Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:13]2[S:14]C=C(C(OCC)=O)[N:17]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C1(C)C=CC=CC=1.C1COCC1>[NH2:17][C:13]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[S:14]
Reactant: CCOC(=O)c1csc(N2CCOCC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NC(=S)N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
A solution of 7.0 ml (7.0 mmol) of lithium aluminum hydride in toluene was diluted with 10 ml of THF, cooled to 0° C., and treated with a solution of 1.7 g (7.0 mmol) of ethyl 2-(4-morpholinyl)thiazole-4-carboxylate in 25 ml of THF. The resulting solution was stirred for 1 h, quenched cautiously with aqueous Rochelle's salts, diluted with chloroform, filtered, dired over Na2SO4, and concentrated in vacuo. Silica gel chromatography using 2-4% methanol in chloroform provided 856 mg (61%) of the desired compound, Rf 0.16 (4% methanol in chloroform). 1H NMR (CDCl3) δ2.44 (br, 1H), 3.46 (t, J=5 Hz, 4H), 3.81 (t, J=5 Hz, 1H), 4.55 (br s, 2H), 6.45 (s, 1H). Mass spectrum: (M+H)+ =200.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C1OC1C>C(COC)OC>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:1]=[C:2]2[CH:11]=1
Reactant: Nc1cc(Cl)c2ccc(Cl)cc2n1
Reactant: CCOC(=O)C(=O)CBr
Agent: CC1CO1
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(cc(Cl)c3ccc(Cl)cc32)n1

Procedure:
1.8 g of 2-amino-4,7-dichloroquinoline [Hardman and Partridge J.C.S. (1958) p. 641] were reacted with 2.1 g of ethyl bromopyruvate in 60 ml of dimethoxyethane in the presence of 0.7 g of propylene oxide by the method of Example 9 to obtain ethyl 5,8-dichloroimidazo-[1,2-a]-quinoline-2-carboxylate as fine colorless needles melting at 229°-230° C.
Reaction SMILES: ClC1C(Cl)=C(OCC(OC)=O)C=C2C=1C1C(CC)(C2)CCC(=O)C=1.[CH2:25]([C:28]12[CH2:40][CH2:39][C:38](=[O:41])[CH:37]=[C:36]1[C:35]1[C:30](=[CH:31][C:32]([O:44][CH2:45][C:46]([O:48]CC)=[O:47])=[C:33]([Cl:43])[C:34]=1[Cl:42])[CH2:29]2)[CH:26]=[CH2:27]>>[CH2:25]([C:28]12[CH2:40][CH2:39][C:38](=[O:41])[CH:37]=[C:36]1[C:35]1[C:30](=[CH:31][C:32]([O:44][CH2:45][C:46]([OH:48])=[O:47])=[C:33]([Cl:43])[C:34]=1[Cl:42])[CH2:29]2)[CH:26]=[CH2:27]
Reactant: C=CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCC)c(Cl)c1Cl)C2
Agent: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OC)c(Cl)c1Cl)C2
Product: C=CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2

Procedure:
Carrying out a reaction as described in Example 20, Step D, except that the methyl [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate is replaced by an equimolar quantity of ethyl [(9a-allyl-5,6-dichloro-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate, there is obtained [(9a-allyl-5,6-dichloro-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.C[Si]([N:28]=[C:29]=[O:30])(C)C.O>CN(C=O)C>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:29]([NH2:28])=[O:30])=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Nc1ccc(CCOCc2ccccc2-c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Nc1ccc(CCOCc2ccccc2-c2ccccc2)cc1
Temperature: 50 °C
Yield: 48.1 %

