Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[CH2:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[CH:21](OC)(OC)OC>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([O:16][CH3:21])=[CH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4]
Reactant: COC(=O)N1c2ccccc2CC(=O)c2ccccc21
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)N1c2ccccc2C=C(OC)c2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 98.4 %

Procedure:
A suspension of 10-oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylic acid methyl ester (15 g, 56 mmol) in methanol (75 ml) is heated to 60° C. and a catalytic amount of p-toluene sulfonic acid (0.213 g, 1.1 mmol) is added. After addition of trimethyl ortho-formate (6.25 g, 58.9 mmol) the solution is stirred at 60–70° C. for 4 hours. During this reaction the product precipitates as white crystals. The mixture is cooled to room temperature, filtered and dried to yield 15.5 g of pure title compound (98%).
Reaction SMILES: [CH2:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1[CH2:8][C:9]([OH:11])=[O:10].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[H][H]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: C=C1C=CC=CC1CC(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Product: Cc1ccccc1CC(=O)O
Yield: 99.9 %

Procedure:
In a 100 ml autoclave, the inside atmosphere of which had previously been replaced with argon, were placed 0.3 g (2 mmoles) of 2-methylenephenylacetic acid and 20 ml of methanol. Then, 8.4 mg (0.01 mmole) of Ru((+)-BINAP)(O2CCH3)2 prepared according to the same manner as in Referential Example 3 except using (+)-BINAP in place of (-)-BINAP was added to the mixture to perform hydrogenation for 24 hours at a hydrogen pressure of 100 kg/cm2 and at a reaction temperature of 30° C. to provide 0.3 g of 2-methylphenylacetic acid. The yield was 100%.
Reaction SMILES: O=C(C1SC=CC=1)CC(OCC)=O.S1C=CC=C1C1C=CN=C(N)N=1.C[C:27]1([CH3:35])[O:32][C:31](=[O:33])[CH2:30][C:29](=[O:34])O1.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:46]=[CH:45][C:41](C(O)=O)=[CH:40][CH:39]=1>>[O:34]=[C:29]([C:41]1[CH:45]=[CH:46][C:38]([C:37]([F:48])([F:47])[F:36])=[CH:39][CH:40]=1)[CH2:30][C:31]([O:32][CH2:27][CH3:35])=[O:33]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)CC(=O)c1cccs1
Agent: Nc1nccc(-c2cccs2)n1
Product: CCOC(=O)CC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
This material is prepared by a method analogous to that described for preparation of ethyl 3-oxo-3-(2-thienyl)propanoate in preparation of 1D, starting from 2,2-dimethyl-1,3-dioxane-4,6-dione and 4-(trifluoromethyl)benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9](=[O:16])[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:27]1[C:28]2[S:35][CH:34]=[CH:33][C:29]=2[N:30]=[CH:31][N:32]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9](=[O:16])[N:10]1[CH2:11][CH2:12][N:13]([C:27]2[C:28]3[S:35][CH:34]=[CH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncnc2ccsc12
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccsc23)CC1
Yield: 86.8 %

