Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=1)=[CH:5]/[CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([C:23]([F:25])([F:24])[F:26])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(C(F)(F)F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(CC1CCCC1)c1ccc(-n2nnnc2C)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
A solution of nickel (II) chloride hexahydrate (102 mg, 0.428 mmol) and (E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-acrylic acid methyl ester (814 mg, 2.14 mmol) in methanol (20 mL) was cooled to 0° C. and then treated with sodium borohydride (265 mg, 7 mmol) in five portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with a 3N aqueous hydrochloric acid solution (50 mL) and ethyl acetate (75 mL). The two layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionic acid methyl ester (815 mg, 99%) as a viscous oil: EI-HRMS m/e calcd for C18H21F3N4O2 (M+) 382.1617, found 382.1617.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[S:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O.C([O:19]CC)C>[N+](C)([O-])=O>[Br-:1].[O:19]=[C:12]1[CH2:13][CH2:14][CH2:15][S+:11]1[CH2:2][CH2:3][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1CCSC1
Reactant: CCOCC
Reactant: O=C(CBr)c1ccccc1
Solvent: C[N+](=O)[O-]
Solvent: O
Product: O=C1CCC[S+]1CCc1ccccc1
Product: [Br-]
Reaction time: 2 h

Procedure:
The 2-bromoacetophenone of 4.97 g (0.025 moles) was dissolved in nitromethane of 9.5 g. Tetrahydrothiophene of 2.2 g (0.025 moles) was added at room temperature, and was matured as it is for two hours at room temperature. A reaction liquid was hardened by the progression of reactions. Solids were dissolved by adding 70 g of water and 50 g of diethyl ether. A water layer was separated and washed with 50 g of diethyl ether of 50 g so that lipophilic impurities were removed.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[S:37]>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:36]([NH:35][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C:27]([F:26])([F:38])[F:39])=[S:37])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: FC(F)(F)Oc1ccccc1N=C=S
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)Nc5ccccc5OC(F)(F)F)c4c(c23)C1=O
Temperature: 25 °C

Procedure:
250 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.75 mmole) were dissolved in 10 ml of acetonitrile. 240 μL (2 molar equivalents) of 2-(trifluoromethoxy)phenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 20 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 368 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=89%) which was characterized as follows:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4]([Cl:10])=[N:5][C:6](Cl)=[N:7][CH:8]=1.[F:13][C:14]([F:25])([F:24])[O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:10][C:4]1[C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=[C:6]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[O:15][C:14]([F:13])([F:24])[F:25])[N:5]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: NCc1ccccc1OC(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccccc1CNc1ncc(C(F)(F)F)c(Cl)n1
Reaction time: 0.33 h
Yield: 51.5 %

Procedure:
To a solution of 5-(trifluoromethyl)-2,4-di-chloropyrimidine (0.5 g, 2.3 mmol) in DMF (8 mL) were added a solution of 2-(trifluoromethoxy)benzylamine (0.44g, 2.3 mmol) in DMF (2 mL) followed by DIPEA (0.44 mL, 2.3 mmol) at −20° C. The reaction mixture was stirred at that temperature for 20 min. When the starting material was all consumed, the mixture was diluted with EtOAc and washed with water (×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 100% CH2Cl2 as an eluent to afford 0.44 g (52%) of (4-chloro-5-trifluoromethyl-pyrimidin-2-yl)-(2-trifluoromethoxy-benzyl)-amine as a white foam.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH:3]=1.[NH2:22][CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH:3]=1
Reactant: Clc1cc(-c2ccc3ccccc3c2)nc2ccccc12
Reactant: NCCCO
Product: OCCCNc1cc(-c2ccc3ccccc3c2)nc2ccccc12

Procedure:
A solution of 4-chloro-(2-napthyl) quinoline (420 mg, 1.4 mmol) in 3-aminopropanol (1.0 mL) was heated to 130° C. for 1.5 h under a nitrogen atmosphere. Treatment with water (2 mL) was followed by extraction of the mixture with AcOEt, drying of the extract with MgSO4, and concentration to give a residue of crude N-(3-hydroxypropyl)-2-(2-naphthyl)quinolin-4-amine. This compound was purified by silica gel chromatography eluting with CH2Cl2/MeOH (5:1) followed by crystallization of its hydrobromide salt; yield 82% of C22H20N2O.HBr.H2O; mp 230-235° C. Anal. Calcd for C22H20N2O.HBr.H2O: C, 61.82: H, 5.43; N, 6.55. Found: C, 61.98; H, 5.28; N, 6.49.
Reaction SMILES: [CH3:1][N:2]([SiH:4]([N:8]([CH3:10])[CH3:9])[N:5]([CH3:7])[CH3:6])[CH3:3].[CH:11]#[CH:12].[SiH4]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:11]([Si:4]([N:8]([CH3:10])[CH3:9])([N:5]([CH3:7])[CH3:6])[N:2]([CH3:3])[CH3:1])[CH3:12]
Reactant: C#C
Reactant: CN(C)[SiH](N(C)C)N(C)C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Agent: [SiH4]
Product: CC[Si](N(C)C)(N(C)C)N(C)C
Temperature: 250 °C