Procedure:
To 100 mg (0.33 mmol) of the product of Example 27 step 1 in 15 mL of DMF was added 57 mg (0.50 mmol) of trimethylsilyl isocyanate the solution was heated to 50° C. for 1.5 hr. At the end of this time it was poured into 100 mL of water. The resulting precipitate was collected by filtration and taken up in hot ethyl acetate. The excess water was removed by decantation and the solution allow to cool. Hexane was introduced to cloudiness and the solution allow to cool further to yield 55 mg (48%) of product as a colorless solid, m.p. 143-144° C. NMR (400 MHz, DMSO) δ 8.42 (s, 1H); 7.34 (m, 10H); 7.10 (t, J=7.7 Hz, 1H); 6.73 (d, J=7.7 Hz, 1H); 5.77 (s, 2H); 4.30 (s, 2H); 3.53 (t, J=6.8 Hz, 2H); 2.72 (t, J=6.8 Hz, 2H). Anal. Calcd. for C21H21N O: C, 83.13; H, 6.98; N, 4.62 Found: C, 75.13; H, 6.41; N, 8.11. (+)FAB m/z 347 (M+H), 369 (M+Na).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH:11][C:12](=[O:15])[CH2:13]Cl.[CH3:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:19](C(O)=O)[C:18]=1N.NC1C=CC=C(C)C=1>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH:11][C:12](=[O:15])[CH2:13][C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([CH3:16])[CH:18]=1
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: Cc1cccc(C(=O)O)c1NC(=O)CCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(N)c1
Product: Cc1cccc(CC(=O)Nc2c(C)cccc2C(=O)O)c1
Temperature: 90 °C
Yield: 49 %

Procedure:
3-Methyl-N(chloroacetyl)anthranilic acid 7.5 g (33 mmol)(synthesized from 3-methylanthranilic acid by the same procedures as those of Example 9) and m-toluidine 11 ml (0.10 mol) were dissolved in 60 ml of dimethylformamide and heated at 90° C. for 4 hours. The reaction solution was poured into ice water and extracted with ether. The resulting ether solution was extracted with 10% sodium hydroxide and the resluting aqueous solution was neutralized with 10% HCl solution. The neutralized solution was extracted with ether, and the ether solution was washed with water and dried. The solvent was distilled off and the residue was recrystallized from benzene-toluene to obtain 3-methyl-N[(3-methylphenyl)acetyl]anthranilic acid 4.8 g (yield: 49%).
Reaction SMILES: [Mg].[CH2:2](I)[CH3:3].[CH:5]([C:8]1[C:16]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]2[N:9]=1)([CH3:7])[CH3:6].[Cl-].[NH4+]>CCOCC.C1C=CC=CC=1>[CH:5]([C:8]1[C:16]([C:17]([OH:21])([CH2:2][CH3:3])[CH:18]([CH3:20])[CH3:19])=[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]2[N:9]=1)([CH3:7])[CH3:6]
Reactant: CCI
Reactant: CC(C)C(=O)c1c(C(C)C)nn2ccccc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCC(O)(c1c(C(C)C)nn2ccccc12)C(C)C

Procedure:
To a suspension of 1.32 g of magnesium in 10 ml of dry ether was gradually added a solution of 17 g of ethyl iodide in 15 ml of dry ether with stirring. After the addition was completed, the stirring was continued for an hour at room temperature. To the mixture was gradually added a solution of 2.5 g of 2-isopropyl-3-isobutyrylpyrazolo[1,5-a]pyridine in 10 ml of dry benzene under stirring. The mixture was stirred for an hour at room temperature, treated with 150 ml of aqueous 20% ammonium chloride solution under ice cooling, and extracted with ether. The ether layer was washed with saturated brine, dried over anhydrous sodium sulfate and cencentrated to dryness. The residue was recrystallized from hexane to give 1.5 g (54%) of the desired derivative as pale gray prisms, mp 96°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:26])=O)[CH2:19][CH2:18]3)=[O:16])[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24](=[O:26])[NH:29][CH:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH2:19][CH2:18]3)=[O:16])[N:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1
Reactant: CN1CCC(N)CC1
Solvent: C1CCOC1
Product: CN1CCC(NC(=O)CN2CCN(C(=O)Cc3csc(NC(=O)c4ccc(Cl)cc4)n3)CC2)CC1

Procedure:
In analogy to example 22.3, (4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetic acid (example 22.2) was coupled with 4-amino-1-methylpiperidine, using general method A, using THF instead of DMF as solvent, to give 4-chloro-N-[4-(2-{4-[(1-methyl-piperidin-4-ylcarbamoyl)-methyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide. White solid. MS 519.3 ([M+H]+)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C@H:6]2[C@H:10]([N:11]=[N+]=[N-])[CH2:9][O:8][CH2:7]2)[CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH:1]1([CH2:4][O:5][C@H:6]2[C@H:10]([NH2:11])[CH2:9][O:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: [N-]=[N+]=N[C@@H]1COC[C@H]1OCC1CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N[C@@H]1COC[C@H]1OCC1CC1

