Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:19]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:25]([N:26]1[CH2:31][CH2:30][N:29]([CH2:17][CH2:16][CH2:15][CH:13]2[O:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:14]2)[CH2:28][CH2:27]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=CCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C2=NOC(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)C2)c1
Yield: 53.4 %

Procedure:
3-[3-(3-nitrophenyl)-4,5-Dihydroisoxazol-5-yl]propanal (21.9 mg, 0.088 mmol), 1-(diphenylmethyl)piperazine (20.3 mg, 0.080 mmol), molecular sieves (5 beads), and NaBH(OAc)3 (51.1 mg, 0.241 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 20.7 mg (48.4%) of the target compound was obtained.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(F)c1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-fluorophenyl)-5-(pent-1-enyl)pyridine (Example 127) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.79 (t, J=7.0 Hz, 3 H), 1.10-1.35 (m, 18 H), 2.28 (m, 2 H), 3.24 (m, 1 H), 3.42 (m, 1 H), 4.33 (s, 2 H), 6.96 (m, 2 H), 7.12 (m, 1 H), 7.40 (m, 1 H). mp 117-118° C. Rf=0.36 (10% ethyl acetate/n-hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C:13]([CH3:17])([CH3:16])[CH2:14]O.N1C=CC=CC=1>O=S(Cl)Cl>[CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:12][C:13]([CH3:17])([CH3:16])[CH3:14])=[O:5]
Reactant: CC(C)(C)CO
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(Br)ccc1C(=O)OCC(C)(C)C
Yield: 67.9 %

Procedure:
Using General Esterification Method C; 2-methyl-4-bromo-benzoic acid (1.82 g, 8.47 mmols) was refluxed for 3 h with 10 mL SOCl2. The resulting solution was concentrated under reduced pressure and the crude acyl chloride combined with 2,2-dimethylpropanol (0.75 g, 8.47 mmols) and pyridine (1.4 mL, 16.9 mmols) to give the title compound (1.64 g, 68%) after work-up and column chromatography (2-5% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: CCN(CC)CC.[F:8][C:9]([F:30])([F:29])[C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=O)[CH:13]=[CH:14][CH:15]=1.[NH2:31][CH2:32][C:33]1[S:34][CH:35]=[CH:36][CH:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[S:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[CH2:32][NH:31][C:22]([C:21]1[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([F:8])([F:30])[F:29])[CH:11]=2)=[N:28][CH:27]=[CH:26][CH:25]=1)=[O:24]
Reactant: O=C(O)c1cccnc1CCCCc1cccc(C(F)(F)F)c1
Reactant: NCc1cccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1cccs1)c1cccnc1CCCCc1cccc(C(F)(F)F)c1
Reaction time: 96 h

Procedure:
NEt3 was added to a solution of 323 mg (1.0 mmol) of 2-(4-(3-trifluoromethyl-phenyl)butyl)nicotinic acid (VB005), 113 mg (1.0 mmol) of 2-(aminomethyl)-thiophene and 381 mg (1.0 mmol) of HATU in THF (8 ml) and stirring was carried out for 4 d at RT. The mixture was then concentrated in vacuo. The residue was taken up in EA and washed with a 1M aq. NH4Cl sol. and a 1M aq. NaHCO3 sol. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by means of CC (EA/hex 3:1), yielding 221 mg (0.5 mmol, 53%). MS: m/z 419.1 [M+H]+.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>C(OCC)C>[P:1]([O:8][Si:17]([CH3:19])([CH3:18])[CH3:16])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: CCOP([O-])OCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOP(OCC)O[Si](C)(C)C
Temperature: 25 °C
Yield: 79.8 %

