Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5](B(O)O)[CH:4]=1)#[N:2].[CH2:16]([O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][N:23]=[C:22](Br)[CH:21]=1)[CH3:17].[F-].[Cs+]>C(COC)OC.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>[CH2:16]([O:18][C:19](=[O:27])[C:20]1[CH:21]=[CH:22][N:23]=[C:24]([C:5]2[CH:4]=[C:3]([C:1]#[N:2])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[CH:25]=1)[CH3:17]
Reactant: N#Cc1cc(B(O)O)cc2ccccc12
Reactant: CCOC(=O)c1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CCOC(=O)c1ccnc(-c2cc(C#N)c3ccccc3c2)c1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 91.2 %

Procedure:
To a suspension of 4-cyano-2-naphthaleneboronic acid (0.10 g), 2-bromoisonicotinic acid ethyl ester (0.12 g) and cesium fluoride (0.09 g) in dimethoxyethane (6 mL) was added tetrakis(triphenylphosphine)palladium (0.06 g), and the mixture was stirred at 150° C. for 40 minutes using microwave reactor (Biotage). The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/0-66/34) to give 2-(4-cyanonaphthalene-2-yl)isonicotinic acid ethyl ester (0.14 g). To a solution of this compound (0.14 g) in a mixed solvent of tetrahydrofuran (4 mL), ethanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.060 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added acetic acid (0.27 mL). The precipitated solid was collected by filtration, and washed with water and n-hexane. The solid was dried under reduced pressure to give the title compound (0.098 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2.[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:5]2
Reactant: OC1CCc2cc(Br)ccc21
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)CCC2Oc1ccccc1
Yield: 80.9 %

Procedure:
A solution of 5-bromo-2,3-dihydro-1H-inden-1-ol (1 g, 4.7 mmol), phenol (835 mg, 8.9 mmol) and triphenylphosphine (1.8 g, 6.9 mmol) in anhydrous tetrahydrofuran (70 mL) was stirred at 0° C. under nitrogen atmosphere. To this mixture was added dropwise diisopropyl azodicarboxylate (1.4 g, 6.9 mmol) over 5 minutes. Until TLC indicated that starting material was consumed, the solvent was evaporated in vacuo and the resulting oil was purified by column chromatography (silica gel, hexane/ethyl acetate=1/1) to give the product 5-bromo-1-phenoxy-2,3-dihydro-1H-indene (1.1 g, 85%) as a white solid. LRMS (M+H+) m/z: calcd 288.01. found 288. 1H NMR (300 MHz, CDCl3): δ 7.46-7.27 (m, 6H), 7.02 (s, 1H), 6.99-6.98 (m, 1H), 5.73-5.70 (m, 1H), 3.14-3.09 (m, 1H), 2.96-2.95 (m, 1H), 2.59-2.54 (m, 1H), 2.27-2.23 (m, 1H).
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[OH:3].P(=O)(O)(O)O.[O-2:12].[Mg+2]>O>[OH:12][CH2:4][C@@H:2]([C@H:1]([C@@H:4]([C@@H:2]([CH2:1][OH:6])[OH:3])[OH:12])[OH:6])[OH:3]
Reactant: CC(O)C(=O)O
Reactant: [O-2]
Agent: O=P(O)(O)O
Agent: [Mg+2]
Solvent: O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Temperature: 120 °C
Yield: 2941.2 %

Procedure:
The poly(lactic acid) was made by adding 102.77 grams of 85% lactic acid into a 4000 ml beaker. 3.03 grams of 85% phosphoric acid was then added. The mixture was heated to 120° C. for four hours until it was apparent that the water had been removed. After the water was removed, 11.75 grams of sorbitol was added and the polylactate continued to react for another 2 hours. The phosphoric acid was neutralized with 1.0 gram of magnesium oxide. A total of 66.47 grams of sorbitol hexapolylactate was produced. The sorbitol hexapolylactate is the hardest and thickest of the three esters.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Cl:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].CO>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:19][C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[Cl:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccccc2Cl)CC1