Procedure:
A solution of trans-3-cyclopropylmethoxy-4-azidotetrahydrofuran from step 3 above (1.2 g, mmol, 6.55 mmol) and 10% Pd on carbon (150 mg) in EtOAc (35 mL) was stirred under an atmosphere of hydrogen at ambient pressure and ambient temperature for 6 h. The catalyst was removed by filtration and the filtrate solvents were removed in vacuo to give the title compound as an oil (1.1 g, TLC Rf=0.3, 95:5:0.25 CH2Cl2:MeOH:NH4OH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](F)(F)[F:16])=C[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20].BrC1C=CC(C(C2C=C([N+]([O-])=O)C=CC=2C)=O)=C(Cl)C=1.FC1C=C(N)C=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:15]([F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Agent: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Agent: Nc1cccc(F)c1
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2cccc(F)c2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (2.82 mmol) and 3-fluoro-phenylamine (2.82 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 30:70 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]([F:26])([F:25])[F:24])[C:17]([C:27]([O:29]CC)=[O:28])=[CH:16]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Li+]>O>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]([F:24])([F:25])[F:26])[C:17]([C:27]([OH:29])=[O:28])=[CH:16]3)[CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:8]=1
Reactant: CCOC(=O)C1=Cc2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc2OC1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1=Cc2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc2OC1C(F)(F)F
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To the solution of 150 mg (0.31 mmol) of ethyl 6-[3,5-bis(trifluoromethyl)phenyl]-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 5 mL of tetrahydrofliran was added a solution of 51 mg (1.24 mmol) of lithium hydroxide (LiOH.2H2O) in 5 mL of water. The resulting mixture was heated to reflux for one hr. After cooling to room temperature, the volatiles were removed. The residue was diluted with water, then acidified at 0° C. with dilute hydrochloric acid to pH=1.5. The product was then extracted with ethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate. Evaporation of the dried organic solution afforded 0.13 g (92%) of a light yellow solid: 1H NMR (CDCl3/400 MHz) 7.89(s, 2H), 7.78(s, 1H), 7.77(s, 1H), 7.51(dd, J=2.4 Hz, 8.4 Hz, 1H), 7.41(d, J=2.4Hz, 1 H), 7.06(d, J=8.4 Hz, 1H), 5.69(m, 1H). MS (ES+) 457.0(M+1, 100).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)CCC.O>O1CCOCC1>[S:25]1[CH:26]=[CH:27][N:28]=[C:24]1[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: O=Cc1ccc(-c2nc3ncccn3c2Br)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc(-c2nc3ncccn3c2-c2nccs2)cc1
Temperature: 100 °C

Procedure:
0.5 g (1.65 mM) 4-(3-bromoimidazo[1,2-a]pyrimidin-2-yl)benzaldehyde is dissolved in 15 mL of 1,4-Dioxane. To this solution is added tetrakis triphenylphosphine palladium (200 mg) 40%. The reaction mixture is heated at 100° C. for 10 min. and 2-(tributylstannyl)-1,3-thiazole is added (681 mg, 1.81 mM). The reaction is heated (oil bath or microwave) at same temp for 5 h. The reaction is cooled to room temperature and 50 mL of water is added and the reaction mixture is extracted with ethyl acetate. The organic layer is dried and concentrated. The crude is purified by flash column chromatography to yield the desired product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1.CN(C)C=O.[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH2:17].C(=O)(O)[O-].[Na+]>O.ClCCl>[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH:17][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: ClCc1cncnc1
Reactant: Nc1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(NCc2cncnc2)c(F)c1

Procedure:
A 26.7 g. portion of 5-chloromethylpyrimidine was dissolved in 25 ml. of dimethylformamide, and 9.4 g. of 2,4-difluoroaniline was added, followed by 6.1 g. of sodium bicarbonate. The mixture was stirred for several days with gentle heating. It was then diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and evaporated under vacuum to obtain 13.75 g. of oil. The oil was dissolved in dichloromethane and purified over silica gel, eluting with dichloromethane, to obtain 4.9 g. of the desired intermediate product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]=2[F:22])[N:3]=1.[CH3:23]CN(C(C)C)C(C)C.CN(C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl.CO>[CH3:23][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Si:18]([CH3:19])([CH3:21])[CH3:20])=[CH:14][C:13]=1[F:22]
Reactant: C[Si](C)(C)c1ccc(Nc2nc(Cl)ccc2C(=O)O)c(F)c1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(Cl)nc1Nc1ccc([Si](C)(C)C)cc1F
Reaction time: 0.17 h

