Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C:51]1[CH:52]=[C:53]([C:57]2[N:66]=[C:65]([NH:67][C:68]3[CH:69]=[C:70]4[C:74](=[CH:75][CH:76]=3)[N:73]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[N:72]=[CH:71]4)[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]=2)[CH:54]=[CH:55][CH:56]=1>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([NH:50][C:51]1[CH:52]=[C:53]([C:57]2[N:66]=[C:65]([NH:67][C:68]3[CH:69]=[C:70]4[C:74](=[CH:75][CH:76]=3)[N:73]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[N:72]=[CH:71]4)[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]=2)[CH:54]=[CH:55][CH:56]=1)=[O:5]
Reactant: CN(C)CC(=O)O
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-(dimethylamino)acetic acid (57 mg, 0.55 mmol), PyBOP® (286 mg, 0.55 mmol), DIEA (240 μL, 1.38 mmol) in CH2Cl2 (2 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (500 mg, 1.10 mmol) and CH2Cl2 (4 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 1.5 equivalent of the acid as described above and stirred for 16 h. Diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (9:1 CH2Cl2:MeOH) to give the desired product tert-butyl 5-(2-(3-(2-(dimethylamino)acetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (570 mg, 1.06 mmol, 96%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=1.O.[NH2:24][NH2:25].O>O1CCOCC1>[N:8]1([C:6]2[N:5]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:16]=[C:4]3[N:3]=[C:2]([NH:24][NH2:25])[CH:7]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Temperature: 90 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
To a solution of 5-chloro-7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidine (150 mg, 0.48 mM) in 1,4-dioxane (5.0 mL), there was added hydrazine monohydrate (0.23 mL, 4.8 mM) and the mixture was stirred at 90° C. for 14 hours. The reaction mixture was cooled down to room temperature, then water was added thereto and the mixture was extracted with ethyl acetate. The organic phase thus obtained was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to thus give the title compound (133 mg, yield: 90%). MS (ESI) m/z (M+H)+ 311
Reaction SMILES: [S-2:1].[Li+].[Li+].Cl[Si:5]([CH3:8])([CH3:7])[CH3:6]>O1CCCC1>[CH3:6][Si:5]([CH3:8])([CH3:7])[S:1][Si:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: C[Si](C)(C)Cl
Reactant: [S-2]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)S[Si](C)(C)C
Yield: 45 %

Procedure:
R. Detty et al. in J. Org. Chem. 1982, 47, 1354-1356 reiterated the above statement about the substantial nonreactivity of lithium sulfide and chlorotrimethylsilane and indicated that commercially available dilithium sulfide and chlorotrimethylsilane, when refluxed for seventy-two hours in tetrahydrofuran, gave only a 45% yield of hexamethyldisilthiane, also called "bis(trimethylsilyl)sulfide.
Reaction SMILES: [B-](F)(F)(F)F.[Na+].[O:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH2:12]>S(=O)(=O)(O)O>[CH3:8][CH2:9][CH2:10][CH2:11][O:7][C@H:9]([CH2:8][OH:12])[CH2:10][CH3:11]
Reactant: C1CCOC1
Reactant: O
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCO[C@@H](CC)CO
Temperature: 20 °C
Reaction time: 2 h

