Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][CH:26]([CH3:35])[CH:27]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[OH:28]>O1CCOCC1.CS(C)=O.CO>[OH:28][CH:27]([CH:29]1[CH2:30][CH2:31][N:32]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:21])[CH3:22])=[CH:18][CH:19]=3)[CH:3]=2)[CH2:33][CH2:34]1)[CH:26]([CH3:35])[CH3:25]
Reactant: CC(C)C(O)C1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CS(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)C(O)C1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 200 mg, 0.604 mmol) and 2-methyl-1-(piperidin-4-yl)propan-1-ol (142 mg, 0.604 mmol) in Dioxane (6 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (59 mg, 23%). 1H NMR (METHANOL-d4) δ: 7.99 (d, J=2.3 Hz, 1H), 7.92-7.97 (m, 2H), 7.61-7.69 (m, 2H), 7.39 (s, 1H), 6.32 (d, J=2.5 Hz, 1H), 4.55 (d, J=12.4 Hz, 2H), 2.93-3.14 (m, 3H), 2.02 (d, J=1.0 Hz, 1H), 1.58-1.89 (m, 5H), 1.57 (s, 6H), 0.96 (dd, 6H). ESI-MS: m/z 452.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]=[CH:5][C:6]([CH3:11])([CH3:10])[CH2:7][CH:8]=[CH2:9])[CH:2]=[CH2:3].[BH4-].[Na+]>CO>[CH2:1]([NH:4][CH2:5][C:6]([CH3:11])([CH3:10])[CH2:7][CH:8]=[CH2:9])[CH:2]=[CH2:3]
Reactant: C=CCN=CC(C)(C)CC=C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCNCC(C)(C)CC=C
Temperature: 25 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
Allyl-(2,2-dimethyl-pent-4-enylidene)-amine of Example 92a (3.76 g, 25 mmol) was diluted in 5 ml MeOH. To the solution NaBH4 (0.95 g, 25 mmol) was added at 0° C. After addition the mixture was stirred at r.t. for 5 h. Methanol was removed on rotavapor and the residue was partitioned between EtOAc/20% NaOH. The organic layer was dried over Na2SO4, fitered and evaperated to give 2.26 g of the title compound: MS (M+H+): 154.0; 1H-NMR (400 MHz, CDCl3): 5.93-5.76(m, 2H), 5.29-4.99(m, 4H), 3.22(d, 2H), 2.34(s, 2H), 2.01(d, 2H), 0.94(s, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[C:8]([NH:9][C:10](=[O:13])[CH2:11][Cl:12])=[C:7]([O:14][CH2:15][CH3:16])[N:6]=[CH:5][N:4]=1.Cl.[NH:19]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[N:20]1.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl.O>[NH:19]1[CH:23]=[CH:22][C:21]([CH2:24][N:9]([C:8]2[C:3]([N:2]([CH3:17])[CH3:1])=[N:4][CH:5]=[N:6][C:7]=2[O:14][CH2:15][CH3:16])[C:10](=[O:13])[CH2:11][Cl:12])=[N:20]1
Reactant: ClCc1cc[nH]n1
Reactant: CCOc1ncnc(N(C)C)c1NC(=O)CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOc1ncnc(N(C)C)c1N(Cc1cc[nH]n1)C(=O)CCl
Reaction time: 2 h

Procedure:
To a mixture of 12.9 g (0.05 mol) N-(4-dimethylamino-6-ethoxypyrimidin-5-yl)-chloroacetamide and 2 g benzyltriethylammoniumchloride in 150 g of CH2Cl2 are added 8.4 g (0.055 mol) of 1-pyrazolylmethylchloride-hydrochloride. To this mixture are quickly added 25 ml of 40% NaOH, whereby the temperature rises from 18° to 32°. The mixture is then stirred for 2 hours and diluted with water. The organic phase is separated off and dried over Na2SO4. The dried solution is evaporated to give an orange oil that is chromatographed on silica gel with the aid of ethylacetate. The thus obtained yellow oil is dissolved in diethylether and crystallised in a deep-freezer. The title compound is obtained in the form of white crystals of m.p. 112°-114°.
Reaction SMILES: [CH2:1]([N:4]([C@@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[OH:27])[CH2:18]1)[CH2:5][CH2:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=O)[O:8]1)[CH2:2][CH3:3].CCOC(C)=O>C1COCC1>[CH:7]1([CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH:17]2[CH2:26][CH2:25][C:24]3[C:23]([OH:27])=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][O:8]1
Reactant: CCCN(CC[C@@H]1OC(=O)c2ccccc21)[C@@H]1CCc2c(O)cccc2C1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN(CCC1OCc2ccccc21)C1CCc2c(O)cccc2C1

