Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13](=[O:25])[CH2:14][C@@:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16]1)([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1.CO>[C:8]([O:12][C:13](=[O:25])[CH2:14][C@@:15]1([CH2:21][C:22]([O:24][CH3:1])=[O:23])[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16]1)([CH3:9])([CH3:10])[CH3:11]
Reactant: C[C@@H]1CC[C@](CC(=O)O)(CC(=O)OC(C)(C)C)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C[C@]1(CC(=O)OC(C)(C)C)CC[C@@H](C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Trimethylsilyldiazomethane (14 mL of a 2 M solution in hexanes, 26.9 mmol) was added dropwise to a stirring solution of [(1S,3R)-1-carboxymethyl-3-methyl-cyclopentyl]-acetic acid tert-butyl ester (6.9 g, 26.9 mmol) in toluene (60 mL) and methanol (15 mL) at 10° C. under argon, and the mixture was allowed to warm to room temperature. The mixture was stirred for 2 hours, and then the solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate (200 mL), washed with saturated sodium hydrogen carbonate solution, dilute hydrochloric acid, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by chromatography (silica gel, eluting with a gradient of heptane to 95:5 heptane:ethyl acetate) to give 6.73 g (92.4%) of [(1S,3R)-1-methoxycarbonylmethyl-3-methyl-cyclopentyl]-acetic acid tert-butyl ester;
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[CH3:3].[Li]CCCC.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[CH3:3]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CN(C)CCCn1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nccn1CCCN(C)C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
1-(N,N-Dimethylaminopropyl) imidazole (2 g) in THF (20 ml) at −78° C. was treated with nBuLi (8.6 ml, 1.6 M) under nitrogen. After 30 minutes at −78° C., tri-n-butylstannyl chloride was added and the mixture allowed to warm to 20° C. The mixture was concentrated in vacuo, taken up in n-hexane and filtered. The filtrate was concentrated in vacuo to give the title compound (4.33 g) as a yellow oil; δH CDCl3 7.28 (1H, s), 7.09 (1H, s), 3.97 (2H, t), 2.25 (2H, t), 2.20(6H, s), 1.90 (2H, m) 1.55 (6H, m), 1.34 (12H, m), 0.92 (9H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](=[O:33])(=[O:32])[NH2:31])=[CH:26][C:25]=2Br)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([F:17])[F:16])[CH:12]=[C:11]([C:18]#[N:19])[CH:10]=1.N[C:36]1C=CC(S(N)(=O)=O)=CC=1Br>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](=[O:33])(=[O:32])[NH2:31])=[CH:26][C:25]=2[CH3:36])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([F:16])[F:17])[CH:12]=[C:11]([C:18]#[N:19])[CH:10]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1Br
Reactant: N#Cc1cc(Oc2ccc(CC(=O)Nc3ccc(S(N)(=O)=O)cc3Br)cc2Br)cc(C(F)F)c1
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)Cc1ccc(Oc2cc(C#N)cc(C(F)F)c2)c(Br)c1

Procedure:
2-[3-Bromo-4-(3-cyano-5-difluoromethyl-phenoxy)-phenyl]-N-(2-bromo-4-sulfamoyl-phenyl)-acetamide I-64) was prepared analogously except in step 4, 4-amino-3-bromo-benzenesulfonamide was used in place of 4-amino-3-methyl-benzenesulfonamide.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[S:14][C:15]3[CH2:24][C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:16]=3[N:17]=2)[CH2:8][CH2:7]1)=O)C.Br.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O>[NH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[S:14][C:15]3[CH2:24][C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:16]=3[N:17]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)N1CCC(Cc2nc3c(s2)Cc2ccccc2-3)CC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc2c(c1)Cc1sc(CC3CCNCC3)nc1-2
Yield: 116.5 %

