Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCCCCCCO)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 62.4 %

Procedure:
20.0 g (164 mmol) of 4-hydroxybenzaldehyde and 30.0 g (182 mmol) of 8-chlorooctan-1-ol are dissolved in 200 mL of N,N-dimethylformamide. 29.0 g (210 mmol) of potassium carbonate and 2.7 g (16 mmol) of potassium iodide are added and the suspension is heated to 100° C. After 48 h, the excess of potassium carbonate is filtered off and the resulting filtrate is poured to icy water. The aqueous layer is extracted twice with ethyl acetate. Combined organic layers are washed with brine and evaporated to dryness. The crude is purified twice on column chromatography (SiO2, Heptane/ethyl acetate: 7/3) and dried overnight at 40° C. 25.6 g of 4-[(8-hydroxyoctyl)oxy]benzaldehyde are obtained as a yellow solid (62% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)CCC>[CH2:15]([N:14]1[C:10]2[N:9]=[CH:8][C:7]3[C:2]([N:29]4[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]4)=[N:3][C:4]4[N:5]([N:17]=[CH:18][C:19]=4[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=3[C:11]=2[CH:12]=[N:13]1)[CH3:16]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cnn2c1nc(Cl)c1cnc3c(cnn3CC)c12
Solvent: CCCCO
Product: CCOC(=O)c1cnn2c1nc(N1CCN(C)CC1)c1cnc3c(cnn3CC)c12
Reaction time: 12 h

Procedure:
3.5 g of 5-chloro-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester (0.01 mol) are dissolved in 20 ml of butanol. 2 g of N-methylpiperazine are added and the solution is refluxed with stirring for 12 hours. After evaporation of the solvent, the residue is extracted three times with 50 ml portions of ethyl acetate. The ethyl acetate is distilled off until the volume is about 30 ml. The 8-ethyl-5-(4-methyl-1-piperazinyl)-8H-pyrazolo[1,5a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester crystallizes, yield 3.1 g (76%); m.p. 111°-113° (ethyl acetate).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1B(O)O>>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ccncc1B(O)O
Product: COc1ccncc1-c1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 4-methoxy-3-pyridineboronic acid in General Procedure A. Purification on silica yielded 162. NMR (CDCl3): 2.67-2.69 (m, 4H, 2×CH2), 2.81 (s 3H, CH3), 3.29-3.31 (m, 4H, 2×CH2), 3.84-3.86 (m, 4H, 2×CH2), 3.88 (s, 2H, CH2), 3.92 (s, 3H, CH3), 4.00-4.02 (m, 4H, 2×CH2), 6.91 (d, H, ArH, J=5.81 Hz), 7.33 (s, H, ArH), 8.52 (d, H, ArH, J=5.83 Hz), 8.85 (s, H, ArH). MS: (ESI+): MH+=505.17
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[F:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]2[C:23]=1[C:24]([Sn](CCCC)(CCCC)CCCC)=[N:25][NH:26]2>CN(C=O)C.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.[Cu]I>[F:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]2[C:23]=1[C:24]([C:2]1[N:3]=[C:4]3[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]3=[N:6][CH:7]=1)=[N:25][NH:26]2
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)cc(F)c12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(F)cc(F)c34)cnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.5 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (1.56 g, 4.38 mmol) and 4,6-difluoro-3-tributylstannanyl-1H-indazole (1.94 g, 4.38 mmol) were dissolved in DMF (40 mL) and tetrakis(triphenylphosphine)palladium(0) (253 mg, 0.22 mmol) and copper(I) iodide (167 mg, 0.88 mmol) were added. The reaction mixture was purged with argon, stirred at room temperature for 4 h, then heated at 80° C. for 1 h. The reaction was cooled to room temperature, quenched with sat NH4Cl and extracted with EtOAc (2×). The combined organics were washed with sat LiCl and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane to provide 1.89 g of 2-(4,6-difluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:24][N:23]=[C:22]([CH3:25])[CH:21]=1)=[CH:16][CH:15]=3.I[CH3:32]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:21]=[C:22]([CH3:25])[N:23]([CH3:32])[N:24]=1)=[CH:16][CH:15]=3
Reactant: Cc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)[nH]n1
Reactant: CI
Product: Cc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)nn1C