Procedure:
A racemic mixture of the product of Example 36 (66 mg, 0.180 mmol) was dissolved in THF and added dropwise to a solution of BH3 in THF (2 mL) and the mixture was refluxed overnight. After workup the crude mixture was subjected to flash chromatography (Silica: EtOAc) and the product showed characteristic peaks at: NMR (300 MHz, CDCl3) δ7.3-6.5(m, 7H), 5.4-5.0(m, 3H), 0.9(t, 3H). Anal. calc. for C22H29NO2 ° HCl: Theor. C; 71.21; H; 7.79; N, 3.61. Observed: C, 71.16, H, 7.61; N, 3.55.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20](CC2C=CC(OC)=CC=2)[C:21]([Br:25])=[C:22]([Br:24])[CH:23]=1)=[O:18].[OH-].[Na+]>C(OCC)(=O)C.S(=O)(=O)(O)O>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[NH:20][C:21]([Br:25])=[C:22]([Br:24])[CH:23]=1)=[O:18]
Reactant: COc1ccc(Cn2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc(Br)c2Br)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1nc2cc(-n3ncc(C(=O)c4cc(Br)c(Br)[nH]4)c3N)ccc2[nH]1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
[5-Amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[4,5-dibromo-1-(4-methoxy-benzyl)-1H-pyrrol-2-yl]-methanone (317 mg) was dissolved in ethyl acetate/sulfuric acid (4/1; 5 ml). This was stirred at 80° C. for four hours. The pH of the reaction mixture was adjusted to 11 (basic) using an aqueous solution of 5 M sodium hydroxide while cooling it on ice. The reaction mixture was extracted with ethyl acetate/tetrahydrofuran (THF) (10 ml). The organic layer was washed with an aqueous solution saturated with sodium chloride (5 ml), and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol). Thus, a brown solid was obtained (135 mg, 54%).
Reaction SMILES: Br[CH:2]([C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]#[N:4].[NH2:13][C:14]([NH2:16])=[S:15].II.[NH4+].[OH-]>O>[NH2:16][C:14]1[S:15][C:2]([C:3]#[N:4])=[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:13]=1
Reactant: NC(N)=S
Reactant: N#CC(Br)C(=O)c1ccccc1
Agent: II
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: N#Cc1sc(N)nc1-c1ccccc1

Procedure:
2-Bromo-3-oxo-3-phenylpropionitrile (0.5 g, 3.4 mmol) was mixed with thiourea (0.52 g, 6.8 mmol) and iodine (0.43 g, 3.4 mmol) and the mixture was heated on a steam bath for 12 h. It was then diluted with water and made alkaline with saturated aqueous NH4OH, and extracted with ethyl acetate. The organic phases were washed with water and brine, dried over sodium sulfate, and evaporated to dryness to give the crude product, which was used in the next reaction without any further purification. Yield: 0.2 g, 29%.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:13]1([NH:12][C:9]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=2)=[O:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: Nc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1n[nH]cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
4-Nitropyrazole-3-carboxylic acid (2.5 g; 15.9 mmol) was added to a stirred solution of aniline (1.6 ml; 17.5 mmol), EDC (3.7 g; 19.1 mmol), and HOBt (2.6 g; 19.1 mmol) in N,N-dimethylformamide (DMF) (25 ml), then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with ethyl acetate/saturated NaHCO3 solution. The resultant solid was collected by filtration, washed with water and diethyl ether then dried under vacuum to give 2.85 g of the title compound (sodium salt) as a yellow/brown solid. (LC/MS: Rt 2.78, [M+H]+ 232.95).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1.CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:26][C:25]([F:28])([F:27])[C:22]1[CH:23]=[CH:24][C:19]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]3)[CH2:10][CH2:9]2)=[N:20][CH:21]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(C(F)(F)F)cn3)CC2)C1
Yield: 40 %