Procedure:
To a mixture of diethyl phosphite (2.8 mL, 0.0217 mol) and triethylamine (9 mL, 0.065 mol, 3.0 eq) in dry diethyl ether (250 mL) at 0° C. was slowly added freshly distilled trimethylsilyl chloride (3.3 mL, 0.0260 mol, 1.2 eq) via syringe. The resulting slurry was allowed to slowly warm to room temperature, and was then warmed to 45° C. for 14 h. Volatiles were removed by distillation using a 55° C. oil bath. The resulting mixture was diluted with pentane (150 mL), filtered to remove triethylammonium salts, and concentrated at atmospheric pressure using a 55° C. oil bath. Distillation of the resulting oil gave diethyl trimethylsilyl phosphite as a colorless oil (3.64 g, 80%). BP 60° C. (5 mmHg). ##STR309## Step 2
Reaction SMILES: C([O:5][C:6]([C@H:8]([C@@H:18]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:19]([NH:21][N:22]1[C:26](=[O:27])[C:25](=[O:28])[N:24]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:23]1=[O:36])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.[CH2:41]([O:48][NH2:49])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O1CCCCC1ON>>[CH2:41]([O:48][NH:49][C:6]([C@H:8]([C@@H:18]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:19]([NH:21][N:22]1[C:26](=[O:27])[C:25](=[O:28])[N:24]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:23]1=[O:36])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:5])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)C(=O)N(Cc2ccccc2)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: NOC1CCCCO1
Product: CC(C)C[C@@H](C(=O)NN1C(=O)C(=O)N(Cc2ccccc2)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1

Procedure:
In an analogous manner to that described in Example 1, parts (vi)-(viii), but using (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-N-(3-benzyl-2,4,5-trioxo-1-imidazolidinyl]-4-methylvaleramide and O-benzylhydroxylamine in place of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-glycinyl-4-methylvalerohydrazide and O-(tetrahydro-2H-pyran-2(RS)-yl)hydroxylamine respectively there was obtained (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-N-(3-benzyl-2,4,5-trioxo-1-imidazolidinyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[N:9]2[N:10]=[CH:11][CH:12]=[C:8]2[N:7]=[C:6]([S:13][CH3:14])[C:5]=1[C:15]#[N:16].CN(C=O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:3][C:4]1[N:9]2[N:10]=[CH:11][CH:12]=[C:8]2[N:7]=[C:6]([S:13][CH3:14])[C:5]=1[C:15]#[N:16])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CSc1nc2ccnn2c(O)c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccnn2c(OCc2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
80 mg of sodium hydride (60%) was added to 400 mg of 7-hydroxy-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile and 6 ml of DMF, followed by stirring at room temperature for about 10 minutes, and then 350 mg of benzyl bromide was added thereto, followed by stirring at about 50° C. overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, about 50 ml of water was added thereto, and the precipitated crystals were collected by filtration, washed with water and dried to obtain crude crystals. The crude crystals were purified by silica gel column chromatography to obtain 490 mg of 7-benzyloxy-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 51) having a melting point of 194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.CC[O-].[Na+].Cl.[NH2:18][CH:19]([CH2:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][C:25]1=[O:33])[C:20]([OH:22])=[O:21]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:18][CH:19]([CH2:23][CH:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][C:25]2=[O:33])[C:20]([OH:22])=[O:21])=[O:8])=[CH:11][CH:12]=1
Reactant: NC(CC1C(=O)Nc2ccccc21)C(=O)O
Reactant: CCOC(=O)c1ccc(Cl)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Yield: 9.8 %