Procedure:
To a solution of 9.199 g (46.168 mM) of 1-(tert-butoxycarbonyl)-4-piperidone and 19.5 g (46.2 mM) of 2-chlorobenzyltriphenylphosphonium chloride in 50 ml of methanol was added 8.91 g (46.2 mM) of 28% sodium methoxide-methanol at room temperature and the mixture was refluxed for 36 hours. This reaction mixture was poured in water and extracted with 2 portions of ethyl acetate. The pooled organic layer was dried over Na2SO4 and the solvent was distilled off under reduced pressure. To the residue was added diethyl ether and the resulting precipitate (triphenylphosphine oxide) was filtered off and washed with diethyl ether. The filtrate and washes were combined and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 6/1) and crystallized from cold hexane to provide the title compound.
Reaction SMILES: [OH-].[K+].Br[CH2:4][CH:5]1[CH2:7][C:6]1([F:9])[F:8].[SH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]>CO>[F:8][C:6]1([F:9])[CH2:7][CH:5]1[CH2:4][S:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCS
Reactant: FC1(F)CC1CBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCSCC1CC1(F)F
Temperature: 65 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
Powdered potassium hydroxide (423 mg, 7.54 mmol) and 2-(bromomethyl)-1,1-difluorocyclopropane (657 mg, 3.84 mmol) were sequentially added to a stirred solution of 3-mercaptopropanoic acid (400 mg, 3.77 mmol) in methanol (2 mL) at room temperature. The resulting white suspension was stirred at 65° C. for 3 hours and quenched with 1N aqueous hydrochloric acid and diluted with ethyl acetate. The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title molecule as a colorless oil (652 mg, 84%): IR (thin film) 3025, 2927, 2665, 2569, 1696 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.85 (t, J=7.0 Hz, 2H), 2.82-2.56 (m, 4H), 1.88-1.72 (m, 1H), 1.53 (dddd, J=12.3, 11.2, 7.8, 4.5 Hz, 1H), 1.09 (dtd, J=13.1, 7.6, 3.7 Hz, 1H); ESIMS m/z 195.1 ([M−H]−).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([CH2:13][CH2:12][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Product: O=[N+]([O-])c1ccc(SCCN2CCOCC2)cc1

Procedure:
Following the procedures of Example 1, the title compound is prepared from 4-nitrothiophenol and 4-(2-chloroethyl)morpholine.
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:16][C:17]([CH3:22])([CH3:21])[O:18]2)=[CH:13][CH:12]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:7][C:16]1[C:17]([CH3:21])([CH3:22])[O:18][C:19]2[C:14]([C:15]=1[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)=[CH:13][CH:12]=[C:11]([Cl:10])[CH:20]=2
Reactant: CC1(C)C=C(c2ccc(F)cc2)c2ccc(Cl)cc2O1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Pyridinium bromide perbromide (1.00 g) was added to a solution of 7-chloro-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen (a compound obtained in Reference Example 5(3); 1.00 g) in dichloromethane (15 mL) under ice-cooling and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into a 15% aqueous solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was washed successively with a saturated solution of sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: n-hexane/chloroform=100/0 to 95/5) to give the titled compound (1.26 g) as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]([CH:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[OH:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]([C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(OCc2ccccc2)cccc1C(O)c1c[nH]c2ncccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: Cc1c(OCc2ccccc2)cccc1C(=O)c1c[nH]c2ncccc12
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 90.1 %