Procedure:
A two liter stirred batch reactor was purged with nitrogen gas and thereafter charged with 840 g (5.22 moles) of tris(dimethylamino)silane and 5 ppm hexachloroplatinic acid. The reactor was then pressurized to approximately 5 psig with nitrogen gas and heated to approximately 250° C. The acetylene inlet feed was started and maintained at 100 psig. The reaction temperature was maintained at 250° C. After four hours the acetylene flow was stopped, the reaction mix cooled and the reaction products analyzed. Vinyltris(dimethyl)amino)silane was the single major product at 90% of theoretical. Ethyltris(dimethylamino)silane and 1,2-bis(trisdimethylamino)silylethane by-products were formed in amounts less than 0.5% each. Vinyltris(dimethylamino)silane polymer was also formed in an amount of 7-8%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[NH2:9][CH2:10][C:11]1[C:12]([CH3:26])=[CH:13][C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:15][C:16]=1[CH3:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:9][CH2:10][C:11]2[C:12]([CH3:26])=[CH:13][C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[N:15][C:16]=2[CH3:17])=[O:8])=[CH:2]1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Reactant: O=C(O)c1cc[nH]c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cc[nH]c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 1H-pyrrole-3-carboxylic acid (1.40 g, 12.60 mmol), tert-butyl 5-(aminomethyl)-4,6-dimethylpyridin-2-ylcarbamate (3.48 g, 13.86 mmol) and DIPEA (6.60 ml, 37.8 mmol) in DCM (100 ml) was added HBTU (5.73 g, 15.12 mmol) at rt and was stirred at rt for 12 hours. The suspension was filtered off. The solid was washed with DCM and dried under reduced pressure to afford pure tert-butyl 5-((1H-pyrrole-3-carboxamido)methyl)-4,6-dimethylpyridin-2-ylcarbamate. HPLC (Method G) Rt=1.35 min; MS [M+H]+=345.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][CH2:7][OH:8])([O-:3])=[O:2].N1C=CN=C1.ClCCl.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(OCC)(=O)C.C(OCC)C>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][CH2:7][O:8][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
Add 2-nitrophenethyl alcohol (20 g, 120 mmol) and imidazole (11.4 g, 167 mmol) to dichloromethane (200 mL). Cooled to 0° C. and add solid tert-butyldimethylsilyl chloride (23.4 g, 155 mmol). Stir the mixture at 20° C. for 2 hours and dilute with 1:1 ethyl acetate:diethyl ether. Wash with distilled water, aqueous 3% acetic acid, aqueous 0.5 molar sodium hydrogen carbonate, and saturated sodium chloride. Dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to give 32.4 g (96%) of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, 1H, J=8.0, 1.2 Hz), 7.50 (dt, 1H, J=7.2, 1.6 Hz), 7.37 (m, 2H), 3.89 (t, 2H, J=6.4 Hz), 3.12 (t, 2H, J=6.4 Hz), 0.83 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: CC(C)([O-])C.[Na+].CO[C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.I[C:17]1[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=1.[C:29]1(C)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>[Cu](I)I>[C:14]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:9]=[CH:10][CH:11]=[C:12]([S:15][C:17]2[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=2)[CH:13]=1
Reactant: Cc1ccccc1
Reactant: COc1ccc(S)cc1
Reactant: COc1cc(I)cc(OC)c1OC
Agent: I[Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: COc1cc(Sc2cccc(-c3ccccc3)c2)cc(OC)c1OC
Temperature: 110 °C

