Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]([NH:25][NH:26][CH2:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:37]1([CH2:42][C:43](O)=[O:44])[CH:41]=[CH:40][N:39]=[CH:38]1>>[CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]([NH:25][N:26]([CH2:27][CH:28]([CH2:29][CH3:30])[CH2:31][CH3:32])[C:43](=[O:44])[CH2:42][N:37]1[CH:41]=[CH:40][N:39]=[CH:38]1)=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1ccnc1
Reactant: CCC(CC)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Product: CCC(CC)CN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1)C(=O)Cn1ccnc1

Procedure:
In a manner analogous to that described in Example 8 from (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-2′-(2-ethylbutyl)-4-methylvalerohydrazide and using imidazole-1-acetic acid in place of N-tert-butoxycarbonyl-β-alanine there was obtained (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-2′-(2-ethylbutyl)-2′-[2-(1H-imidazol-1-yl)acetyl]-4-methylvalerohydrazide in the form of a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH:11]3[S:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])=[N:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH2:28]Br)=[CH:22][CH:21]=1.FC1C=C(C#CCBr)C=C(F)C=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][C:11]3([CH2:28][C:27]#[C:26][C:23]4[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=4)[S:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])=[N:7][C:6]=2[CH:18]=1
Reactant: Clc1ccc(C#CCBr)cc1
Reactant: O=C1NC(=O)C(Sc2nc3cc(Cl)ccc3s2)S1
Agent: Fc1cc(F)cc(C#CCBr)c1
Product: O=C1NC(=O)C(CC#Cc2ccc(Cl)cc2)(Sc2nc3cc(Cl)ccc3s2)S1

Procedure:
Prepared from 5-(5-chloro-benzothiazol-2-ylsulfanyl)-thiazolidine-2,4-dione, (III), Example 88 and [3-(4-chlorophenyl)-prop-2-ynyl]-bromide of formula (IX), Example 21: mp 187°-188° C.; Anal. Calc. for C19H10Cl2N2O2S3 : C, 49.04; H, 2.17; N, 6.02; Found: C, 48.94; H, 2.31; N, 6.21.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[S:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[C:13]([C:18]#[N:19])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1.[I:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[OH:39].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:39][C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[I:31])=[C:13]([C:18]#[N:19])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1
Reactant: Oc1ccc(F)cc1I
Reactant: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2ccc(Oc3ccc(F)cc3I)c(C#N)c2)c(OC)c1

Procedure:
N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-N-(2,4-dimethoxybenzyl)-4-fluorobenzenesulfonamide (Preparation 207, 410 mg, 0.876 mmol), 2-iodo-4-fluorophenol (Preparation 218, 229 mg, 0.964 mmol) and potassium carbonate (363 mg, 2.63 mmol) in dimethyl sulphoxide (20 ml) were stirred at room temperature under nitrogen for 18 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (3×30 ml). The combined organics were washed with saturated aqueous sodium chloride solution (30 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as an off-white solid, 670 mg, quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([OH:11])[CH3:10].[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1.ClCCl.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]([O:11][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH3:10])[N:14]=1
Reactant: COc1ccccc1C(C)O
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccccc1C(C)Oc1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
K-t-BuO (0.67 g, 5.97 mmol) was added to a stirred solution of 1-(2-methoxyphenyl)ethanol (0.96 g, 6.28 mmol) in dioxane (15 mL) at 0° C. (ice-bath). After 5 min of stirring at room temperature, the reaction mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (0.78 g, 5.23 mmol) was added whereupon the reaction mixture turned yellow. After being stirred for 35 min, dichloromethane and K2CO3 were added and the mixture was filtered. Concentration in vacuo furnished a yellow oil that was purified by silica gel chromatography (15×4 cm) using n-hexane ethyl acetate (8:2) as eluent. This gave 1.21 g (92%) of the title compound as a colorless oil. HRMS m/z calcd for C13H13ClN2O2 (M)+ 264.0666, found 264.0677. Anal. (C13H13ClN2O2) C, H, N.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][CH:7]=1.C(Cl)(Cl)Cl>[O-2].[O-2].[Mn+4].O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cccc(-c2ccco2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1cccc(-c2ccco2)n1
Yield: 73.4 %

Procedure:
8 g of manganese dioxide are added to a solution of 2 g of (6-furan-2-yl-pyridin-2-yl)methanol (11.4 mmol) and 50 ml of chloroform. The reaction mixture is heated under reflux for 1 hour 30 minutes with removal of the water formed continuously. The solid in suspension is removed by filtration on celite and then the solvent is evaporated off. The title product is isolated by chromatography on a silica column (eluent: chloroform). 1.45 g of a yellow solid are recovered.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=[CH:28][C:21]=34)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.O1CCOCC1>C1COCC1.CO>[CH3:35][Si:33]([CH3:34])([CH3:36])[CH2:32][CH2:31][O:30][CH2:29][N:26]1[C:22]2=[N:23][CH:24]=[CH:25][C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]4)[CH:19]=3)=[C:21]2[CH:28]=[CH:27]1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 126.8 %