Procedure:
To a solution of (3-Benzyloxy-2-methyl-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (59, 0.12 g, 0.35 mmol) in tetrahydrofuran (15 mL) was added Dess-Martin periodinane (0.37 g, 0.89 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 50 minutes, then quenched with a saturated solution of sodium thiosulfate, extracted with ethyl acetate, washed with sodium bicarbonate, brine, and dried over magnesium sulfate. After removal of solvent, the residue was washed with a mixture of ethyl ether and hexanes (1:1) to provide the compound as a yellow solid (P-1848, 108 mg, 90%). MS (ESI) [M+H+]+=343.22.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([NH:12][N:13]1[CH2:16][CH:15]([OH:17])[CH2:14]1)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)(=O)C(Cl)=O.CS(C)=O>C(Cl)Cl>[C:1]([NH:8][C@H:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([NH:12][N:13]1[CH2:14][C:15](=[O:17])[CH2:16]1)=[O:11])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
(2R)-2-(BOC)Amino-N-(3-hydroxyazetidine-1-yl)-3-(4-chlorophenyl)propionamide (3.54 g, 10 mmol) was placed in a round-bottomed flask, filled with nitrogen, and DCM (30 mL) and oxalyl chloride (872 μl, 10 mmol) were added. The mixture was cooled to −78-C, and DMSO (709 μl, 10 mmol) was added. The reaction solution was stirred for 3 h keeping the temperature below −50° C. The reaction mixture was quenched by addition of TEA and warmed to rt. The reaction solution was diluted with a saturated aqueous NH4Cl solution, and the organic material was extracted with EtOAc. The extracts was dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chomatography (eluent: EtOAc/Hex=1/3) to give the title compound (2.88 g, 84%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>O>[CH:12]([NH:11][C:4]1[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1)([CH3:14])[CH3:13]
Reactant: CC(C)Nc1nc(Cl)nc2cscc12
Reactant: C1COCCN1
Solvent: O
Product: CC(C)Nc1nc(N2CCOCC2)nc2cscc12

Procedure:
6 g (0.26 moles) of 2-chloro-4-isopropylamino-thieno[3,4-d]pyrimidine and 25 mls. of morpholine are mixed and then heated under reflux for 4 hours. The mixture is cooled and poured into water with vigorous agitation; a brown solid appears, which is separated by filtration, washed with water and put to dry. The product is converted into the maleate, which is recrystallized from acetone. The free base is obtained again by treatment with alkali and is this way one obtains 3.4 g of pure product. M.P. 202°C. with decomposition.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[S:7][C:8]2[C:9]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[N:10][C:11]([C:15]3[CH:16]=[N:17][C:18]([N:21]4[CH2:26][CH2:25][C:24]([CH3:32])([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]4)=[N:19][CH:20]=3)=[CH:12][C:13]=2[N:14]=1)[CH3:2].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[S:7][C:8]2[C:9]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[N:10][C:11]([C:15]3[CH:16]=[N:17][C:18]([N:21]4[CH2:26][CH2:25][C:24]([CH3:32])([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]4)=[N:19][CH:20]=3)=[CH:12][C:13]=2[N:14]=1)[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)nc(-c3ccccn3)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)nc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 63.6 %

Procedure:
To a solution of ethyl 1-(5-(2-(3-ethylureido)-4-(pyridin-2-yl)thiazolo[5,4-c]pyridin-6-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (0.050 g, 0.091 mmol) in DMSO (2.0 mL) at rt was added potassium tert-butoxide (0.052 g, 0.45 mmol) and the mixture stirred at rt for 15-20 min. After completion of reaction (by TLC), water (25 mL) was added, followed by extraction with EtOAc (3×50 mL) and the organic layer was discarded. The pH of the aqueous layer was adjusted up to 4-5, extracted with hot EtOAc (3×50 mL) and the combined organic layer washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue thus obtained was triturated with ether to afford Compound 162 (0.030 g, 64%). 1H NMR (DMSO-d6): δ 1.10 (t, J=7.20 Hz, 3H), 1.20 (s, 3H), 1.44 (m, 2H), 2.04 (m, 2H), 3.22 (m, 2H), 3.37 (m, 2H), 4.35 (m, 2H), 6.86 (br s, 1H), 7.53 (m, 1H), 8.05 (m, 1H), 8.16 (s, 1H), 8.80 (d, J=8.40 Hz, 1H), 8.84 (d, J=4.40 Hz, 1H), 9.26 (s, 2H), 10.93 (br s, 1H) and 12.45 (br s, 1H). MS: 519.28 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:3]=1.C(N(CC)C(C)C)(C)C.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]>CN1CCCC1=O>[C:38]([O:37][C:36](=[O:42])[NH:35][C@H:30]1[CH2:31][CH2:32][CH2:33][CH2:34][C@H:29]1[NH:28][C:2]1[N:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:3]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: Cc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Temperature: 150 °C
Yield: 36.1 %