Procedure:
A mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.5 mmol, 1.0 eq.) and 2-bromo-5-(trifluoromethyl)pyridine (2.5 mmol, 1.0 eq.) and tBuONa (7.5 mmol, 3.0 eq.) in toluene (12 ml) was degassed with argon for 10 min. BINAP (0.15 mmol, 0.06 eq.) and Pd(OAc)2 (0.05 mmol, 0.02 eq.) were added and the reaction mixture obtained was heated under reflux for 14 h. The reaction mixture was filtered over Celite and the filtrate was concentrated in vacuo in order to obtain the crude product, which was purified by column chromatography (silica gel, 22-25% ethyl acetate in hexane), in order to obtain the desired product. Yield: 40%
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)#[N:32]>C(O)C>[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[N:30][NH:29][C:16]2[CH:15]=[C:14]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=2)=[CH:35][CH:34]=1)#[N:32]
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.0 mg, 0.0557 mM), then 4-cyano-benzaldehyde (6.7 mg, 0.061 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (23.6 mg, yield: quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:45][CH:46]([F:48])[F:47])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)=[O:35])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.[C:49](OC(N1CCC(C)(C(O)=O)CC1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:45][CH:46]([F:48])[F:47])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][C:31]([CH3:49])([C:34]([O:36][CH2:37][CH:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)=[O:35])[CH2:32][CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CN1CCC(COC(=O)C2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Product: CN1CCC(COC(=O)C2(C)CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1

Procedure:
Using synthetic method analogous to that of (1-methylpiperidin-4-yl)methyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate, the title compound was prepared from 1-[(tert-butoxy)carbonyl]-4-methylpiperidine-4-carboxylic acid. LCMS (Method 28) [M+H]+=699.2, RT=0.95 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.0, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 3.99-3.96 (m, 2H), 3.94-3.88 (m, 1H), 3.78-3.71 (m, 1H), 3.26-3.20 (m, 1H), 3.08-3.00 (m, 1H), 2.85-2.80 (m, 2H), 2.20 (s, 3H), 2.02-1.94 (m, 4H), 1.68-1.59 (m, 4H), 1.54-1.48 (m, 1H), 1.41-1.34 (m, 1H), 1.28-1.23 (m, 2H), 1.18 (s, 3H).
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:3]([OH:5])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:1]/[C:2](=[CH:6]\[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:3]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:5]
Reactant: Nc1ccccc1
Reactant: C/C(=C\Sc1ccccc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: C/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A suspension of 2.5 g (12.8 mmol) of (E)-2-methyl-3-(phenylthio)-2-propenoic acid and 3.5 g (25.7 mmol) of thionyl chloride in 25 ml of toluene was refluxed for 1 hour and then concentrated under vacuum. The residue was dissolved in 25 ml of ethyl acetate and cooled in ice bath. To the solution was added dropwise 2.9 g (32 mmol) of aniline and stirred at room temperature for 30 minutes. The reaction mixture was washed sequentially with 1N HCl solution, a saturated NaHCO3 solution, and a saturated NaCl solution. The organic layer was dried over anhydrous MgSO4 and concentrated to obtain 3.0 g of (E)-2-Methyl-N-phenyl-3-(phenylthio)-2-propenamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:4][C:3]=1I.[Si:15]([O:22][CH2:23][CH2:24][CH2:25][C:26]#[C:27][Si:28]([CH3:31])([CH3:30])[CH3:29])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Si:15]([O:22][CH2:23][CH2:24][CH2:25][C:26]1[C:3]2[C:2](=[CH:7][CH:6]=[C:5]([CH2:8][S:9]([NH:12][CH3:13])(=[O:11])=[O:10])[CH:4]=2)[NH:1][C:27]=1[Si:28]([CH3:29])([CH3:30])[CH3:31])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CNS(=O)(=O)Cc1ccc(N)c(I)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCC#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CNS(=O)(=O)Cc1ccc2[nH]c([Si](C)(C)C)c(CCCO[Si](C)(C)C(C)(C)C)c2c1
Temperature: 100 °C
Yield: 87.7 %