Procedure:
In the same manner as in Example 17, a solution prepared by dissolving 1.5 g of sodium borofluoride in 55 g of 25% fuming sulfuric acid was dropped into 500 g of tetrahydrofuran at -10° C. over 30 minutes, and the mixture was subjected to reaction at -10° C. for one hour. The conversion at this point was 20%. Then the reaction mixture was heated to 20° C. and subjected to reaction at this temperature for 2 hours. The final conversion was 61%. Then, to the polymerization product was added 520 g of water and heated in an oil bath at 80° C. with stirring for 2 hours while distilling off and recovering the unreacted tetrahydrofuran. Then, the oil bath temperature was elevated to 100° C. and 50 g of a 48% by weight aqueous sodium hydroxide solution was added continuously over a period of one hour to accomplish the hydrolysis of the reaction mixture. Recovery of the unreacted tetrahydrofuran was continued during said addition, and upon completion of said addition, the mixture was allowed to stand at 100° C. to cause the separation of layers. The aqueous layer was withdrawn, and to the remaining PTMG layer was added 250 g of water and a part of the withdrawn aqueous layer, after which the sulfuric acid concentration in the aqueous layer was adjusted to about 1% by weight, and the mixture was again heated and stirred in an oil bath at 100° C. for 2 hours to complete the hydrolysis and then allowed to stand at 100° C. to cause separation of layers. A part of the separated PTMG layer was sampled and analyzed to determined the amount of residual sulfuric ester groups and acid number. They were 4 ppm and 0.27, respectively. Then, without withdrawing the aqueous layer, 9.7 g of a 20% by weight aqueous sodium hydroxide solution was added and the mixed system was heated and stirred in an oil bath at 80° C. for about 15 minutes and then, 1.3 g of a 15% by weight aqueous suspension of a basic magnesium carbonate to adjust the pH of the mixture about 8, followed by additional heating and washing with stirring in an oil bath at 80° C. for 2 hours. Then, the mixture was allowed to stand to cause separation of layers. The mixture showed no emulsification phenomenon throughout the treatment, the separation of layers was easy, and the separated PTMG layer was only slightly turbid. After removing the aqueous layer, the remaining PTMG layer was treated in the same manner as in Example 17 to obtain PTMG. Its analytical results are shown in Table 3.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][CH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[N+:12]([C:3]1[CH:4]=[C:5]([S:8](=[O:10])(=[O:9])[NH2:11])[CH:6]=[CH:7][C:2]=1[NH:16][CH2:17][C@H:18]1[CH2:19][CH2:20][C@H:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:22][CH2:23]1)([O-:14])=[O:13]
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](CNc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
To 4-fluoro-3-nitrobenzenesulfonamide (0.265 g) and trans-methyl 4-(aminomethyl)cyclohexanecarboxylate hydrochloride in tetrahydrofuran (5 mL) was added N,N-diisopropylethylamine (0.526 mL) and the reaction was stirred at room temperature. After stirring overnight the reaction was loaded onto silica gel (Reveleris 40 g) and eluted using a gradient of 0.5% to 3.5% methanol/dichloromethane over 30 minutes to provide the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[CH:12][S:11][C:10]=12)=O)C.[BH4-].[Li+].CO.Cl>O1CCCC1>[OH:3][CH2:4][C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[CH:12][S:11][C:10]=12
Reactant: CCOC(=O)c1ncn2ccsc12
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ncn2ccsc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of 95 mg (0.49 mmol) of the above-obtained 7-ethoxycarbonylimidazo[5,1-b]thiazole in 10 ml of tetrahydrofuran (THF) was added 300 mg of lithium borohydride. The mixture was stirred at 80° C. (the oil bath temperature) for one hour, and then cooled. To this reaction solution, 15 ml of methanol was added little by little with ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Concentrated hydrochloric acid was added to this solution little by little with ice-cooling. The resulting mixture was stirred at room temperature for one hour, and concentrated under reduced pressure. To the residue was added a 50% aqueous solution of potassium carbonate to obtain a solution, which was then extracted four times with methylene chloride. The organic layer was dried over anhydrous potassium carbonate, concentrated under reduced pressure, and purified by flash column chromatography using silica gel, eluting with a 3:17 mixture of methanol and ethyl acetate to give 30 mg (yield 40%) of 7-hydroxymethylimidazo[5,1-b]thiazole.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:44]([C:60]([N:62]2[CH2:66][CH2:65][C@H:64]([CH2:67][N:68]3[CH2:72][CH2:71][CH2:70][CH2:69]3)[CH2:63]2)=[O:61])[CH2:43]1>CN(C)C=O.C(N(C(C)C)CC)(C)C>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:19]2[C:20]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])=[C:16]([S:41][C@@H:42]3[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=4)=[O:48])[C@H:44]([C:60]([N:62]4[CH2:66][CH2:65][C@H:64]([CH2:67][N:68]5[CH2:69][CH2:70][CH2:71][CH2:72]5)[CH2:63]4)=[O:61])[CH2:43]3)[C@H:17]([CH3:40])[C@H:18]12)[CH3:37]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](CN2CCCC2)C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](CN5CCCC5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 20 h

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (225 mg) in anhydrous dimethylformamide (3 ml), a solution of (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3R)-3-(pyrrolidin-1-ylmethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (198 ml) in anhydrous dimethylformamide (1 ml) and diisopropylethylamine (97 μl) were added in an ice bath. The resulting mixture was stirred for 20 hours at the same temperature. The reaction mixture was concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate. The resulting mixture was washed successively with water and saturated saline solution and dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was subjected to chromatography through a silica gel column and from the fraction eluted with ethyl acetate/methanol=4/1, 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3R)-3-(pyrrolidin-1-ylmethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (235 mg) was obtained as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:24]1([N:30]2[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:33][C:32]([CH:41]=O)=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][NH:21][CH2:41][C:32]3[CH:33]=[C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:31]=3)[CH2:17][CH2:18]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:22][CH:23]=1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: O=Cc1cc(-c2ccccc2)n(-c2ccccc2)n1
Product: Clc1ccc(C(c2ccccc2)N2CCN(CCNCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)cc1
Yield: 61 %