Procedure:
A solution of tert-butyl 3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (341 mg, 0.67 mmol) in THF (5 mL) and methanol (5 mL) was added a 4.0 M solution of hydrogen chloride in 1,4-dioxane (5 mL, 20 mmol). The mixture was stirred at room temperature for 2 hours and concentrated to give 347 mg (100%) of {3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile.2[HCl] as a yellowish solid. LC/MS found: 409.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH2:15][OH:16])[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].CN(C1C=CC=CN=1)C>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH2:15][O:16][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO)CN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1

Procedure:
A solution of cis (+/−)-benzyl 3-(tert-butoxycarbonylamino)-5-(hydroxymethyl)piperidine-1-carboxylate (1.0 eq.), imidazole (1.1 eq.), tert-butyldimethylsilylchloride (1.1 eq.) and dimethylaminopyridine (0.1 eq.) in dichloromethane at a concentration of 0.1 M was stirred for 18 hours at which time the volatiles were removed in vacuo. Direct purification of the crude material by column chromatography (20% ethyl acetate/hexanes) yielded cis (+/−)-benzyl 3-(tert-butoxycarbonylamino)-5-((tert-butyldimethylsilyloxy)methyl)piperidine-1-carboxylate. LCMS (m/z): 379.0 (MH-Boc+); LC Rt=5.95 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(3-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (19 g, 51.3 mmol) in methanol (100 ml) was added 2N aqueous sodium hydroxide solution (51 ml, 102 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2RS,3RS)-3-(3-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (15.6 g, 89%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[O:19][C:20]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][C:21]=2[N:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[O:19][C:20]4[CH:26]=[CH:25][C:24]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][C:21]=4[N:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1nc2cc(-c3ccccc3)ccc2o1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1ccc(-c2ccc3oc(COc4ccc(CCCn5ccnc5)cc4)nc3c2)cc1
Yield: 77 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-chloromethyl-5-phenylbenzoxazole to give 2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-phenylbenzoxazole. The yield was 77%. Recrystallization from ethyl acetate-hexane gave pale yellow plates, mp 123-124° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:23]=[N:22][C:21]([NH:24][NH:25]C(=O)CC2CCCCC2)=[CH:20][C:19]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:23]=[N:22][C:21]([N:24]([C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH2:25])=[CH:20][C:19]=1[C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C(CC1CCCCC1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Product: NN(C(=O)Cc1ccccc1)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Yield: 47 %

Procedure:
The title compound (42 mg, 47%) as a white foam was prepared from 2-phenylacetic acid (41 mg, 0.3 mmol) and 1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3)hydrazine (66 mg, 0.2 mmol) according to the procedures described for N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-cyclohexylacetohydrazide (Example 7A). HPLC/MS (method A): retention time=3.30 min, (M+H)+=449.2.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:22][CH3:23])=[C:5]([CH:10]([CH2:20][CH3:21])[CH2:11][C@:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:13]=O)[CH:6]=[CH:7][C:8]=1[F:9])[CH3:2].[NH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][C:29](=[O:35])[NH:30]2.C(O)(=O)C.O>C1(C)C=CC=CC=1.CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[CH2:1]([C:3]1[C:4]([O:22][CH3:23])=[C:5]([CH:10]([CH2:20][CH3:21])[CH2:11][C@:12]([OH:19])([C:15]([F:16])([F:17])[F:18])[CH:13]=[N:24][C:25]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:26]=2[CH:27]=[CH:28][C:29](=[O:35])[NH:30]3)[CH:6]=[CH:7][C:8]=1[F:9])[CH3:2]
Reactant: CCc1c(F)ccc(C(CC)C[C@@](O)(C=O)C(F)(F)F)c1OC
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1c(F)ccc(C(CC)C[C@@](O)(C=Nc2cccc3[nH]c(=O)ccc23)C(F)(F)F)c1OC