Procedure:
To 0.25 g of 2-[(1-ethoxycarbonyl-4-piperidyl)methyl]-8H-indeno[1,2-d]thiazole was added 10 ml of a 25% solution of hydrogen bromide in acetic acid, followed by heating under reflux for one hour. After cooling, water was added, and the mixture was alkalized with a 1N aqueous solution of sodium hydroxide and potassium carbonate, followed by extraction with chloroform. The extract was dried over anhydrous potassium carbonate. The solvent was then evaporated, whereby 0.23 g of 2-(4-piperidylmethyl)-8H-indeno[1,2-d]thiazole was obtained. The resulting product was dissolved in methanol, fumaric acid was added thereto, followed by crystallization from acetonitrile. The crystals were recrystallized from acetonitrile-methanol to give a fumarate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[C:31]([O:35][C:36](=[O:49])[NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[NH:44][C:45](=[O:48])[CH:46]=[CH2:47])([CH3:34])([CH3:33])[CH3:32].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:31]([O:35][C:36](=[O:49])[NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[NH:44][C:45](=[O:48])/[CH:46]=[CH:47]/[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[C:9](=[O:10])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: C=CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)C(OCCN1CCOCC1)c1ccc(Br)cc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(OCCN2CCOCC2)C(=O)Nc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 24.5 %

Procedure:
A mixture of 2-(4-bromo-phenyl)-2-(2-morpholin-4-yl-ethoxy)-N-(4-trifluoromethyl-phenyl)-acetamide (481 mg, 0.720 mmol), (2-acryloylamino-phenyl)-carbamic acid tert-butyl ester (240 mg, 0.920 mmol), tri-o-tolyl-phosphine (51 mg, 0.17 mmol), triethylamine (421 mg, 4.16 mmol) and Pd2(dba)3 (76 mg, 0.08 mmol) in DMF (4 mL) was heated at 105 degrees Celcius for 1 hr under N2 atmosphere, and then at 95 degrees Celcius overnight. After cooling to room temperature, the mixture was poured into a saturated aqueous solution of NH4Cl and extracted with ethyl acetate four times. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography (dichloromethane/methanol 500:1-100:1) to obtain a brown solid (118 mg, 24.6%). MS: calc'd 669 (MH+), exp 669 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccnc(OCc3nc(-c4ccco4)oc3C)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccnc(OCc3nc(-c4ccco4)oc3C)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-4-pyridylmethyl]-1H-pyrazol-4-yl]propionate (639 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-4-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (569 mg, yield: 94%). This was recrystallized from ethanol-hexane. Melting point: 138–139° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([C@H:17]2[CH2:21][O:20][C:19](=[O:22])[N:18]2[C:23](=[O:33])[CH2:24][C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:52]=[N+:53]=[N-:54])(=O)=O)(C)C.C(O)(=O)C>O1CCCC1.O>[N:52]([C@@H:24]([C@@H:25]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH3:26])[C:23]([N:18]1[C@@H:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:21][O:20][C:19]1=[O:22])=[O:33])=[N+:53]=[N-:54]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: C[C@@H](CC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@H](c1ccccc1)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Potassium bis(trimethylsilyl)amide (2.0 mL, 1.8 mmol, 0.91 M in tetrahydrofuran) was added to (S)-4-phenyl-3-((S)-3-phenyl-butyryl)-oxazolidin-2-one (500 mg, 1.6 mmol) in anhydrous tetrahydrofuran (8 mL) at −78° C. and stirred for 1 hour. In a separate flask, a solution of 2,4,6-triisopropylbenzenesulphonyl azide (625 mg, 2.0 mmol) in anhydrous tetrahydrofuran (10 mL) at −78° C. was added via cannula to the anion at −78° C. and stirring continued for 2 hours. Acetic acid (0.45 mL, 7.8 mmol) was added to the reaction at −78° C., the mixture warmed to room temperature and stirred overnight. The mixture was poured into water (30 mL) and extracted with ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. The crude product was purified on silica gel with 2:1 dichloromethane/hexane to give (S)-3-((2S,3R)-2-azido-3-phenyl-butyryl)-4-phenyl-oxazolidin-2-one (230 mg, 41%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][CH2:20][NH2:21].[Na]>ClCCl>[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][CH2:20][NH:21][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CN1CCCC1CCN
Agent: [Na]
Solvent: ClCCl
Product: CN1CCCC1CCNCc1ccc2ccccc2c1

