C:14]([C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:9][C:8]=2[CH:10]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)c1cc2ccccc2o1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)c1cc2cc(C(C)=O)ccc2o1

Procedure:
To a solution of 2-benzofuranoic acid methyl ester in carbon disulphide (240 ml) cooled to 5° C. was added acetyl chloride (70 ml) followed portionwise over 1 hour by aluminium trichloride (40 g). The mixture was heated under reflux for 42 hours before cooling and decanting the carbon disulphide. The residual complex was destroyed by the addition of iced water (50 ml) and 2N HCl (50 ml). The resulting mixture was extracted with ethyl acetate (3×200 ml). The organic layers were combined, washed with water (100 ml), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography, eluting with ethyl acetate/hexane (10:90 to 40:60, v/v), to give methyl 5-acetylbenzofuran-2-carboxylate as a solid (3.099 g); NMR 2.68 (3H,s), 4.00(3H,s), 7.6-8.35(4H,m).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][S:29]([C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:31])=[O:30])=[CH:18][CH:17]=1)[C:5]2=[O:36].C[Sn](C)(C)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>CN(C=O)C.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:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][S:29]([C:32]([CH3:33])([CH3:34])[CH3:35])(=[O:30])=[O:31])=[CH:20][CH:21]=1)[C:5]2=[O:36]
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: CCCc1nc2ccc(I)cc2c(=O)n1Cc1ccc(-c2ccccc2NS(=O)(=O)C(C)(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCc1nc2ccc(-c3ccccn3)cc2c(=O)n1Cc1ccc(-c2ccccc2NS(=O)(=O)C(C)(C)C)cc1

Procedure:
A solution of 0.5 g (0.8 mmol) of 6-iodo-2-propyl-3-[(2'-(t-butylsulphonamido)biphen-4-yl)methyl]-quinazolin-4(3H)-one in 3 mL of dry DMF under nitrogen was treated with 0.24 g (1.1 mmol) of 2-trimethylstannylpyridine and 10 mg (0.01 mmol) bis(triphenylphophine)palladium dichloride. The solution was heated at 80°-90° C. for 2 hours to give a black solution. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography over silica gel eluting with 40% EtOAc/hexanes to give the title compound. 1H-NMR (CDCl3, 200 MHz): δ0.98 (s, 9H), 1.06 (t, 3H,), 1.78 (m, 2H), 2.76 (t, 2H,), 5.49 (bs, 2H), 7.29 (m, 7H), 8.50 (m, 8H), 7.75-7.91 (m, 2H), .8.15 (dd,1H), 8.57 (dd, 1H), 8.71 (dm, 1H), 8.82 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[Br:17].[F:19][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C.O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([F:19])=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[Br:17]
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1Br
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: COC(=O)Cc1c(F)c(O)c2cc(F)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a solution of (1-bromo-6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (135 mg, 0.433 mmol) in acetonitrile (4 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (230 mg, 0.650 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight, then diluted with water (10 mL), and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (30% ethyl acetate in petroleum ether) to give (1-bromo-3,6-difluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (60 mg, 42%) as a yellow solid. MS cald. for C13H9BrF2O3 330, obsd. (ESI+) [(M+H)+] 331.