Procedure:
To a solution of 0.326 g (1.0 mmol, 1.0 equiv.) of 4-amino-3-iodo-N-methylbenzenemethanesulfonamide in 20 mL of dimethylformamide was added 0.541 g (2.0 mmol, 2.0 equiv.) of 1-t-butyldimethylsilyloxy-5-trimethylsilyl-4-pentyne, 0.278 g (1.0 mmol, 1.0 equiv.) of tetrabutylammonium chloride, 0.530 g (5.0 mmol, 5.0 equiv.) of sodium carbonate, 0.0131 g (0.05 mmol, 0.05 equiv.) of triphenylphosphine, and 0.0112 g (0.05 g, 0.05 equiv.) of palladium (II) acetate. The mixture was heated in a 100° C. oil bath for 16 hours. The mixture was cooled to room temperature and the dimethylformamide removed in vacuo. The residue was diluted with 75 mL of ethyl acetate and washed with 25 mL of saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield an oil. The oil was filtered through a plug of silica gel with 25% ethyl acetate in hexane to yield 0.411 g (88%) of 3-(3-t-butyldimethylsilyloxypropyl)-2-trimethylsilyl-N-methyl-1H-indole-5-methanesulfonamide.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[S:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:19]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[N:28]=[N:29][C:30](Cl)=[CH:31][CH:32]=2)=[O:26])[CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].O1CCOCC1>[CH:19]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[N:28]=[N:29][C:30]([N:4]3[CH2:5][CH2:6][N:1]([C:7](=[S:8])[C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]([F:18])([F:16])[F:17])[CH2:2][CH2:3]3)=[CH:31][CH:32]=2)=[O:26])[CH2:21][CH2:20]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: FC(F)(F)c1ccccc1C(=S)N1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1COCCO1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=S)c3ccccc3C(F)(F)F)CC2)nn1
Yield: 76 %

Procedure:
A mixture of piperazin-1-yl-(2-trifluoromethylphenyl)methanethione (1.1 g, 4.0 mmol), 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.98 g, 3.98 mmol), K2CO3(0.83 g, 6.0 mmol) and n-Bu4NI (0.010 g) in dioxane (10 mL) was heated to reflux for 21 h, and then concentrated. The residue was purified by column chromatography and recrystalization from ethyl acetate and hexanes to afford the title compound in 76% yield (1.42 g). m.p. 117-120° C. 1H NMR (300 MHz, CDCl3) δ 8.05-7.93, 7.65, 7.55, 7.44, 7.24, 6.98, 4.61-4.40, 3.98-3.40, 1.51-1.47, 0.73-0.64, 0.44-0.35, 0.07-0.01. 13C NMR (75 MHz, CDCl3) δ 197.0, 162.8, 159.6, 145.6, 140.2, 132.4, 128.8, 127.2, 127.0, 126.9, 125.5, 124.8, 124.4, 124.0, 121.8, 112.5, 50.4, 47.6, 44.2, 43.6, 40.0, 39.6, 34.4, 8.6, 4.2. MS (ES+) m/z 464.0 (M+1).
Reaction SMILES: [N:1]1([CH2:6][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH:5]=[CH:4][N:3]=[CH:2]1.N1(CCO[C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[C:29](=[O:33])[CH2:28][CH2:27][CH2:26]3)C=CN=C1>>[N:1]1([CH2:6][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:8][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[C:29](=[O:33])[CH2:28][CH2:27][CH2:26]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OC(Cn1ccnc1)c1ccccc1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Product: O=C1CCCc2cc(OC(Cn3ccnc3)c3ccccc3)ccc21
Yield: 93.7 %