Procedure:
Experimental condition analogous to Example 1, from 2-naphthalencarboxaldehyde 0.15 g (1 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethylamine 0.14 g (1.1 mmol), and sodium triacethoxyborohydride 0.31 g (1.5 mmol), in 10 mL dichloromethane. The crude material is 110 mg pale yellow oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]#[N:21])[CH:14]=[CH:13]2>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[Cl:1][C:11]1[C:10]([OH:9])=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([C:20]#[N:21])=[CH:16]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1ccc2cc(O)ccc2c1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: N#Cc1ccc2c(Cl)c(O)ccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
To a cooled (0° C.) solution of N-chlorosuccinimide (1.4 g, 10.4 mmol) in 80 mL of CH2Cl2, ZrCl4 (0.122 g, 5% mol) was added, followed by 6-hydroxynaphthalene-2-carbonitrile (1.76 g, 10.4 mmol). The mixture was stirred for 18 h at room temperature until the complete disappearance of the starting material as judged by GC analysis. The mixture was quenched with saturated NH4Cl aqueous solution (30 mL) and transferred to a separatory funnel. The two phases were separated and the organic one was washed with water (3×10 mL), dried over Na2SO4 and evaporated under vacuum to give a yellow oil. The crude was purified by flash cromatography (petroleum ether/ethyl acetate 75:25) to afford 5-chloro-6-hydroxynaphthalene-2-carbonitrile (1.38 gr, 65% yield), as whitish solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>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:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]4[CH:27]=[N:22][CH:23]=[N:24][CH:25]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
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: C1CCOC1
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(Br)cc12
Temperature: 110 °C

Procedure:
A 10-20 mL microwave vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (503 mg, 1.098 mmol), pyrimidin-5-ylboronic acid (143 mg, 1.153 mmol), tetrakis(triphenylphosphine)palladium (127 mg, 0.110 mmol). The vial was flushed with Ar(g), then THF (5489 μL, 1.098 mmol) and potassium carbonate (1.5 M) (1464 μL, 2.195 mmol) (aq. solution) were added in sequence. The vial was sealed and heated at 110° C. for 2 hours. The mixture was diluted with water and extracted with 10% i-PrOH/EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 100-g SNAP column, eluting with 0-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to provide (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:14])[N:3]=1.CC(C)([O-])C.[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[F:67][C:68]([F:78])([F:77])[O:69][C:70]1[CH:75]=[CH:74][C:73]([NH2:76])=[CH:72][CH:71]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:14][C:4]1[N:3]=[C:2]([NH:76][C:73]2[CH:74]=[CH:75][C:70]([O:69][C:68]([F:67])([F:77])[F:78])=[CH:71][CH:72]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=1
Reactant: Clc1cc(N2CCOCC2)cc(Cl)n1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(Nc2cc(N3CCOCC3)cc(Cl)n2)cc1
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
To a solution of 4-(2,6-dichloro-pyridin-4-yl)-morpholine (0.500 g, 2.15 mmol) in toluene (6 mL) were added potassium tert-butoxide (0.109 g, 0.973 mmol), palladium(II)acetate (24.13 mg, 0.107 mmol), BINAP (67.0 mg, 0.107 mmol) and 4-trifluoromethoxyphenylamine (456 mg, 2.58 mmol), in a 10 mL reaction vessel. This reaction mixture was subjected the microwave radiation, in which the microwave power was 250 W, to attain a reaction temperature of 150° C. After this reaction proceeded for 30 min, water (200 mL) was added to the reaction mixture and the reaction product was extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered, and the filtrate concentrated under vacuum. The product was purified through column chromatography using 230-400 mesh silica gel (elution 30:70 ethyl acetate:petroleum ether) to afford the desired compound as a light yellow solid (140 mg, yield 18%).
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[C:9]1[CH:14]=[CH:13][C:12](F)=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CN(C=O)C>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][C:12]2[CH:13]=[CH:14][C:9](/[CH:8]=[C:2](\[CH3:1])/[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:10][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH:28]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc(F)c(C(F)(F)F)c1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/c1ccc(Oc2cccnc2)c(C(F)(F)F)c1

Procedure:
3 b) The ester from 3 a, 3 eq. of potassium carbonate and 1.1 eq. of 3-hydroxypyridine were heated under reflux in DMF for 3 hours. After standard working up and purification, ethyl E-3-[4-(3-pyridyloxy)-3-(trifluoromethyl)phenyl]-2-methyl-propenoate was obtained.
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:16](=O)/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH:16](=[N:13][C:12]1[CH:14]=[CH:15][C:9]([CH2:1][C:2]2[CH:3]=[CH:4][C:5]([N:6]=[CH:10][CH:9]=[CH:1][C:2]3[CH:8]=[CH:7][CH:5]=[CH:4][CH:3]=3)=[CH:7][CH:8]=2)=[CH:10][CH:11]=1)[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Reactant: O=C/C=C/c1ccccc1
Solvent: CCO
Product: C(=Cc1ccccc1)C=Nc1ccc(Cc2ccc(N=CC=Cc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 188.7 %