Procedure:
The solution of [1-(4-chlorobenzyl)-2-oxo-2-piperazin-1-yl-ethyl]-carbamic acid tert-butyl ester (60 mg, 0.163 mmol) and 4-Chlorothieno[3,2-d]pyrimidine 950 mg, 0.293 mmol) in Toluene (5 mL)/TEA (1 mL) was refluxed for 12 hours. After the solvent was removed, the residue was subject to chromatography on silica gel to afford [1-(4-chlorobenzyl)-2-oxo-2-(4-thieno[3,2-d]pyrimidin-4-yl-piperazin-1-yl)-ethyl]-carbamic acid tert-butyl ester (71 mg, 86.7%). 1H NMR (CDCl3, 400 Hz) δ 8.60 (s, 1H), 7.76 (d, J=5.2 Hz, 1H), 7.45 (d, J=5.2 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 5.39 (d, J=8.8 Hz, 1H), 4.88-4.82 (m, 1H), 3.94-3.76 (m, 4H), 3.69-3.58 (m, 3H), 3.25-3.22 (m, 1H), 2.98 (d, J=7.2 Hz, 2H), 1.43 (s, 9H). MS (ESI+) [M+H]+ 503.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.Cl.[C:11]1(NN)[CH:16]=CC=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:16]=[CH:11][C:12]([CH3:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc(Cl)c1
Reactant: NNc1ccccc1
Agent: Cl
Product: Cc1ccn(-c2cccc(Cl)c2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 1 with 3-chlorophenyl hydrazine.HCl substituted for phenyl hydrazine. There was obtained the title compound; HRMS (M+H)+: calc. 467.094465; found 467.091517.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.C(N(CC)CC)C.[C:39]([O:42][CH2:43][C:44](Cl)=[O:45])(=[O:41])[CH3:40]>O1CCCC1>[C:39]([O:42][CH2:43][C:44]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:12]=3)=[N:6][N:5]2[CH:31]=1)=[O:45])(=[O:41])[CH3:40]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)ccc2n1
Yield: 73.6 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (200 mg, 0.487 mmol), triethylamine (101 μL, 0.730 mmol), 2-chloro-2-oxoethyl acetate (63 μL, 0.584 mmol) and tetrahydrofuran (5 mL) as starting materials and in the same manner as in Example 385, the title compound (183 mg, 74%) was obtained as a gray powder.
Reaction SMILES: [C:1](O)(=O)C.C=O.[CH:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>O.C(NCCCC)CCC>[CH2:1]=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:7]=[O:14]
Reactant: CC(=O)O
Reactant: CCCCCCC=O
Agent: C=O
Solvent: O
Solvent: CCCCNCCCC
Product: C=C(C=O)CCCCC
Temperature: 50 °C
Yield: 848.9 %