Procedure:
In 100 ml of ethanol, 1.66 g of ethyl p-chlorobenzoate, 0.5 g of sodium ethylate and 1.98 g of 2-amino-3-(oxindol-3-yl)propionic acid hydrochloride prepared in Reference example 1 were added, then the mixture was placed in an autoclave, and reacted under 110 atmospheric pressure at 140°-150° C. for 6 hours. After cooling, the reaction mixture was concentrated under a reduced pressure, the residue was dissolved in 200 ml of chloroform, then the chloroform solution was washed with 1% potassium carbonate aqueous solution, diluted hydrochloric acid and water in this order, the chloroform solution was dried with anhydrous sodium sulfate. The solvent was removed by evaporation, the residue was recrystallized from methanol-water to obtain 270 mg of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate in the form of colorless powdery substance. Melting point: 133-135° C. [α]D25 -50.3° (C=1, methanol)
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH2:13][C:14]2[C@H:15]3[CH2:20][CH:17]([CH2:18][CH:19]=2)[C:16]3([CH3:22])[CH3:21])[CH2:4][C@H:3]1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:28]=1)=[O:25].Br[CH2:41][C:42]([C:44]([CH3:47])([CH3:46])[CH3:45])=[O:43]>CN(C)C(=O)C>[C:44]([C:42]([CH2:41][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH2:13][C:14]2[C@H:15]3[CH2:20][CH:17]([CH2:18][CH:19]=2)[C:16]3([CH3:21])[CH3:22])[CH2:4][C@@H:3]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:28]=2)=[O:25])[C:2]1=[O:1])=[O:43])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(C)(C)OC(=O)c1cccc(NC(=O)N[C@@H]2CN(CC3=CCC4C[C@H]3C4(C)C)c3ccccc3NC2=O)c1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1cccc(NC(=O)N[C@@H]2CN(CC3=CCC4C[C@H]3C4(C)C)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
Step 2 of Example 1 was repeated except that 1-[(3R)-2-oxo-5-[(1S)-2-pinen-10-yl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea was used instead of 2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine, that bromomethyl-tert-butylketone was used instead of 2-bromo-2′-methylacetophenone, and that N,N-dimethyl acetamide was used instead of tetrahydrofuran as solvent, to thereby obtain the title compound.
Reaction SMILES: [ClH:1].C1([C:8]2[CH:23]=[CH:22][C:11]([NH:12][N:13]=NNC3C=CC=CC=3)=[CH:10][CH:9]=2)C=CC=CC=1.C(O)C.[NH4+].[OH-].Cl.[NH:30]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]3[N:49]=[CH:48][NH:47][C:45]3=2)[N:40]=[C:39]([CH3:50])[CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO>[ClH:1].[C:11]1([N:12]=[N:13][C:34]2[CH:35]=[CH:36][C:31]([NH:30][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[C:44]5[N:49]=[CH:48][NH:47][C:45]5=4)[N:40]=[C:39]([CH3:50])[CH:38]=3)=[CH:32][CH:33]=2)[CH:22]=[CH:23][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: c1ccc(NN=NNc2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: Cc1cc(Nc2ccc(N=Nc3ccccc3)cc2)c2c(ccc3nc[nH]c32)n1

Procedure:
A solution of 11.7 g. (0.05 m.) of p-phenylazoaniline hydrochloride in 500 ml. of ethanol was adjusted to pH 7.0 with 28% NH4OH. After the addition of 11 g. (0.05 m.) of the compound of Example I, C., the mixture was refluxed overnight. It was chilled, filtered, washed with ether and airdried to give 22 g. The crude product was recrystalled from MeOH to yield 17 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH2:13]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Trans (4-hydroxymethyl-cyclohexyl)-carbamic acid tert-butyl ester (3.49 g, 15.0 mmol) in DCM (50 mL) was treated with pyridine (4.98 mL, 60.8 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride (2.36 mL, 30.4 mmol) was added dropwise over 5 minutes. The mixture was stirred at room temperature for 5 hours. The mixture was then concentrated under vacuum. The residue was partitioned between ethyl acetate and water and the aqueous phase was extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried with sodium sulfate and concentrated under vacuum. The residue was triturated with cyclohexane then dried under vacuum to give a white solid. Further purification by column chromatography on silica gel (eluting with 1:1 cyclohexane/ethyl acetate) gave 4.17 g (90%) of trans methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohexylmethyl ester as a white solid. 1H NMR (400 MHz, CDCl3) δ: 4.37 (br s, 1H), 4.02 (d, 2H), 3.39 (br s, 1H), 3.00 (s, 3H), 2.11-2.00 (m, 2H), 1.91-1.81 (m, 2H), 1.77-1.64 (m, 1H), 1.43 (s, 9H), 1.18-1.05 (m, 4H).
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[Si](C)(C)[CH3:14]>CO>[C:1]1([S:7][CH2:8][C:9]([O:11][CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)CSc1ccccc1
Solvent: CO
Product: COC(=O)CSc1ccccc1
Reaction time: 16 h