Procedure:
To a solution of 198.2 g (1 mole) of 4,4'-methylene dianiline in 2000 ml of ethanol was added a solution of 277.6 g (2.1 moles) of transcinnamaldehyde in 500 ml of ethanol over a 2 minute period. Immediately an exothermic reaction ensued and within 2 minutes the reaction mixture set up to a yellow solid. An additional 1000 ml of ethanol was added, the reaction mixture was heated at reflux for 1 hour with stirring, and then cooled to room temperature. The product was filtered and dried in vacuum at room temperature, yielding 402.5 g (94% of theory) of N,N'-biscinnamal-4,4'-methylene dianiline, m.p. 162.5°-163.5°C.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[CH:42]=[CH:41][C:40]([C:43]2([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:45][CH2:44]2)=[CH:39][N:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:42]=[CH:41][C:40]([C:43]4([S:46]([CH3:49])(=[O:47])=[O:48])[CH2:45][CH2:44]4)=[CH:39][N:38]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CS(=O)(=O)C1(c2ccc(Cl)nc2)CC1
Product: C[C@@H](c1ccc(-c2ccc(C3(S(C)(=O)=O)CC3)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 20 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 2-chloro-5-(1-methanesulfonyl-cyclopropyl)-pyridine following a procedure analogous to that described in Example 1. Yield: 20% of theory; LC (method 1): tR=1.83 min; Mass spectrum (ESI+): m/z=549 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C1CCNC1
Product: Brc1ccc(-c2nsc3cc(OCCCCN4CCCC4)ccc23)cc1

Procedure:
According to the method in example 4, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and pyrrolidine were converted to yield 3-(4-Bromo-phenyl)-6-(4-pyrrolidin-1-yl-butoxy)-benzo[d]isothiazole, MS: 432 (MH+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:26]1([CH2:32][CH2:33][CH2:34][CH2:35]O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:35][CH2:34][CH2:33][CH2:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Reactant: OCCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCCCCc2ccccc2)=C(C)N1

Procedure:
259 mg (0.718 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 0.122 ml (0.79 mmol) of 4-phenylbutyl alcohol, 193 mg (1.01 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 17.5 mg (0.144 mmol) of 4-dimethylaminopyridine were stirred together in 7.2 ml of dichloromethane at room temperature overnight. Water was added to the reaction liquid. After the extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/1) to obtain the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:33]([CH2:35][NH2:36])[OH:34]>CS(C)=O>[OH:34][CH2:33][CH2:35][NH:36][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccc(F)cc4)c3)csc12
Solvent: CS(C)=O
Product: O=C(Nc1cccc(OCc2csc3c(C(=O)NCCO)cncc23)c1)c1ccc(F)cc1
Temperature: 135 °C

Procedure:
A suspension of 3-[3-(4-fluoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (25.1 mg, 0.056 mmol) (from Example 8 supra) in methyl sulfoxide (0.5 mL) and ethanolamine (1.5 mL) (Aldrich) was heated at 135° C. for 2 hours in a microwave reactor. The solvent was removed in vacuum and the crude product was purified by column chromatography (CH2Cl2/MeOH, 98/2 to 80/20) to give two products. The faster eluting material gave 3-[3-(4-fluoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white solid. (Yield 7.3 mg, 28%).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][CH:26]=[C:27]([CH2:28][C:29]#[N:30])[C:16]=3[N:15]=2)[C:5]1=[O:31])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:30][CH2:29][CH2:28][C:27]1[C:16]2[N:15]=[C:14]([CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]3=[O:31])[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]=2[CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(CC#N)cccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(CCN)cccc21

Procedure:
A mixture of [2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-4-yl]-acetonitrile (51 mg, 0.12 mmol) and 10% Pd/C (9 mg) in methanol (20 mL) was rocked in a Parr shaker under a hydrogen atmosphere (40 psi) for 15 hrs. The catalyst was removed by filtration and the filtrate concentrated. The residue was purified by preparative HPLC (30-100% B) to give 1-[4-(2-amino-ethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one; HCl salt as the TFA salt, that was converted into the HCl salt by treatment with excess acetyl chloride in methanol, followed by removal of the volatiles in vacuo: 5 mg, 9% as a white solid.