Procedure:
6-Chloro-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (130 mg, 0.49 mmol), N,N-diisopropylethylamine (0.17 mL, 0.986 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (211 mg, 0.986 mmol) were dissolved in N-methylpyrrolidinone (2 mL) and heated at 150° C. for 2 d. The reaction mixture was cooled and concentrated in vacuo, then diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica, 0 to 5% methanol in dichloromethane) gave {(1S,2R)-2-[6-carbamoyl-5-(6-methyl-pyridin-2-ylamino)-pyridazin-3-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (78 mg, 35%) as a light brown amorphous residue. LCMS (EI/CI) m/z: 442 [M+H].
Reaction SMILES: [C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9](Br)=[C:10]3[C:19]4[CH:18]=[C:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[C:16]([O:25][CH3:26])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)CCC>C1(C)C=CC=CC=1.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>[C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[C:16]([O:25][CH3:26])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCS(=O)(=O)c1cc2c(cc1OC)CCn1c3c(c(Br)c1-2)CCCCN(C(C)(C)C)C3=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)c1cc2c(cc1OC)CCn1c3c(c(-c4cccs4)c1-2)CCCCN(C(C)(C)C)C3=O
Yield: 67.6 %

Procedure:
A solution of 50 mg of 23e, 60 mg of 2-tributylstannylthiophene and 10 mg of tetrakis(triphenylphosphine)palladium(0) in 2 ml of toluene was heated at 125° C. for 16 hr under a nitrogen atmosphere. Reaction was cooled and applied onto silica gel column and eluted with a gradient of toluene/acetone. The fractions containing the product were pooled and concentrated and the remainder crystallized from ethylacetate/ether, providing 34 mg of 23f; Mp: 223-224° C. Rf 0.55 (toluene/acetone 2/1). LC-MS-ESI: [M+1] 527.08. NMR (CDCl3) δ 6.82 and 7.63 (2×s, Ar—H), 6.92, 7.16 and 7.41 (3×m 3, thienyl-H), 1.12 (t, 3, ethyl), 3.22 (m, 3, ethyl), 3.94 (s, 3, OCH3), 4.70 (bm, 1, CH2,) 3.80 (bm, 2, CH2), 3.55 (bm, 1, CH2), 3.02 and 3.20 (2×b.m, 2, CH2), 2.55 (b.m, 2, CH2), 1.60-2.00 (b.m, 4, CH2), 1.56 (s, 9, tertC4H9).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:17][O:18][C:19](=[O:44])[CH2:20][CH2:21][C:22]1[C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]/[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)=[CH:26][CH:25]=[C:24](I)[N:23]=1>>[CH3:17][O:18][C:19](=[O:44])[CH2:20][CH2:21][C:22]1[C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]/[C:35]2[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)=[CH:26][CH:25]=[C:24]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][S:10]([C:13]([F:16])([F:14])[F:15])(=[O:12])=[O:11])[CH:4]=2)[N:23]=1
Reactant: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Reactant: C#Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Product: COC(=O)CCc1nc(C#Cc2cccc(NS(=O)(=O)C(F)(F)F)c2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 32.7 %