Procedure:
To a solution of 52a (1.1 g, crude compound) in ethanol (8 mL) was added potassium hydroxide (2.1 g, 12 mL) and heated to reflux for overnight. The solution was cooled to RT and the ethanol was evaporated under reduced pressure. The residue was dissolved in water and washed with diethyl ether (10 mL). The aqueous layer was acidified with 2 N HCl and extracted with diethyl ether (3×50 mL). The organic extracts were washed with water (50 mL), brine (50 mL), dried over MgSO4, filtered and evaporated under reduced pressure to afford 0.85 g (77.3%) of crude biphenyl-3-thiol product (overall, 3 steps). Into a round-bottomed flask, stirred magnetically, were placed 0.1 g (1.04 mmol) of sodium tert-butoxide and 83 mg of copper iodide (0.43 mmol). After the reaction vessel was sealed, 0.13 g (0.71 mmol) of 4-methoxybenzenethiol and 0.19 g (0.65 mmol) of 5-iodo-1,2,3-trimethoxybenzene in 3.0 mL of toluene were injected through the septum. The reaction mixture was heated for overnight at 110° C. Purification was performed by flash chromatography, and an amorphous solid was obtained (40% yield). 1H NMR (500 MHz, CDCl3) δ 7.54-7.52 (m, 3H), 7.44-7.41 (m, 3H), 7.37-7.33 (m, 2H), 7.23 (s, br, 1H), 6.69 (s, 2H), 3.86 (s, 3H), 3.80 (s, 6H). MS (ESI) m/z 353.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[S:9][CH:10]=[C:11]([Cl:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.[CH3:14][C:15]([CH3:24])([CH3:23])[C:16]#[C:17]/[CH:18]=[CH:19]/[CH2:20][NH:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].ClCCl>CS(C)=O>[ClH:12].[Cl:12][C:11]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][N:21]([CH2:20]/[CH:19]=[CH:18]/[C:17]#[C:16][C:15]([CH3:24])([CH3:23])[CH3:14])[CH3:22])[C:8]=2[S:9][CH:10]=1
Reactant: CNC/C=C/C#CC(C)(C)C
Reactant: Clc1csc2c(CBr)cccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc2c(Cl)csc12
Temperature: 25 °C
Reaction time: 19 h
Yield: 77 %

Procedure:
To a solution of 0.34 g (1.3 mmol) of 7-bromomethyl3-chlorobenzo[b]thiophene in 3 ml of dimethyl sulfoxide were added 0.246 g (1.31 mmol) of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine hydrochloride, and 0.27 g (1.95 mmol) of potassium carbonate under ice cooling. The mixture was stirred for 19 hours at room temperature, poured into 40 ml of dichloromethane, washed with 30 ml ×2 of water, and adjusted to pH 2 with 25 ml of water and 2N hydrochloric acid. The organic layer was separated, washed with 20 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and cooled to crystallize. The crystals were suspended in isopropylalcohol, filtered, washed with isopropyl alcohol and dried to obtain 0.37 g (yield: 77%) of the above identified compound as white crystalline powder.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])[CH3:22])=O)(C)(C)C.C1(C)C=CC=CC=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Si:14]([O:13][C@H:10]1[CH2:11][CH2:12][NH:8][C@@H:9]1[C@@H:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])[CH3:22])([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15]
Reactant: Cc1c(N[C@@H](C)[C@@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(N[C@@H](C)[C@H]2NCC[C@@H]2O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
Intermediate 14F (825 mg, 1.67 mmol) was dried azeotropically with toluene (2×). The residue was taken up in 15% TFA in CH2Cl2 (10 mL) and stirred at rt for 5 h. Toluene (10 mL) was added and solvent was removed under vacuum. The product was purified by reverse phase HPLC (Phenoenex Luna 30×100 mm S5 C18, 10 min. grad, 25 mL/min, 20-100% B solvent, A=10% MeOH/water+0.1% TFA, B=90% MeOH/Water+0.1% TFA, 4 injections). Solvent was reduced to 10% volume and the product was then extracted into EtOAc, washed with sat. aqueous NaHCO3, dried over MgSO4 and filtered. Solvents were removed to provide the title compound (371 mg): MS (ES) m/z 394.53 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][CH2:55][O:56][CH3:57])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:57][O:56][CH2:55][CH2:54][CH2:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:47][CH:48]=1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: COCCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (10/1/1, 19.2 ml) and then were added 4-(3-methoxypropoxy)phenyl borate (145 mg) and potassium carbonate (175 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 14 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[4-(3-methoxypropoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 102) (190 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[Bi:14]([C:24]1[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=1[CH3:32])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23]>CCCCCC>[Cl-:3].[Cl-:3].[CH3:23][C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[C:15]=1[Bi:14]([C:24]1[C:25]([CH3:32])=[CH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30])[C:7]1[C:6]([CH3:5])=[CH:11][C:10]([CH3:12])=[CH:9][C:8]=1[CH3:13]
Reactant: O=S(Cl)Cl
Agent: Cc1cc(C)c([Bi](c2c(C)cc(C)cc2C)c2c(C)cc(C)cc2C)c(C)c1
Solvent: CCCCCC
Product: [Cl-]
Reaction time: 1 h