Procedure:
A room temperature solution of (phenylsulfanyl)acetic acid (8.4 g, 50.0 mmol) in methanol (100 mL) was treated with chlorotrimethylsilane (13 mL, 100.0 mmol), stirred for 16 hours, and concentrated. The concentrate was dissolved in 5:1/hexanes:diethyl ether, filtered through a pad of silica gel (80 g), rinsed with 5:1/hexanes:diethyl ether, and concentrated to provide the desired product.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32]N)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:28][CH:27]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(Cl)cc3)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and 4-chloro-phenylhydrazine according to the method described for example 43. MS: M=427.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32](Cl)=[O:33])[CH:25]=2)=[CH:20][CH:19]=1>C(#N)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]([NH:1][C:2]3[N:3]=[CH:4][S:5][C:6]=3[C:7]([O:9][CH3:10])=[O:8])=[O:33])[CH:25]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1scnc1N
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1CC(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)c1scnc1NC(=O)Cc1cc(-c2ccc(Cl)cc2)ccc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.7 %

Procedure:
1.8 g (11.38 mmol) of methyl 4-amino-1,3-thiazole-5-carboxylate were dissolved in 40 acetonitrile, and 1.8 ml (22.76 mmol) of pyridine were added. After 5 min of stirring at room temperature (RT), a solution of 3.18 g (11.38 mmol) of (4′-chloro-4-methylbiphenyl-3-yl)acetyl chloride (obtained from (4′-chloro-4-methylbiphenyl-3-yl)acetic acid according to WO 99/48869 A1) in 20 ml of acetonitrile was added dropwise. The mixture was stirred at RT for 12 h. The precipitate formed was filtered off, washed with water and dried under reduced pressure. The resulting mother liquor was concentrated by evaporation, dissolved in chloroform and chromatographed (ethyl acetate/n-heptane: 20/80 to 80/20). This gives a total of 1.81 g of methyl 4-{[(4′-chloro-4-methylbiphenyl-3-yl)acetyl]amino}-1,3-thiazole-5-carboxylate.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].Br[CH2:12][C:13]1[N:18]=[C:17]([CH2:19][N:20]2[C:24]3[N:25]=[C:26]([NH2:34])[N:27]=[C:28]([C:29]4[O:30][CH:31]=[CH:32][CH:33]=4)[C:23]=3[N:22]=[N:21]2)[CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[NH2:34][C:26]1[N:27]=[C:28]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)[C:23]2[N:22]=[N:21][N:20]([CH2:19][C:17]3[N:18]=[C:13]([CH2:12][N:2]([CH3:1])[C:3](=[O:8])[C:4]([F:7])([F:6])[F:5])[CH:14]=[CH:15][CH:16]=3)[C:24]=2[N:25]=1
Reactant: Nc1nc(-c2ccco2)c2nnn(Cc3cccc(CBr)n3)c2n1
Reactant: CNC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)n1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of N-methyl-2,2,2-trifluoroacetamide (197 mg, 1.55 mmol) in DMF (5 mL) at 0° C. was treated with sodium hydride (60% dispersion in mineral oil; 62 mg, 1.55 mmol), stirred for 15 min, treated with 3-(6-bromomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (120 mg, 0.310 mmol), stirred at 50° C. for 1 h, cooled to room temperature, poured into water (20 mL), extracted with EtOAc (3×10 mL) and the combined organic phase dried (MgSO4) and concentrated in vacuo to give N-(6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-2-pyridylmethyl)-N-methyltrifluoroacetamide. A solution of this product in MeOH (20 mL) was treated with a solution of sodium (71 mg, 3.10 mmol) in MeOH (10 mL), stirred for 16 h, concentrated in vacuo, treated with EtOAc (20 mL), filtered through Celite and concentrated in vacuo. The resulting solid was suspended in MeOH (2 mL), treated with HCl (4-M in dioxane, 1.0 mL), stirred for 10 min, concentrated in vacuo and triturated with Et2O to give the title compound (80 mg, 58%) as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[C:6]=1[C:16](=O)[CH2:17][C:18]([O:20]CC)=O>C(O)C>[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[C:6]=1[C:16]1[CH:17]=[C:18]([OH:20])[N:2]([CH3:1])[N:3]=1
Reactant: CCOC(=O)CC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CNN
Solvent: CCO
Product: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
A solution of 1.0 g of methylhydrazine in 15 ml of ethanol was added dropwise to 6.0 g of ethyl 3-(2,6-dichloro-4-trifluoromethylphenyl)-3-oxopropionate (5) in 50 ml of ethanol at room temperature, and the mixture was thereafter stirred at room temperature for 1 hour and further refluxed overnight. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was washed with hexane to give 2.8 g of the desired compound in the form of white crystals (crude yield 50.0%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([O:12][CH3:13])=[O:11]>CN(C=O)C.[Ag]=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: Oc1ccccn1
Reactant: COC(=O)CBr
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.4 %