Procedure:
A 3-L three-neck flask fitted with an overhead stirrer and a condenser was charged with di-n-butylamine (33 g) and acetic acid (31 g). Formaldehyde solution in water (500 mL, 33%) was added and the resulting solution was heated to 50° C. with stirring. Heptanal (500 g) was fed in over about 1.5 hours. A slight exotherm was noticed during the feed. GC analysis showed the consumption of heptanal and the production of 2-methylene heptanal, and a conversion rate of about 95% after the feed was completed. The reaction was cooled to room temperature and the reaction mixture was poured into a separatory funnel and washed once with HCl solution (5%). The organic layer was then washed once with saturated sodium carbonate to provide crude 2-methylene heptanal (553 g), which was loaded into a 2-L stainless steel pressure reactor along with dicyclopentadiene (343 g). The pressure reactor was sealed and heated to 170° C. with stirring for two hours. The reaction was then cooled to room temperature. The resulting crude product was purified by distillation to yield 2-pentylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde (217 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.[N:41]([CH:44]([CH3:46])[CH3:45])=[C:42]=[O:43]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH:29][C:42]([NH:41][CH:44]([CH3:46])[CH3:45])=[O:43])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:39][CH:40]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(N)nc3)n2)cc1
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(NC(=O)NC(C)C)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
A stirred solution of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)pyridine-2,5-diamine (Example 190, Step 4, 0.124 g, 0.233 mmol) in THF (2 mL) was treated with 2-isocyanatopropane (Aldrich) (0.046 mL, 0.465 mmol) and the yellow solution was stirred at rt overnight. The mixture was concentrated and the crude product was purified by silica gel chromatography (25 g, eluent: iPrOH (w/10% NH4OH) in CHCl3 0%-7.5%) to give 1-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-yl)-3-isopropylurea (0.1044 g, 72% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 11.74 (s, 1H); 8.98-9.14 (m, 1H); 8.83 (d, J=7.75 Hz, 1H); 8.35 (d, J=1.75 Hz, 1H); 8.24-8.33 (m, 1H); 7.84 (dd, J=8.77, 1.90 Hz, 1H); 7.35 (s, 1H); 7.20 (t, J=8.33 Hz, 4H); 6.86 (t, J=7.38 Hz, 4H); 6.77 (dd, J=7.75, 4.82 Hz, 1H); 6.65 (d, J=8.77 Hz, 1H); 4.84 (d, J=4.97 Hz, 4H); 4.01-4.18 (m, 1H); 3.80 (d, J=7.31 Hz, 6H); 2.60 (s, 3H); 1.28 (d, J=6.58 Hz, 6H). m/z (ESI, +ve ion) 620.0 (M+H)+.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)=[O:12].IC.Cl>O1CCCC1>[CH3:9][O:10][C:11]([C:13]1([CH3:1])[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)=[O:12]
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of lithium diisopropyl amide (1.8 M in tetrahydrofuran/heptane/ethylbenzene, 46.2 mL, 83 mmol) at −78° C. was added a solution of 4-(methoxycarbonyl)-cyclohexanecarboxylic acid (6.2 g, 33.3 mmol) in tetrahydrofuran (80 mL) over 15 minutes via cannula needle. After 40 minutes of stirring, iodomethane (3.12 mL, 49.9 mmol) was added over 30 seconds to the brown reaction mixture. After 45 minutes the reaction bath was allowed to warm to room temperature over four hours, then the reaction mixture was cooled to 0° C. before hydrochloric acid (2.0 M in water, 100 mL) was added. The reaction mixture was diluted with hexanes (50 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (3×50 mL), dried over sodium sulfate, filtered, and concentrated to give 4-(methoxycarbonyl)-4-methylcyclohexanecarboxylic acid, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[C:11]1[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].S1(CCCC1)(=O)=O>O>[OH:9][C:3]1[C:2]2[NH:1][C:13](=[O:14])[C:12]3[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:21])[F:22])=[N:19][C:11]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: Nc1cccc(O)c1N
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: O=C1Nc2c(O)cccc2Nc2nc(C(F)(F)F)ccc21
Temperature: 150 °C

Procedure:
A mixture of 2,3-diaminophenol (79 g, 0.64 mol), 2-chloro-6-(trifluoromethyl)nicotinic acid (100 g, 0.44 mol) and sulfolane (1 L) was heated under nitrogen at 150° C. overnight. After cooling to rt, the reaction mixture was poured into water. The precipitate was collected by filtration, and was re-dissolved in EtOAc, washed with water and brine, dried over MgSO4, filtered and concentrated to give 7-hydroxy-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:14])[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1.[C:15]1([S:21]([N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)CCl>[C:15]1([S:21]([N:24]2[CH:25]=[CH:26][C:27]([C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH3:14])=[CH:6][CH:7]=3)=[O:12])=[CH:28]2)(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C(=O)c2ccn(S(=O)(=O)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 105.3 %