Procedure:
Thionyl chloride (1.48 g, 11 mmol) was added to a solution of tris(2,4,6-trimethylphenyl)bismuthine (Example 14) (5.66 g, 10 mmol) in hexane (100 ml) at ambient temperature. The mixture was stirred for one hour and the precipitated product was isolated and recrystalized from ethanol. Yield: 5.70 g (90%).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.N1C=CC=CC=1.[CH2:30]([S:34](Cl)(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33].O>ClCCl>[CH2:30]([S:34]([NH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1)(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)Nc1ccc(Cn2c(C)nc3ccc(C(=O)OC)nc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (300 mg) in dichloromethane (3.0 ml) was added pyridine (143 mg). To this suspension was added 1-butanesulfonyl chloride (156 mg) under ice-cooling and the mixture was stirred for 5 min and at room temperature for 7 hr. Water was added to the reaction mixture and extracted twice with chloroform. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. Methanol was added to the residue. The mixture was crystallized, collected by filtration, and dried under reduced pressure to give methyl 3-(4-(N-(1-butanesulfonyl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate as ochroid crystals (287 mg).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].[Cl:13][C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=CC=1N.NC1C=[CH:46][C:29]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][CH2:39][CH2:40][O:41][Si](C)(C)C)[N:32]=2)=[CH:28][CH:27]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.C1COCC1>[Cl:13][C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:11][C:12]=1[NH:8][C:1]([NH:3][C:7]1[CH:6]=[CH:46][C:29]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][CH2:39][CH2:40][OH:41])[N:32]=2)=[CH:28][CH:27]=1)=[O:2]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[Si](C)(C)OCCCNc1nccc(Oc2ccc(N)cc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc(NCCCO)n2)cc1)Nc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 120 h

Procedure:
105 mg (0.65 mmol) 1,1′-Carbonyl-diimidazol (CDI) was given to a solution of 115 mg (0.59 mmol) 2-chloro-5-(trifluoromethyl)aniline in 4.0 ml dichloromethane. After stirring for 12 h at r.t. a solution of 220 mg (0.59 mmol) [4-(4-Amino-phenoxy)-pyrimidin-2-yl]-(3-trimethylsilanyloxy-propyl)-amine in 6 ml dichloromethane within 30 min. was added and the mixture stirred for 5 d at r.t. A solution of 1.4 ml (1.4 mmol) 1 M tetrabutylammonium fluoride in THF was given to the mixture and stirring continued for 12 h. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel (dichloromethane/ethanol 96:4). Yield: 6 mg (2%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[NH:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:17]([C:21](O)=[O:22])[CH:18]([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)(Cl)Cl>[NH:16]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C@H:17]([C:21]([N:1]1[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4])=[O:22])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boc-Val-Pro-OBzl was prepared by dissolving H-Pro-OBzl (20 g, 83 mmol) in 50 mL of chloroform and adding Boc-Val-OH (18.0 g, 83 mmol), HOBt (23.0 g, 165 mmol), NMM (9.0 mL, 83 mmol) and DCC (17.0 g, 83 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was filtered and solvent was evaporated. Ethyl acetate was added and insoluble material was removed by filtration. The filtrate was washed with 0.2N HCl, 5% NaHCO3, and saturated aqueous NaCl. It was dried over Na2SO4, filtered and evaporate to give a white solid (30 g, 75 mmol, 90%). ESI/MS calculated for C22H32N2O5 +H: 405.2. Found 405.6.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1>>[Cl:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][S:17][C:15]2[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=2)=[CH:4][CH:5]=1
Reactant: Clc1ccc(CBr)cn1
Reactant: Cc1cc(O)nc(S)n1
Product: Cc1cc(O)nc(SCc2ccc(Cl)nc2)n1
Yield: 62 %

Procedure:
The title compound was prepared by following the procedure described for Example 55 from 6-chloropyridine-3-carbaldehyde to provide (6-chloropyridin-3-yl)methanol, which was converted to 5-(bromomethyl)-2-chloropyridine. The reaction of 6-methyl-2-sulfanylpyrimidin-4-ol with 5-(bromomethyl)-2-chloropyridine provided 2-{[(6-chloropyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (0.82 g, 62% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.17 (s, 3H), 4.33 (s, 2H), 5.99 (bs, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 8.45 (s, 1H), 9.30 (s, 1H); M+ 268.2.