Procedure:
Compound 98 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 1,5-diphenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[N:4]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: Cc1ccc(N)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N=C=S)c(Cl)c1
Yield: 58.3 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2-chloro-4-methyl aniline (2.0 g, 14.00 mmol), thiophosgene (1.62 g, 14.00 mmol) and N-ethyl di-isopropyl amine (3.63 g, 28.00 mmol) to afford 1.5 g of the desired product.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:31]=2)[C:16]([NH:18][C:19]2[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:22]([O:24]C)=[O:23])=[O:17])[CH2:6]1.CO>C1COCC1>[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:31]=2)[C:16]([NH:18][C:19]2[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:22]([OH:24])=[O:23])=[O:17])[CH2:6]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(CO)C3)ccc2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCCC(CO)C2)cc1C(=O)Nc1c(C)ccc(C(=O)O)c1C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
A solution of aqueous 4N NaOH (4.00 ml) is added to a stirred solution of methyl 3-[[5-[3-(hydroxymethyl)-1-piperidyl]-2-methyl-benzoyl]amino]-2,4-dimethyl-benzoate (0.4 g, 0.975 mmol) in THF:MeOH (10 ml:5 ml). After 4 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 4 with 1N HCl, and extracted twice with 10% IPA in CH2Cl2. The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with diethyl ether and filtered to afford the title compound as a light brown solid (0.28 g, 72.5%). Mass spectrum (m/z): 397.2 (M+1).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:14][CH2:13][C:12]3=[CH:15][NH:16][N:17]=[C:11]3[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:18][C:19]1[N:24]=[CH:23][C:22]([N:16]2[CH:15]=[C:12]3[C:11]([CH2:10][CH2:9][N:8]([CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:14][CH2:13]3)=[N:17]2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Br)nc1
Reactant: c1ccc(CN2CCc3c[nH]nc3CC2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Brc1ccc(-n2cc3c(n2)CCN(Cc2ccccc2)CC3)cn1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A mixture of 6-(phenylmethyl)-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 5) (200 mg, 0.88 mmol), (6-bromo-3-pyridinyl)boronic acid (355 mg, 1.76 mmol), copper acetate (478 mg, 2.64 mmol), pyridine (0.142 ml, 1.76 mmol) and molecular sieves (600 mg) in dichloromethane (10 ml) was allowed to stir at room temperature in a flask open to the atmosphere for 240 hours. The reaction mixture was filtered through a pad of celite, washing with dichloromethane and methanol. The filtrate was evaporated, redissolved in methanol and passed down a 10 g SCX cartridge, eluting with methanol, then a 2 M solution of ammonia in methanol. The basic fractions were combined, evaporated and purified by column chromatography, eluting with a mixture of 2M ammonia in methanol and dichloromethane (0-10%). The impure product was re-purified using reverse phase chromatography, eluting with a mixture of acetonitrile and water (5-100% and 3-60%) to afford the product (D15); MS (ES+) m/e 383 & 385 [M+H]+.
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8]1=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>O.O1CCOCC1>[O:16]=[C:8]1[N:7]([CH2:6][CH2:5][NH:4][C:17](=[O:19])[CH3:18])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9]1
Reactant: CC(=O)OC(C)=O
Reactant: NCCn1c(=O)[nH]c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NCCn1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of NaOH (0.41 g, 10 mmoles) in water (5 ml) were simultaneously added 1-(2-aminoethyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (0.7 g, 3.3 mmoles) and a solution of acetic anhydride (0.37 ml, 3.9 mmoles) in dioxane (10 ml). The reaction mixture was stirred for 2 hours at room temperature and then taken to dryness. The residue was dissolved in water, adjusted to pH 4 with 10% aqueous HCl, and extracted with CHCl3. The organic layer was taken to dryness and from the crude residue 0.35 g of the title compound was obtained after crystallization from diethyl ether. M.p. 153° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1(=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36](=[O:43])[NH:35]1.[F:45][C:46]([F:61])([F:60])[C:47]1[CH:52]=[CH:51][N:50]=[C:49]([CH2:53][CH:54]2[CH2:58][CH2:57][CH2:56][CH:55]2O)[CH:48]=1>C1COCC1>[F:61][C:46]([F:45])([F:60])[C:47]1[CH:52]=[CH:51][N:50]=[C:49]([CH2:53][CH:54]2[CH2:58][CH2:57][CH2:56][CH:55]2[N:35]2[C:36](=[O:43])[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:34]2=[O:44])[CH:48]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC1CCCC1Cc1cc(C(F)(F)F)ccn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1CCCC1Cc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
DIAD (0.26 ml, 1.36 mmol) was added to a solution of triphenylphosphine (0.350 g, 1.34 mmol), 2,3-dihydro-1H-isoindole-1,3-dione (CAS number 136918-14-4; 0.197 g, 1.34 mmol) and 2-{[4-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentan-1-ol (Diastereomer 2) (0.252 g, 1.03 mmol) in THF (5 ml). The reaction was stirred at room temperature for 24 hours and then further triphenylphosphine (0.175 g, 0.69 mmol) and DIAD (0.130 ml, 0.69 mmol) was added. The reaction was stirred for 72 hours at room temperature and then concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) and then by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH:13]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>ClCCCl.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10](/[CH:13]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cc(-c2ccc(Cl)cc2)on1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cc(-c2ccc(Cl)cc2)on1
Temperature: 55 °C