Procedure:
The process is carried out as in Example 36 above, using 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(3-methyl-1H-pyrazol-5-yl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one described in Example 46 above and iodomethane.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>C(#N)C.CO>[C:19]([NH:23][CH2:18][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: NS(=O)(=O)c1nc2ccc(OCC3CO3)cc2s1
Reactant: CC(C)(C)N
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)NCC(O)COc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 50 °C

Procedure:
A solution of 6-(2,3-epoxypropoxy)benzothiazole-2-sulfonamide (1.14 gm, 4.0 mmol) in acetonitrile (16 mL) and methanol (4 mL) containing t-butylamine (0.88 mL, 0.4 mmol) was warmed at 50° C. for 15-20 hours. The solvents were evaporated and the residue (1.1 gm) was chromatographed on silica gel eluting with 20-30% methanol/chloroform (V/V). The appropriate fractions were combined and evaporated. The residue was digested in acetonitrile, cooled and the produce collected (0.62 gm), m.p. 195°-196° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1.II.[C:13]([O:17][C:18]([NH:20][C@H:21]([C:23](N(OC)C)=[O:24])[CH3:22])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([C:23](=[O:24])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[CH3:22])=[CH:4][CH:5]=1)[CH3:10]
Reactant: CCc1ccc(Br)cc1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)[C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred suspension of magnesium turnings (243 mg, 10 mmol) in dry THF (10 ml) was added a solution of 1-bromo-4-ethylbenzene (1.85 g, 10 mmol) in dry THF (10 ml), followed by a small crystal of iodine. The reaction mixture was heated with reflux for 4 h, then cooled to r.t. A solution of N2-(tert-butoxycarbonyl)-N-methoxy-N-methyl-L-alaninamide (464 mg, 2 mmol) in dry THF (15 ml) was added dropwise, and the stirring was continued for 5 h at r.t. Then the reaction mixture was quenched with sat. aqueous NH4Cl (25 ml) stirred for 30 min, and the layers were separated. The aqueous layer extracted with ethyl acetate (50 ml). The combined organic layers were dried with Na2SO4, and the solvent was removed under reduced pressure to give the subtitle compound as colourless oil, 718 mg, 70% purity (as determined by NMR). Used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1
Reactant: ON=C(Cl)Cc1ccc(CCc2ccco2)cc1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(CCc3ccco3)cc2)no1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 40.8 %

Procedure:
To an anhydrous tetrahydrofuran (5 mL) solution of 3-ethynyl-pyridin-2-ylamine (33.1 mg, 0.281 mmol) described in Manufacturing Example 1-2-3 was added (4-(2-furan-2-yl-ethyl) phenyl)-acetohydroximoyl chloride (224 mg, 0.85 mmol) described in Manufacturing Example 80-1-7 under nitrogen atmosphere at room temperature. Triethylamine (0.24 mL, 1.7 mmol) was then added dropwise, followed by 1.5 hours of stirring at 60° C. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:9 then 3:7) to obtain the title compound (39.6 mg, 40.8%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH:19]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:19]1([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: c1cnc2c(c1)NCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2ncccc21
Yield: 55.1 %

Procedure:
The product is prepared according to the procedure described in example 5, using 350 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 177 mg of 4-azaindoline and 340 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 216 μl of pyridine and 6.5 ml of N,N-dimethylformamide. 252 mg of 2-[2-(2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[C:12](=[S:17])(OCC)[S-:13].[K+].Cl>CN(C=O)C.O>[N+:9]([C:6]1[CH:7]=[CH:8][C:2]2[S:13][C:12]([SH:17])=[N:4][C:3]=2[CH:5]=1)([O-:11])=[O:10]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2sc(S)nc2c1
Temperature: 110 °C
Yield: 93.5 %

Procedure:
A mixture of 2-fluoro-5-nitro aniline (11, 1.00 g, 6.40 mmol) and potassium O-ethyl dithiocarbonate (1.53 g, 9.60 mmol) in DMF (15 mL) was heated overnight at 110-110° C. under N2. After cooling, the reaction mixture was diluted with water and acidified with 1N HCl. The precipitate was collected by filtration, washed with water, and dried under vacuum to yield compound 12 (1.27 g, 94%).
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9])([CH3:3])[CH3:2].[NH2-].[Na+].C1(C)C=CC=CC=1.Cl[CH2:29][CH2:30][N:31]1[CH2:37][CH:36]2[CH2:38][CH2:39][CH:33]([CH2:34][CH2:35]2)[CH2:32]1>O>[CH:16]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH2:29][CH2:30][N:31]1[CH2:37][CH:36]2[CH2:38][CH2:39][CH:33]([CH2:34][CH2:35]2)[CH2:32]1)[C:8]#[N:9])([CH3:18])[CH3:17]
Reactant: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N(CCC(C#N)(CCN1CC2CCC(CC2)C1)c1ccccc1)C(C)C