Procedure:
45 mg (0.13 mmol) of (2R,4R/S)-4-(3-ethyl-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal and 21.4 mg (0.13 mmol) of 5-aminoquinolin-2(1h)-one are dissolved in 20 ml of toluene and the solution is admixed with 0.56 ml (1.86 mmol) of titanium tert-butoxide and 0.11 ml of acetic acid. The reaction mixture is heated at 1000 for 2 hours, cooled, poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 80 mg of (5-{[(2R,4R/S)-4-(3-ethyl-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one as a crude product. The imine is dissolved in 4.4 ml of CH2Cl2 and the solution is cooled to −30° C. 1.5 ml (1.5 mmol) of a 1M BBr3 solution in dichloromethane are added slowly dropwise over 15 minutes and the reaction solution is allowed to warm to room temperature over 22 hours. It is poured onto a mixture of saturated NaHCO3 solution and ice. It is extracted repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/isopropanol 16%) and subsequent preparative thin-layer chromatography on an amine phase (Merck NH2F254, ethyl acetate/triethylamine, 2%) yield 8 mg of the title compound and 6 mg of the corresponding 8R-diastereomer.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[C:2]=[O:3].[CH:17]1([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=[CH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1(=O)CCCCCCCC=CCCCCCC1.[BH4-].[Na+].[N-]=C=O>C(O)C.C(N(CC)CC)C>[CH2:12]([O:11][Si:7]([O:14][CH2:15][CH3:16])([O:8][CH2:9][CH3:10])[CH2:6][CH2:5][CH2:4][NH:1][C:2](=[O:3])[O:33][CH:17]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=[CH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:13]
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Reactant: OC1CCCCCCC=CCCCCCCC1
Agent: O=C1CCCCCCC=CCCCCCCC1
Agent: [BH4-]
Agent: [N-]=C=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCO[Si](CCCNC(=O)OC1CCCCCCC=CCCCCCCC1)(OCC)OCC
Reaction time: 24 h

Procedure:
1 ml of 3-isocyanatopropyltriethoxysilane and 50 mg of triethylamine are added to 0.9 g of 8-cyclohexadecen-1-ol, prepared by reduction of 8-cyclohexadecen-1-one using NaBH4 in ethanol, and the mixture is kept at 80° C. for 24 hours. Low-boiling components are removed at 90° C./0.1 mbar. The residue solidifies on cooling to form a wax and shows only traces of an isocyanate band in the IR spectrum, but instead a strong band (1700 cm-1) of the ##STR5## 5.2(m, 2H, --CH=CH--); 0.6 (m, --CH2Si).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].[O:13]1CCC[CH2:14]1.CCCCCC.C([Li])(CC)C>C(O)(=O)C.CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([O:11][CH3:12])=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[CH:14]=[O:13]
Reactant: C1CCOC1
Reactant: COc1cccc(OC)c1OC
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(C=O)c(OC)c1OC
Reaction time: 0.75 h
Yield: 24 %

Procedure:
A mixed solution of 20 g of 1,2,3-trimethoxybenzene and 100 ml of tetrahydrofuran (THF) was cooled to -78° C., and 140 ml of a hexane solution containing 1M sec-butyl lithium (sec-BuLi) was added dropwise thereto. After stirring the mixture at the same temperature for 45 minutes, 11 ml of dimethylformamide (DMF) was added to the reaction mixture. The mixture was stirred at -50° C. or lower for 45 minutes. Then, a 10% acetic acid aqueous solution was added to the mixture, and the resulting mixture was extracted with diethyl ether. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=9:1) to give 5.7 g of 2,3,4-trimethoxybenzaldehyde (yield: 24%, oily product).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3](=[O:19])[NH:4][C@H:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([O:8]C(C)(C)C)=[O:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]([CH3:20])[C:3](=[O:19])[NH:4][C@H:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([OH:8])=[O:7]
Reactant: CN(C)C(=O)N[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)N[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ((R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate (0.86 g, 3.10 mmol) in CH2Cl2 (250 mL) was added TFA (15 mL) dropwise and the resulting solution was stirred at rt for 3 h. The desired compound was then precipitated out of solution with a mixture of EtOAC:Hexanes (5:20), filtered off and dried under reduced pressure. (R)-2-(3,3-dimethylureido)-2-phenylacetic acid was isolated as a white solid (0.59 g, 86%) and used without further purification. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.82 (s, 6H) 5.22 (d, J=7.32 Hz, 1H) 6.58 (d, J=7.32 Hz, 1H) 7.28 (t, J=7.17 Hz, 1H) 7.33 (t, J=7.32 Hz, 2H) 7.38-7.43 (m, 2H) 12.65 (s, 1H). LCMS: Anal. Calcd. for C11H14N2O3: 222.24. found: 223.21 (M+H)+. HPLC XTERRA C-18 3.0×50 mm, 0 to 100% B over 2 minutes, 1 minutes hold time, A=90% water, 10% methanol, 0.2% H3PO4, B=10% water, 90% methanol, 0.2% H3PO4, RT=0.75 min, 93% homogeneity index.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OCc2ccc(F)c(F)c2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccc(F)c(F)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.7 %