Procedure:
Under the conditions of example 5 A, 370 mg of crude N-(3-ethinylphenyl)-1,1,1-trifluoromethanesulfonamide is reacted with 735 mg of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-20% ethyl acetate. 299 mg of 3-{3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-6-[2-(3-trifluoromethanesulfonamidophenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1B(O)O.[CH2:24]([O:26][C:27](=[O:41])[C:28]1[C:33]([NH2:34])=[CH:32][CH:31]=[C:30]([C:35]2[CH2:39][CH2:38][CH2:37][C:36]=2Br)[CH:29]=1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:41])[C:28]1[C:33]([NH2:34])=[CH:32][CH:31]=[C:30]([C:35]2[CH2:39][CH2:38][CH2:37][C:36]=2[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][C:3]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:2]=2[F:1])[CH:29]=1)[CH3:25]
Reactant: CCOC(=O)c1cc(C2=C(Br)CCC2)ccc1N
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1F
Product: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3F)CCC2)ccc1N

Procedure:
Prepared by general procedure C(iii) but using 2-(2,4-difluorobenzyloxy)-5-trifluoromethylphenylboronic acid instead of 2-(benzyloxy)-5-chlorophenylboronic acid and 3-(2-bromocyclopent-1-enyl)-6-aminobenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-methylbenzoic acid ethyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=2)[CH2:3][CH2:2]1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[NH:24]([C:25]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=2)[CH2:3][CH2:2]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(NC2CCNCC2)nc1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC2CCN(C(=O)Nc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.5 %

Procedure:
A mixture of methyl 6-(4-piperidylamino)nicotinate (0.73 g) and phenyl isocyanate (388 mg) in THF (30 ml) was stirred at ambient temperature for 12 hours. IPE (30 ml) was added to a reaction mixture and the precipitate was collected by filtration to give methyl 6-{[1-(anilinocarbonyl)-4-piperidyl]amino}nicotinate (0.72 g)
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[N:13]=[CH:14][C:15]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])=[N:16][C:17]=1[C:18]([NH:20][CH3:21])=[O:19]>>[NH2:11][C:12]1[C:17]([C:18]([NH:20][CH3:21])=[O:19])=[N:16][C:15]([C:22]2[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:10][CH2:9][CH2:8][NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:26])[CH:23]=2)=[CH:14][N:13]=1
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)O)c2)cnc1N
Reactant: NCCNc1ccccc1
Product: CNC(=O)c1nc(-c2cccc(C(=O)NCCNc3ccccc3)c2)cnc1N
Yield: 45 %

Procedure:
3-amino-N-methyl-6-[3-({[2-(phenylamino)ethyl]amino}carbonyl)phenyl]pyrazine-2-carboxamide was synthesized according to the procedure described in above from N-phenylethane-1,2-diamine and 3-{5-amino-6-[(methylamino)carbonyl]pyrazine-2-yl}benzoic acid. Yield 45%: 1H NMR (400 MHz, CDCl3): 8.90 (s, 1H), 8.82 (br d, 1H), 8.70 (br t, 1H), 8.45 (br s, 1H), 8.32 (br d, 1H), 7.82 (br d, 1H), 7.52 (t, 1H), 7.02 (t, 2H), 6.62 (d, 2H), 6.50 (t, 1H), 5.72 (br t, 1H), 3.52 (d, 2H), 3.20 (d, 2H), 2.92 (d, 3H); MS (EI) for C21H22N6O2: 391 (MH+)
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].CCN(CC)CC.[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[NH2:22]>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:23]=[CH:24][C:25]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1ccc(Oc2cccc(Cl)c2)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2cccc(Cl)c2)c(Cl)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
According to Scheme 3 Step 3: Picolinoyl chloride hydrochloride (1.52 mmol, 271 mg) and Et3N (3.05 mmol, 0.42 mL) were added sequentially to a solution of 3-chloro-4-(3-chlorophenoxy)aniline (1.02 mmol, 258 mg) in DCM (6 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The organic phase was washed with a saturated solution of NaHCO3 and with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (90:10) as eluent to afford N-(3-chloro-4-(3-chlorophenoxy)phenyl)picolinamide (0.52 mmol, 187 mg, 51%) as a white solid.