Procedure:
A solution of 16 parts of α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile and 5 parts of sodium amide in 200 parts by volume of toluene is heated to about 100° C. over a period of 15 minutes and then 20 parts of 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane in 100 parts by volume of toluene is added slowly over a period of 20 minutes. This mixture is heated at 105°-110° C. for an hour and then cooled to room temperature when 200 parts by volume of water is added. The organic layer is separated, dried over calcium sulfate, concentrated, and then distilled to afford 2-[2-(diisopropylamino)ethyl]-2-phenyl-4-(3-azabicyclo[3.2.2]non-3-yl)butyronitrile, as an oil. This compound is represented by the following structural formula ##STR16##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br.C(OCC)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[F:17])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: Fc1ccccc1CBr
Reactant: COc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: COc1cc(Br)ccc1OCc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A suspension of 4-bromo-2-(methyloxy)phenol (3.0 g, 14.78 mmol), potassium carbonate (2.99 g, 22.17 mmol) and 2-fluorobenzylbromide (1.78 ml, 14.78 mmol) in acetonitrile (20 ml) was stirred at room temperature overnight. Diethylether was added. The organic phase was then washed with water and 1M NaOH, dried (Na2SO4), filtered and evaporated to afford the title compound (4.388 g, quant.). Rt (HPLC): 6.25 min; 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 7.5 (m, 1H), 7.4 (m, 1H), 7.2 (m, 2H), 7.1 (s, 1H), 7.0 (m, 2H), 5.1 (s, 2H), 3.7 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][N:3]=1.C([Li])CCC.[CH2:12]([Sn:16]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])Cl)[CH2:13][CH2:14][CH3:15].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([Sn:16]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][CH2:13][CH2:14][CH3:15])[S:4][N:3]=1
Reactant: Cc1ccsn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)ns1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 3-methylisothiazole (100 mg, 1.0 mmol) in anhydrous THF (2.0 mL) was added n-butyllithium (0.693 mL, 1.1 mmol) dropwise. After stirring for 60 min at −78° C., a solution of tributylchlorostannane (0.326 mL, 1.210 mmol) in anhydrous THF (0.5 mL) was added to the reaction mixture. The reaction mixture was stirred for 30 min at −78° C. and then allowed to warm to RT over a 2 to 3 h period. Saturated aq NaHCO3 was added and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (9:1 Hexane/EtOAc, Flash 60 column) to give the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 0.86-0.94 (m, 9H), 1.05-1.21 (m, 6H), 1.26-1.38 (m, 6H), 1.44-1.65 (m, 6H), 2.56 (s, 3H), 6.97-7.04 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14](C=O)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1C=CC=CC=1N>>[C:4]1([CH3:19])[CH:3]=[CH:2][C:1]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc2nc(-c3ccccc3)oc2c1
Reactant: Nc1ccccc1Cl
Product: Cc1ccc(-c2nc3ccccc3o2)cc1