Procedure:
To a solution of 2-hydroxypyridine(5 g) in DMF(150 ml) was added silver oxide (I) (24 g) and methyl bromoacetate(20 g) and stirred at room temperature for 2 hours. After the catalyst was filtered off through celite, the filtrate was evaporated. The residue was dissolved in ethyl acetate and the solution was washed with brine, dried(MgSO4) and evaporated to dryness. The residue was purified by column chromatography on silica gel (chloroform: methanol=100:1) to obtain methyl 2-(2-pyridyloxy)acetate(1.0 g). According to the same manner as described above, the title compound was synthesized (0.1 g). m.p. 110° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: c1nc[nH]n1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1cncn1

Procedure:
Using general procedure 4 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.125 g, 0.47 mmol) and 1,2,4-triazole (0.036 g, 0.52 mmol) gives the title compound (recrystallized from ethyl acetate).
Reaction SMILES: CCC[CH2:4][CH2:5][CH3:6].C[Si](C#C)(C)C.[Li+].CCC[CH2-].[CH:18]([SiH:21](Cl)[CH:22]([CH3:24])[CH3:23])(C)[CH3:19]>O.O1CCCC1>[CH:22]([SiH:21]([C:18]#[CH:19])[CH:5]([CH3:4])[CH3:6])([CH3:24])[CH3:23]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: CCCCCC
Agent: C#C[Si](C)(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C#C[SiH](C(C)C)C(C)C
Temperature: 25 °C
Yield: 54 %

Procedure:
An oven dried 500 mL round bottom flask with nitrogen atmosphere was charged with hexane (100 mL), tetrahydrofuran (20 mL), and trimethylsilylacetylene (4.8 g, 48.9 mmol) and cooled with an ice bath. N-butyllithium (2.5 M in hexane, 19.4 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature. The reaction product (20.0 g) from the previously described step, “Synthesis of 3-(N-methylnonafluorobutanesulfonamido)propyl) diisopropylsilyl chloride,” was slowly added and the contents allowed to stir for sixteen hours. Water was added slowly (100 mL) and the mixture was stirred vigorously. The organic layer was separated, and the water layer extracted with 100 mL of hexane. The organic layers were combined and concentrated under reduced pressure to a brown oil. The oil was purified using chromatography on silica gel with hexane as an eluant, resulting in 23.9 g of the trimethylsilyl-protected acetylene as a clear oil. The oil (23.9 g, 42.2 mmol) was charged to an oven dried 500 mL round bottom flask. Methanol (50 mL), tetrahydrofuran (50 mL), and 5% aqueous NaOH (1 mL) were added to the flask and then stirred for one hour. Water (100 mL) was then added, and stirred vigorously. The organic layer was separated, and the aqueous layer was extracted two times with hexane (2×100 mL). The organic layers were combined and concentrated under reduced pressure to yield 3-(N-methylnonafluorobutanesulfonamido)propyl)diisopropylsilyl acetylene as a clear oil (11.2 g, 54%).