Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.Cl.[CH3:22][OH:23]>C(Cl)(Cl)Cl>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[NH:17])[O:23][CH3:22])[N:8]=1
Reactant: N#CCCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Reactant: CO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=N)CCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Reaction time: 62 h

Procedure:
A solution of 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeronitrile (2 g.) in MeOH (15 ml.) and chloroform (35 ml.) at 0° was saturated with HCl gas and the solution allowed to stand for 62 hours at 0°. The solvent was evaporated and the residue partitioned between aqueous potassium carbonate and chloroform. The chloroform extracts were washed, dried and evaporated to give methyl 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valerimidate as pale yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:16][C:15]2[CH:17]=[C:18]([CH:21]=[C:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])[CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]1.O>COCCOC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:16][C:15]2[CH:17]=[C:18]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])[CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]1
Reactant: O=C1NC(=O)C(=Cc2ccc3c(c2)CN(c2nc4ccccc4o2)CCO3)S1
Solvent: COCCOC
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc3c(c2)CN(c2nc4ccccc4o2)CCO3)S1
Temperature: 8.5 °C
Reaction time: 4 h

Procedure:
5-(4-Benzooxazol-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethylene)-thiazolidine-2,4-dione [compound of Example 6] (0.118 g, 0.3 mmol) was taken in 1,2-dimethoxyethane (40 mL) under nitrogen. The mixture was cooled to 7-10° C. by using dry ice-acetone bath, freshly prepared Al-amalgam strips and water (0.54 mL, 30 mmol) were added and the reaction mixture was stirred for 4 hours. The reaction mixture was then filtered through a celite bed and washed with 1,2-dimethoxyethane. The organic layer was concentrated under high vacuum and purified using silica gel column in 50% ethyl acetate in petroleum ether. The product obtained after concentration was washed with 2% ethyl acetate in petroleum ether, to give 5-(4-benzooxazol-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethyl)-thiazolidine-2,4-dione.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([O:33]C)=[O:32])[O:25][C:26]=3[CH3:27])=[CH:18][CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:40](P(=O)(OCC)OCC)[P:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44].CN(C)C=O.[H-].[Na+]>O>[CH2:43]([O:42][P:41](/[CH:40]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([OH:33])=[O:32])[O:25][C:26]=3[CH3:27])=[CH:38][CH:39]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:45][CH2:46][CH3:47])=[O:48])[CH3:44]
Reactant: COC(=O)c1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3)c(C)o2)c1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C(=O)O)c3)oc2C)cc1)OCC
Reaction time: 15 h
Yield: 64.5 %

Procedure:
To a mixture of methyl 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (0.29 g), tetraethyl methylenediphosphonate (0.18 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.03 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give an oily substance (0.28 g) from a fraction eluted with ethyl acetate-hexane (8:1, v/v). To a mixture of the oily substance, tetrahydrofuran (2 mL) and methanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added dilute hydrochloric acid to acidify the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid as colorless crystals (0.23 g, yield 88%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 153-155° C.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:25]1([CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=O)[CH2:31][CH2:30]2)[CH2:27][CH2:26]1.[NH2:38][CH2:39][C:40]1[CH:56]=[CH:55][C:43]([C:44]([N:46]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)[CH3:47])=[O:45])=[CH:42][C:41]=1[CH3:57]>ClCCl.CN(C=O)C>[Cl:54][C:51]1[CH:52]=[CH:53][C:48]([N:46]([CH3:47])[C:44]([C:43]2[CH:55]=[CH:56][C:40]([CH2:39][NH:38][C:35]([CH:32]3[CH2:31][CH2:30][N:29]([CH2:28][CH:25]4[CH2:26][CH2:27]4)[CH2:34][CH2:33]3)=[O:37])=[C:41]([CH3:57])[CH:42]=2)=[O:45])=[CH:49][CH:50]=1
Reactant: O=C(O)C1CCN(CC2CC2)CC1
Reactant: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CN
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CNC(=O)C1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
PyBroP (212 mg, 0.45 mmol) and 1-cyclopropylmethyl-piperidine-4-carboxylic acid from Example E15a (76 mg, 0.42 mmol) were added to a solution of 4-aminomethyl-N-(4-chloro-phenyl)-3,N-dimethyl-benzamide from Example E115.2 (100 mg, 0.35 mmol) in dichloromethane (5 ml) and DMF (1 ml). The mixture was stirred at room temperature for 18 h then solvents were removed in vacuo and azeotroped with toluene. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (34 mg, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[C:29]1([CH2:37]O)[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][OH:36])[CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:37][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][OH:36])[CH:30]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: OCc1cccc(CO)c1
Product: O=C1c2ccccc2C(OCc2cccc(CO)c2)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 55.3 %