Procedure:
Following the procedure of Example 78, Step 3, but using 2.63 g (14.0 mmol) of 2-(1H-1-imidazolyl)-1-phenyl-1-ethanol and 2.0 g (12.3 mmol) of 6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone, there was obtained 3.83 g (93.6% yield) of the product as a glass. The structure was confirmed by NMR and mass spectroscopy. MS m/z 333 (M+H+).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.ClCl>ClC1C=CC=CC=1>[Cl:1][C:7]1[CH:8]=[C:3]([NH2:2])[C:4]([CH3:9])=[CH:5][CH:6]=1
Reactant: Cl
Reactant: Cc1ccccc1N
Agent: ClCl
Solvent: Clc1ccccc1
Product: Cc1ccc(Cl)cc1N

Procedure:
57 g of hydrogen chloride (= 1.56 mols) were introduced, while thoroughly stirring, into a solution of 160 g of distilled o-toluidine (= 1.5 mols) in 1300 ml of chlorobenzene in the course of 30 - 45 minutes. It is advisable but not necessary to cool the reaction mixture slightly in a water bath. 105 g of chlorine gas (= 1.48 mols) were introduced at 35°C within 13/4 hours. Then, the hydrogen chloride still in solution was blown out with air. The hydrochloride was suction-filtered through a Buchner funnel and dried in the air. To isolate the free 5-chloro-2-toluidine the dried filter residue was introduced portionwise into 350 g of sodium hydroxide solution (18%). The temperature rose to about 40° - about 50°C. Then, the crude amine was separated in a separating funnel and subjected to a fractionated distillation under reduced pressure. The amount of product obtained was 60.1 g of 2-toluidine (= 0.56 mol), which was reused, 101.0 g of 5-chloro-2-toluidine (= 0.71 mol) corresponding to 75.5 % calculated on reacted 2-toluidine (introduced 2-toluidine minus 2-toluidine recovered) and 14.3 g of 3.5-dichlorotoluidine (= 0.08 mol).
Reaction SMILES: C1C=CC(C(O)[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=CC=1.Cl.[OH2:18]>>[C:8]([OH:18])(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: Cl
Product: O=C(O)c1ccccc1

Procedure:
An amount of 25 g of ground Siam benzoin resin was dispersed in 500 ml of a solution (pH of 3) prepared by adding hydrochloric acid to water and was extracted five times by using 20 v/v% of diethylether in a separatory funnel. The combined ether layer was evaporated to remove solvents until the volume thereof reached 5 ml. Benzoic acid with a concentration of 5 g/l was detected by HPLC analysis.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH:5]([O:7][P:8]([CH2:17][C:18]([CH3:41])=[CH:19][CH2:20][C:21]1[C:22]([O:34]CC[Si](C)(C)C)=[C:23]2[C:27](=[C:28]([CH3:32])[C:29]=1[O:30][CH3:31])[CH2:26][O:25][C:24]2=[O:33])([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[CH3:6])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:42])[CH:5]([O:7][P:8]([CH2:17][C:18]([CH3:41])=[CH:19][CH2:20][C:21]1[C:22]([OH:34])=[C:23]2[C:27](=[C:28]([CH3:32])[C:29]=1[O:30][CH3:31])[CH2:26][O:25][C:24]2=[O:33])([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)OP(=O)(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)Oc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)OP(=O)(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a solution of 2-({4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phenoxy-phosphinoyloxy)-propionic acid ethyl ester (24 mg, 0.039 mmol) in DCM (1 mL) was added TFA (0.5 mL) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was dried under reduced pressure and the residue was purified by RP-HPLC to provide 18 mg (90%) of the desired product as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.18-1.34 (m, 3H), 1.36-1.48 (dd, 3H), 2.02 (m, 3H), 2.17 (s, 3H), 2.78-2.98 (dd, 2H), 3.45 (m, 2H), 3.79 (s, 3H), 4.05-4.25 (m, 2H), 4.97 (m, 1H), 5.21 (s, 2H), 5.48 (t, J=7.2 Hz, 1H), 7.05-7.18 (m, 5H) ppm; 31P (121.4 MHz, CDCl3) δ 24.59, 26.13 ppm; MS (m/z) 517 [M−H]−, 519 [M+H]+.