Procedure:
To a suspension of 6-chloro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid (33.7 g, 99.5 mmol) in dichloromethane (500 mL) at 0° C. was added DIPEA (17.1 mL, 99.5 mmol). The reaction mixture was stirred for 10 minutes, then DMF (2 mL) and oxalyl chloride (8.7 mL, 99.5 mmol) were added dropwise (CAUTION: EFFERVESCENCE). The reaction mixture was stirred at room temperature for 2 hours and then added dropwise to a solution of DIPEA (17.1 mL, 99.5 mmol) in MeOH (500 mL) at 0° C. over a 45 minutes period. The reaction mixture was stirred at room temperature for 18 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium hydrogen carbonate, followed by water, then brine, dried (Na2SO4), filtered and evaporated in vacuo to afford the title compound as a brown foam which was used without purification into the next step (36.4 g). LCMS (method B) RT=5.35 min, M+H+=353.
Reaction SMILES: [CH2:1]([CH:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:20][C:21]1[CH:26]=[C:25]([O:27]C)[CH:24]=[CH:23][C:22]=1[O:29]C)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Na].N>>[CH2:31]([CH:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH:21]1[CH2:26][C:25](=[O:27])[CH2:24][CH2:23][C:22]1=[O:29])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCCCCCCCCCCCCC(CCCCCCCCCCCCCCCCCC)Cc1cc(OC)ccc1OC
Agent: N
Agent: [Na]
Product: CCCCCCCCCCCCCCCCCCC(CCCCCCCCCCCCCCCCCC)CC1CC(=O)CCC1=O

Procedure:
10 m mol of 2-octadecyleicosanyl-p-dimethoxybenzene was treated with sodium in liquid ammonia, thus forming 7.2 m mol of 2-octadecyl-eicosanyl-cyclohexane-1,4-dione. This product, 6 m mol, was reacted with 13 m mol of malononitrile. The resultant reaction product was treated with bromine in pridine, thus obtaining 7 m mol of 2-octadecyleicosanyl-tetracyanoquinodimethane, which is represented by the following formula: ##STR47##
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[S:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][C:11]=1[C:12]#[N:13].[CH3:17][N:18]([CH3:21])[CH:19]=O>>[CH3:17][N:18]([CH:21]=[N:6][C:7]1[S:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][C:11]=1[C:12]#[N:13])[CH3:19]
Reactant: N#Cc1cc([N+](=O)[O-])sc1N
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=Nc1sc([N+](=O)[O-])cc1C#N
Reaction time: 120 h

Procedure:
Phosphorus oxychloride (5 ml) was added dropwise, with stirring, to dry N,N-dimethylformamide (20 ml) maintaining the temperature below 5° C. The solution was allowed to stand for fifteen minutes then treated, at 0°-5° C., with a suspension of 2-amino-3-cyano-5-nitrothiophene (5.1 g) in dry N,N-dimethylformamide (50 ml), allowed to attain room temperature, then kept at 20° C. for five days. It was then poured on to ice, the precipitate removed and the filtrate basified with ammonium hydroxide solution to give 2-dimethylaminomethyleneamino-3-cyano-5-nitrothiophene (m.p. 230°). A mixture of this material (0.5 g), benzylamine (0.26 g) and ethanol (100 ml) was refluxed for twelve hours, treated with acetic acid (0.5 ml) and heating continued for a further thirty minutes. The solvent was removed in vacuo and the residue diluted with water to give 4-benzylamino-6-nitrothieno[2,3-d]pyrimidine (0.4 g) (Compound No. 136).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[CH:21][C:20]=2[O:27][C:28]([C:31]([O:33][CH3:34])=[O:32])([CH3:30])[CH3:29])/[C:9]1=[O:35])=O)(C)(C)C.[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:52])=[C:41]([CH:43]=[N:44][C:45]([O:47][Si](C)(C)C)=[CH2:46])[CH:42]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:35])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[CH:21][C:20]=4[O:27][C:28]([C:31]([O:33][CH3:34])=[O:32])([CH3:29])[CH3:30])[CH2:46][C:45](=[O:47])[NH:44][CH:43]3[C:41]3[CH:42]=[C:37]([F:36])[CH:38]=[CH:39][C:40]=3[CH3:52])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 3.8 %