Procedure:
Under nitrogen atmosphere, to a suspension of aluminum chloride (4.62 g, 34.7 mmol) in ethylene chloride (50 mL) was added a solution of p-toluoyl chloride (4.91 g, 31.8 mmol) in ethylene chloride (5 mL) at room temperature over a period of 10 minutes. The mixture was stirred for 30 minutes, and thereto was added a solution of 1-benzenesulfonyl-1H-pyrrole (6.00 g, 28.9 mmol) in ethylene chloride (10 mL) over a period of 10 minutes. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice-water, and the aqueous layer was extracted twice with dichloromethane. The organic layers were combined, dried, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (9.9 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]([NH2:18])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]3)[CH:5]=[N:6][CH:7]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([NH:18][C:15]2[N:16]=[CH:17][C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)=[N:21][CH:22]=1
Reactant: Fc1ccc(Br)nc1
Reactant: Nc1ncc(-c2cncc(F)c2)c2cccnc12
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Fc1ccc(Nc2ncc(-c3cncc(F)c3)c3cccnc23)nc1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
5-(5-Fluoro-pyridin-3-yl)-[1,7]naphthyridin-8-ylamine (0.1 g, 0.42 mmol) and 2-bromo-5-fluoropyridine (0.13 g, 0.76 mmol) (Example C) were dissolved in 3 ml dry dioxane. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (48 mg, 0.084 mmol), cesium carbonate (0.22 g, 0.67 mmol) and tri(dibenzylideneacetone)dipalladium chloroform complex (43 mg, 0.042 mmol) were added and the reaction mixture was stirred for 20 hrs at 130° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (heptane/ethyl acetate 95:5->30:70 gradient). The desired product was obtained as a light red solid (35 mg, 25%), MS: m/e=336.3 (M+H+).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21](Br)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH2:24][OH:23])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: OCc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccccc3CO)c2s1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
200 mg (0.45 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 67.9 mg (0.45 mmol) of 2-(hydroxymethyl)phenylboronic acid are introduced into 2 ml of DMF. Addition of 0.67 ml of 2 M sodium carbonate solution and 18.2 mg (0.02 mmol) of PdCl2(dppf) is followed by heating at 80° C. After 18 h, the reaction mixture is filtered through kieselguhr and purified by separation by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 4N hydrogen chloride in dioxane, again concentrated. Drying under high vacuum results in 148 mg (72% of theory) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:21])[CH3:22])[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])=[O:32]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccccc1Cl

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 2-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22]I)[CH:5]=1)([O-:3])=[O:2].[O:24]1CC[CH2:26][CH2:25]1>C(O)C.C(=O)([O-])[O-].[Ag+2]>[CH2:25]([O:24][CH2:22][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]2[C:11]1=[O:21])[CH3:26]
Reactant: C1CCOC1
Reactant: O=C1c2ccc(Cl)cc2C(=O)N1c1ccc([N+](=O)[O-])cc1CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOCc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc(Cl)cc2C1=O

Procedure:
The starting material is prepared as follows: The solution of 2 g of N-(4-nitro-2-iodomethylphenyl)-4-chlorophthalimide in 25 ml of tetrahydrofuran and 25 ml of ethanol, is stirred with 8.7 g of freshly prepared silver carbonate for 20 hours, with protection from light. The mixture is filtered and the filtrate evaporated, to yield the N-(2-ethoxymethyl-4-nitrophenyl)-4-chlorophthalimide.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[N:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=13)[C:8]([CH2:17][CH3:18])=[C:7]2[C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)(=[O:3])[CH3:2].B(Br)(Br)Br.[O-2].[Al+3].[O-2].[O-2].[Al+3]>ClCCl.ClCCl.CO>[C:1]([C:4]1[CH:5]=[C:6]2[N:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=13)[C:8]([CH2:17][CH3:18])=[C:7]2[C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)(=[O:3])[CH3:2]
Reactant: CCc1c(-c2ccc(OC)cc2)c2cc(C(C)=O)c3cc(OC)cc1n32
Agent: BrB(Br)Br
Agent: [Al+3]
Agent: [O-2]
Solvent: CO
Solvent: ClCCl
Product: CCc1c(-c2ccc(O)cc2)c2cc(C(C)=O)c3cc(OC)cc1n32
Reaction time: 1 h
Yield: 56.5 %