Procedure:
To a stirred solution of methyl 3-chloro-4-[(3,4-difluorobenzyl)oxy]benzoate (Preparation 10, 10.86 g, 34.7 mmol) in methanol (700 mL) and water (150 mL) was added sodium hydroxide (6.946 g, 173.7 mmol) and the resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, diluted with water (285 mL), adjusted to pH 3 with hydrochloric acid and the resulting precipitate collected by filtration, washed with water and the azeotroped with toluene in vacuo twice to yield the title compound as a solid (6.5 g, 62% over 2 steps).
Reaction SMILES: CCC[C@H](N[C@H](C([N:15]1[C@H:23](C(O)=O)C[C@H:21]2[C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2)=O)C)C(OCC)=O.CC(N)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([C@@H]1C[C@H:53]2[C@H:48]([CH2:49][CH2:50][CH2:51][CH2:52]2)[NH:47]1)(O)=O.C([C@@H](N[C@H](C(O)=O)C)CCC)(OCC)=O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>>[CH:48]1([N:47]=[C:23]=[N:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: O=C(O)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Reactant: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Agent: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(C)(C)N
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
WO 01/58868 discloses a method for preparation of perindopril erbumine comprising reacting benzyl ester of (2S,3aS,7aS)-2-carboxyperhydroindole, p-toluenesulfonate salt with (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine in the presence of 0.4 to 0.6 moles of 1-hydroxybenzotriazole; 1 to 1.2 moles of dicyclohexylcarbodiimide and 1 mole of triethylamine at 77° C. to give the dipeptide compound, which on debenzylation gives perindopril.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:21]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(CCCO)c1ccc(F)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(CCCO)c1ccc(Oc2ccccc2)cc1
Reaction time: 24 h
Yield: 70.8 %

Procedure:
Part C: A solution of 13 g (58 mmol) of 3-[(4-fluorophenyl)sulfonyl]propan-1-ol from part B and 16 g (175 mM) of phenol in 100 mL of anhydrous DMF was purged with nitrogen for one-half hour then treated with 24 g (175 mM) of potassium carbonate. The reaction mixture was then placed in a 100° C. oil bath. After 24 hours, the reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with 1N HCl solution, saturated sodium bicarbonate solution and brine, dried (MgSO4), and concentrated to afford 29 g of crude product. This was chromatographed on silica gel using 30-45% ethyl acetate/hexane to yield 12 g of pure 3-[(4-phenoxyphenyl)sulfonyl]propan-1-ol, m/z=299 (M+Li).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]=[CH:11][C:10]2[CH:9]=[CH:8][C:7]3[C:13]([C:23]([NH2:25])=[O:24])=[N:14][N:15]([CH2:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:6]=3[C:5]=2[N:4]=1.C(O)(=O)C.O=[CH:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37].[BH3-]C#N.[Na+]>CO.CN(C=O)C>[C:36]([O:35][C:34](=[O:40])[NH:33][CH2:32][CH2:31][N:20]1[CH2:21][CH2:22][CH:17]([CH2:16][N:15]2[C:6]3[C:5]4[N:4]=[C:3]([S:2][CH3:1])[N:12]=[CH:11][C:10]=4[CH:9]=[CH:8][C:7]=3[C:13]([C:23](=[O:24])[NH2:25])=[N:14]2)[CH2:18][CH2:19]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CSc1ncc2ccc3c(C(N)=O)nn(CC4CCNCC4)c3c2n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CO
Product: CSc1ncc2ccc3c(C(N)=O)nn(CC4CCN(CCNC(=O)OC(C)(C)C)CC4)c3c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of 8-(methylsulfanyl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide 26 mg (0.073 mmol) in methanol (1.5 ml) and DMF (1 ml), acetic acid 13 μl (0.219 mmol), tert-butyl (2-oxoethyl)carbamate 69.6 mg (0.438 mmol) and NaCNBH3 28 mg (0.438 mmol) were added. The mixture was stirred at r.t. for 18 hours, consequently the volatiles were removed in vacuo. The residue was dissolved with ethyl acetate and portioned with water; the organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude was purified by flash chromatography (DCM/MeOH 95/5) to give tert-butyl[2-(4-{[3-carbamoyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazolin-1-yl]methyl}piperidin-1-yl)ethyl]carbamate 27 mg as a white solid (75%). LC/MS (254) HPLC method 2 Rt 3.86 min. 1H NMR (401 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.28 (d, J=8.67 Hz, 1H), 7.81 (s, 1H), 7.74 (d, J=8.79 Hz, 1H), 7.54 (br. s., 1H), 6.56 (br. s., 1H), 5.08 (d, J=7.32 Hz, 2H), 2.93-3.05 (m, 2H), 2.76-2.84 (m, J=10.25 Hz, 2H), 2.71 (s, 3H), 2.27 (br. s., 1H), 2.14 (br. s., 1H), 1.75-1.94 (m, 2H), 1.12-1.49 (m, 17H). HRMS (ESI) calcd for C24H33N7O3S [M+H]+ 500.2439 found 500.2436.