Procedure:
4.2 g (0.02 mole) of 2-(p-tolyl)-benzoxazole of the formula ##STR48## and 6.7 g (0.02 mole) of the Schiff's base, obtained from 2-phenyl-6-formyl-benzoxazole and o-chloroaniline, of the formula ##STR49## (melting point: 112.5°-113.5° C.) are dissolved in 80 ml of dimethyl formamide. To this solution are added in small amounts in the course of 20 minutes 2.1 g (0.002 mole) of sodium tert.butylate at 20° to 25° C. while introducing nitrogen. During the first 10 minutes, the reaction mixture is irradiated with ultraviolet light. While further introducing nitrogen and stirring for 2 hours at 20° to 25° C. the colour of the mixture changes gradually from yellow through violet brown to brown. Then 320 ml of methanol are added and the batch is cooled to 0° C. The precipitate is collected by filtration, washed repeatedly with a total of 40 ml of methanol and dried, affording 3.2 g (39% of theory) of 1-(2-phenyl-benzoxazol-6-yl)-2-(4'-benzoxazol-2-yl-phenyl)-ethylene of the formula ##STR50## in the form of a light beige-coloured powder with a melting point of 233°-237° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([O:24]C)=[O:23])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([OH:24])=[O:23])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(=O)O)c2)c1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Methyl 3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoate (710 mg) was dissolved in tetrahydrofuran (5 mL) and methanol (3 mL), and 1 mol/L aqueous sodium hydroxide solution (3 mL) was added at 0° C. The mixture was stirred at 0° C. for 1 hr, and at room temperature for 2 hr, cooled again to 0° C., acidified with 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residual crystals were washed with a mixed solvent of isopropyl ether and hexane to give the title compound as colorless crystals (yield 577 mg, 83%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH2:14]1[O:17][CH:15]1[CH3:16]>C(O)C>[CH3:1][N:2]([CH2:14][CH:15]([OH:17])[CH3:16])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Reactant: CC1CO1
Solvent: CCO
Product: CC(O)CN(C)CCc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of N-methyl-4-nitrophenethylamine (1.8 g) and propylene oxide (0.66 g) in ethanol (50 ml) was stirred at reflux for 5 hours. After evaporation to dryness the residual orange oil was chromatographed on silica (37 Kieselgel 60" - Trade Mark) eluting with ethyl acetate followed by collection and evaporation of suitable fractions to give the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][NH:23][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH2:21][CH2:20]1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCC1CC1
Product: O=C(NCC1CC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(cyclopropylmethyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.2 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.23 mmol of cyclopropylmethylamine. LC/MS [9.79 min; 412 (M+1)]
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10]O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:10][Br:32])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: CSc1ncc(Br)c(CO)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ncc(Br)c(CBr)n1
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of [5-bromo-2-(methylthio)pyrimidin-4-yl]methanol (Step 13, 2.20 g, 9.34 mmol) in CH2Cl2 (46.7 mL) was added triphenylphosphine (3.19 g, 12.14 mmol) followed by carbon tetrabromide (4.03 g, 12.14 mmol). The resulting mixture was stirred cold for 1 h. LCMS trace of the aliquot indicated completion of reaction. Volatiles were removed under reduced pressure. Half of the crude material was purified by flash chromatography (SiO2, Biotage 40M cartridge). The column was eluted with an isocratic acetone/hexanes mixture (2.5%, v/v). No purification was obtained. All fractions and reaction crude were combined and purified by preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with MeCN/water+0.1% TFA (51% to 62% organic in 10 min, hold 62% for 2 min, 20 mL/min). Related fractions were combined and evaporated under reduced pressure. The desired compound azeotroped with the water and was extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated to afford a light brown oil as the titled compound. LCMS calc.=297.86; found=298.87.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[F:17][C:18]1[CH:19]=[C:20]([N:32]2[CH2:36][C@H:35]([CH2:37][NH2:38])[O:34][C:33]2=[O:39])[CH:21]=[CH:22][C:23]=1[CH:24]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([N:32]2[CH2:36][C@@H:35]([CH2:37][N:38]=[C:1]=[S:2])[O:34][C:33]2=[O:39])[CH:21]=[CH:22][C:23]=1[CH:24]1[CH2:25][CH2:26][S:27](=[O:30])(=[O:31])[CH2:28][CH2:29]1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Product: O=C1O[C@H](CN=C=S)CN1c1ccc(C2CCS(=O)(=O)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,1′-thiocarbonyldi-2(1H)-pyridone (304 mg, 1.31 mmol) in anhydrous methylene chloride (13 mL) at 0° C. under a nitrogen atmosphere was treated with a solution of (S)-(−)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2-oxazolidinone, as prepared in Example 11, Step 1, (375 mg, 1.09 mmol) in anhydrous methylene chloride (88 mL) over 30 minutes. The resulting mixture was stirred at 0° C. for 30 minutes and at ambient temperature for 30 minutes and was then diluted with methylene chloride (40 mL), washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel (230-400 mesh, 45 g), eluting with acetonitrile/methylene chloride (7.5/92.5), and those fractions with an Rf=0.64 by TLC (acetonitrile/methylene chloride, 20/80) were pooled and concentrated to give (S)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)phenyl]-5-isothiocyanatomethyl-2-oxazolidinone, mp 158-162° C. (dec.).