Procedure:
A solution of 4-acetyl-1-ethyl-6-methoxy-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine (0.3 g, 0.85 mmol) in 7 ml of dry dichloromethane was cooled to -65° C. and stirred in a nitrogen atmosphere while 1.2 ml of a 1 M boron tribromide solution in dichloromethane was added. Stirring was continued for one hour and the cooling source was removed. The reaction mixture was allowed to reach room temperature and then poured into a stirred medium of dichloromethane (100 ml) and a saturated sodium hydrogen carbonate solution (100 ml). The usual work up afforded 200 mg of a substance which was submitted to column chromatography (aluminium oxide) with dichloromethane/methanol (20:1) as eluent. The fractions having RF 0.4 (silica gel 60, dichloromethane/methanol (20:1)) was collected and evaporated to afford 160 mg (58%) of the title compound. M.p. 245-46° C. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.37 (t, 3H), 2.62 (s, 3H), 3.13 (q, 2H), 4.07 (s, 3H), 7.00 (d, 2H), 7.70 (d, 2H), 7.79 (d, 1H), 7.87 (d, 1H), 8.12 (s, 1H), 9.87 (s, 1H). (Compound 7).
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:34]=[CH:33][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:18][C:17]=3[C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:34]=[CH:33][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:35][CH:36]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2cccs2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2cccs2)c1
Reaction time: 3 h
Yield: 37.4 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(thiophen-2-yl)phenyl)acetate (20 mg, 0.038 mmol) was diluted with dioxane (500 μL) followed by the addition of NaOH (0.052 ml, 0.26 mmol) and 200 μL of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(thiophen-2-yl)phenyl)acetic acid (7 mg, 37% yield) as a white solid. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.69 (s, 1H), 7.64 (d, 2H), 7.45 (d, 1H), 7.30 (d, 2H), 7.22 (d, 1H), 7.15 (d, 2H), 6.98-7.05 (m, 2H), 6.90 (d, 2H), 3.65 (m, 4H), 2.90 (t, 2H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[N:17]4[CH:18]=[C:19](Br)[CH:20]=[C:21](Br)[C:16]4=[N:15][C:14]=3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[N:17]4[CH:18]=[C:19]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:20]=[C:21]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[C:16]4=[N:15][C:14]=3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: Fc1ccc(-c2nc3c(Br)cc(Br)cn3c2-c2ccnc(NC3CCCC3)n2)cc1
Product: Fc1ccc(-c2nc3c(N4CCOCC4)cc(N4CCOCC4)cn3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 24 %

Procedure:
In a similar manner as described in Example 3 from N-cyclopentyl-4-[6,8-dibromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-2-pyrimidinamine (100 mg, 0.19 mmol) and morpholine at 100° C. for 3 days was obtained N-cyclopentyl-4-[2-(4-fluorophenyl)-6,8-di(4-morpholinyl)imidazo[1,2-a]pyridin-3-yl]-2-pyrimidinamine (25 mg, 24%) as a yellowish solid. 1H NMR (CDCl3) δ 8.66 (s, 1H), 8.11 (d, 1H), 7.66 (q, 2H), 7.10 (t, 2H), 6.49 (d, 1H), 6.43 (d, 1H), 5.24 (d, 1H), 4.45 (m, 1H), 4.03 (m, 4H), 3.94 (m, 4H), 3.60 (m, 4H), 3.13 (m, 4H), 2.0–2.1 (m, 2H), 1.4–1.9 (m, 6H); 19F NMR (CDCl3) δ −114.1; MS m/z 545 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[C:12]([OH:14])=[O:13].Cl.[CH3:16]O>O.CO.Cl[Cu]>[CH3:16][O:7][C:6](=[O:8])[C:5]1[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=1)[C:12]([OH:14])=[O:13]
Reactant: COc1cccc(C(=O)O)c1C(=O)O
Reactant: CO
Agent: Cl[Cu]
Agent: Cl
Solvent: O
Product: COC(=O)c1cccc(OC)c1C(=O)O
Yield: 63 %

Procedure:
A solution of methoxyphthalic acid obtained as per Example 5 (0.1 mol) in 100 ml methanol was added with CuCl (0.1 mol) and HCl (0.1 mol). The solution was heated to reflux for 30 min. The clear solution obtained was evaporated to dryness under reduced pressure. The residue obtained was dissolved in a 1:3 water-methanol mixture and acidified. The product was separated by cooling, collected by filtration and air dried. The product yield was 63-66%.