Procedure:
A mixture of, E/Z-6-chloro-3-[5-chloro-4-fluoro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.4 g, 2.6 mmol) and 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (13 mmol) prepared in Example 4 in toluene (13 mL) was heated at 60° C. for 3 h, and concentrated. To the residue was added DCM (30 mL) and TFA (5 mL), and the resultant solution was stirred at room temperature for 3 h, then concentrated. The residue was partitioned between ethyl acetate and diluted aqueous NaOH solution. The organic layer was separated, washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (60 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([CH2:16][CH2:17][CH3:18])[CH2:14][O:13][C:12]3=[O:19])=[N:7][C:6]=12.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[N:35]=3)=[CH:30][CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.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]>[CH2:16]([C@H:15]1[CH2:14][O:13][C:12](=[O:19])[N:11]1[C:8]1[CH:9]=[CH:10][N:5]2[N:4]=[CH:3][C:2]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[N:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[N:35]=4)=[CH:32][CH:33]=3)=[C:6]2[N:7]=1)[CH2:17][CH3:18]
Reactant: CCC[C@H]1COC(=O)N1c1ccn2ncc(Br)c2n1
Reactant: CC1(C)OB(c2ccc(-c3ncn(COCC[Si](C)(C)C)n3)cc2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCC[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Temperature: 90 °C
Yield: 71.8 %

Procedure:
To a sealed tube were added (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-propyloxazolidin-2-one (0.100 g, 0.308 mmol), 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (0.160 g, 0.400 mmol), in dioxane (1.6 mL) and 2.0 M Na2CO3 (0.461 ml, 0.923 mmol). The mixture was degassed by bubbling N2 through the solution. Pd2 dba3 (0.0141 g, 0.0154 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.0147 g, 0.0308 mmol) were added and the vessel was sealed under a N2 atmosphere. The mixture was heated at 90° C. for 18 hours. The reaction mixture was cooled to ambient temperature, filtered through GF/F paper, diluted with H2O and separated, and the aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with brine, dried and concentrated. Purification of the crude material by normal phase chromatography, eluting with 1-25% EtOAc/dichloromethane, provided (S)-4-propyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one as a bright yellow-orange foamy solid (0.115 g, 72%). LCMS (APCI+) m/z 520 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CO.C(Cl)Cl.O>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:2]=2[Cl:1])(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Nc1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1

Procedure:
To a solution of the compound of Step 1 (2.12 g) in methanol (50 mL) and CH2Cl2 (50 mL) was added a solution of sodium metabisulfite (2.52 g) in water (50 mL) at room temperature. After 3 hrs the methanol was evaporated in vacuo. The residue was partitioned between sat. aq. Na2CO3 and EtOAc, Dried over MgSO4 and evaporated in vacuo. The resulting orange solid was absorbed onto silica gel (10 g) and purified by flash chromatography SiO2, 0-50% EtOAc Hexanes gradient elution to afford the title compound as a yellow solid. C18H14Cl2N2O3S MH+ requires 409.0175 found 409.0162.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C1(C)C=CC=CC=1.C(N(CC)CC)C.[C:19]1([N:25]2[C:29]([SH:30])=[N:28][N:27]=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[Cl:4][C:1]([S:30][C:29]1[N:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:26]=[N:27][N:28]=1)=[O:2]
Reactant: Sc1nnnn1-c1ccccc1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cl)Sc1nnnn1-c1ccccc1
Temperature: 5 °C
Yield: 72 %

Procedure:
A 20% phosgene solution in toluene (14.4 ml, 25.2 mmole) was added to a mixture of triethylamine (2.58 ml, 18.5 mmol) and 1-phenyl-1H-tetrazol-5-thiol (3.00 g, 16.8 mmole) in THF (15 ml) at 5° C. over 10 min. The reaction mixture was stirred for an hour at 5° C. and filtered. The filtrate obtained was evaporated and the residue washed thoroughly with ethyl ether. It was then recrystallized by dissolving in THF and precipitating with ethyl ether to give white crystal (2.92 g, 72%) m.p. 112°-114° C. IR (Film) 1718, 1645, 1590, 1490 and 1395 cm-1. 1H-NMR (CDCl3) δ7.52 (s, aromatic H).