Procedure:
A suspension of 5-(4-chlorophenyl)isoxazole-3-carbaldehyde (2.00 g, 9.63 mmol), (R)-2-methylpropane-2-sulfinamide (1.28 g, 10.6 mmol, 1.1 equiv) and anhydrous copper(II) sulfate (2.31 g, 14.5 mmol, 1.5 equiv) in 1,2-dichloroethane (19 mL) was heated at 55° C. for 2-18 hours. The reaction was then cooled to room temperature and filtered through a pad of celite, using 1,2-dichloroethane to wash through. The filtrate was concentrated in vacuo to give crude (R,E)-N-((5-(4-chlorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide as a green solid, which was used without further purification. MS m/z 311.0 (M+H)+; Rt-1.11 min.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[C:18]3[S:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)=[CH:23][C:17]=3[N:16]=[CH:15]2)=[CH:10][C:9]=1[O:31][CH3:32].[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[S:21][C:18]3[C:19](=[O:20])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([NH:7][S:39]([C:36]5[CH:37]=[CH:38][C:33]([CH3:43])=[CH:34][CH:35]=5)(=[O:41])=[O:40])=[C:9]([O:31][CH3:32])[CH:10]=4)[CH:15]=[N:16][C:17]=3[CH:23]=2)=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A pyridine (1 mL) solution of 3-(4-Amino-3-methoxyphenyl)-6-(4-chloro-phenyl)thieno[3,2-d]pyrimidin-4(3H)-one (0.050 g, 0.0013 mol, the preparation of which is found in Example K13) and p-toluenesulfonyl chloride and was agitated overnight at RT, then diluted with water and filtered to give a white powder (0.056 g 81%). LCMS m/z 538 (MH+). 1H NMR (300 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.40 (s, 1H), 8.00 (s, 1H), 7.95 (d, 2H), 7.70 (d, 2H), 7.60 (d, 2H), 7.38 (d, 2H), 7.35 (d, 1H), 7.20 (s, 1H), 7.05 (d, 1H), 3.62 (s, 3H), 2.41 (s, 3H) ppm.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[C:16]([N+]([O-])=O)=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:11](=[O:20])[NH:12]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[CH3:28][O:27][C:26]1[CH:25]=[CH:24][NH:23][C:22]=1/[CH:21]=[C:10]1\[C:11](=[O:20])[NH:12][C:13]2[C:9]\1=[C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:16]=[CH:15][CH:14]=2
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#C[Si](C)(C)C)c21

Procedure:
Using Method D above, trimethylsilyl acetylene (0.94 g, 9.63 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (2.05 g, 6.42 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (0.23 g) and Cul (61 mg) as catalyst in DMF (15 mL) and Et3N (15 mL) as solvent at 80° C. for 2 days to give (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-(2-trimethylsilyl-ethynyl)-2H-indol-2-one. (Yield 1.3 g, 60%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]([F:24])([F:23])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:19]3[N:20]=[CH:21][CH:22]=[C:18]3[N:17]=[CH:16][CH:15]=2)[CH:9]=1.CN(C)[CH:27]=[O:28]>>[F:24][C:7]([F:23])([F:6])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:19]3[N:20]=[CH:21][C:22]([CH:27]=[O:28])=[C:18]3[N:17]=[CH:16][CH:15]=2)[CH:9]=1
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Temperature: 0 °C

Procedure:
Five milliliters of phosphorus oxychloride is added dropwise to an ice cooled solution of 25 ml. of dimethylformamide and when this is complete 5.26 g. of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine is added and the reaction mixture is heated on a steam bath for one hour. This is poured onto ice and made strongly basic to yield the desired compound, recovered by subsequent filtration, m.p. 168°-170° C.