Procedure:
The named compound was synthesised from 3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (541 mg, 1.37 mmol, 1 equiv.) and 1,3-benzenedimethanol (946 mg, 6.85 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (390 mg, 75%). 1H NMR (300 MHz, CDCl3): 8.01-7.90 (m, 3H, O2N—C—CH and C(O)═C═CH), 7.62-7.53 (m, 2H, Ar—H), 7.39-7.17 (m, 9H, Ar—H), 6.95-6.91 (m, 2H, Ar—H), 4.80 and 4.13 (d: AB, J=15.0 Hz, 2H, N—CH2), 4.64 (d, J=5.1 Hz, CH2—OH), 3.93 and 3.73 (d: AB, J=11.4 Hz, 2H, OCH2), 1.95 (t, J=5.4 Hz, 1H, OH). 13C NMR (75 MHz, CDCl3): 168.51, 145.42, 144.88, 141.59, 137.45, 135.37, 133.39, 131.79, 130.56, 130.34, 129.17, 128.81, 128.38, 126.61, 126.51, 125.82, 124.32, 123.69, 95.55, 65.42, 65.35, 42.91. m/z (ES): 515 [M+H]+. HPLC: Rt=3.58 min. Anal.: calc. for C29H23ClN2O5+0.15 CH2Cl2: C, 66.34; H, 4.46; N, 5.31. Found: C, 66.12; H, 4.44; N, 5.03.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([NH2:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=O)C1C=CC=CC=1.[CH:24]1([C:27]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:28]=2[C:29](O)=[O:30])[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][C:28]=2[C:29]([NH:23][C:13]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)=[O:30])[CH2:26][CH2:25]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Reactant: NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Product: O=C(NC1(c2ccccc2)CCCNC1)c1ccc(C(F)(F)F)cc1C1CC1

Procedure:
In analogy to the procedure described for the synthesis of example 29, the title compound was prepared from rac-3-amino-3-phenyl-piperidine-1-carboxylic acid benzyl ester and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (Example B.3). MS (m/e): 389.1 (MH+).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=1.F>>[CH3:5][C:6]1[CH:7]=[C:8]([C:2](=[S:1])[NH2:3])[C:9]([S:12][CH3:13])=[CH:10][CH:11]=1
Reactant: CSc1ccc(C)cc1
Reactant: N#C[S-]
Agent: F
Agent: [K+]
Product: CSc1ccc(C)cc1C(N)=S
Temperature: 25 °C
Reaction time: 10 h

Procedure:
At a temperature and in the manner as indicated in Example 1, 39 g of potassium thiocyanate (0.4 mol) and 46 g of 4-methyl-thioanisol (0.33 mol) are stirred with 0.3 l of 98% hydrofluoric acid. The mixture is then stirred first for 10 hours at room temperature and then for 3 hours in a steel autoclave at 40° - 50° C, subsequently cooled, the reaction mixture is poured onto ice, the 4-methyl-thioanisol-2-thiocarboxylic acid amide precipitated is suction-filtered and dried. The yield (54 g) is 81% of the theoretical yield, relative to the 4-methyl-thioanisol used. After recrystallization of the product from chlorobenzene, the melting point is 160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:31]([F:35])[CH:30]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Reactant: COC(=O)c1cccc(F)c1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3ccccc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-benzoimidazol-1-yl]-2-cyclohexyl-ethanol and 3-fluoro-hydroxy-benzoic acid methyl ester (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White solid (91%). MS (Turbo Spray): m/z=507.3 [M+H].
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([NH:10][C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:9])=[CH:6][CH:5]=1.F[B-](F)(F)F.[H+].[H][H]>CO>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:9])=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: CCOC(=O)C1=C(NC(=O)c2ccc(OC(F)F)cc2)CCCC1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CO
Product: CCOC(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccc(OC(F)F)cc1

Procedure:
In a 120 ml pressure resistant vessel were charged ethyl 2-{4-(difluoromethoxy)benzoyl}aminocyclohexene-1-carboxylate <5.0 g, 14.7 mmol>, diacetato{(S)-2,2′-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-1,1′-binaphthyl}ruthenium (II) (0.125 g, 0.0886 mmol), 42% tetrafluoroboric acid (14.3 ml, 0.1772 mmol) and methanol (25 ml) and the mixture was stirred. Thereafter, hydrogen (1 MPa) was filled therein, and the mixture was stirred at 45° C. for 40 hr. After confirmation of the completion of hydrogen absorption, the ordinary pressure was restored, and the mixture was concentrated into a diastereomer/enantiomer mixture to give the title compound as white crystals. yield 5.0 g. NMR data of (1S,2R) form 1H NMR (CDCl3) δ1.27 (3H, t, J=7.1 Hz), 1.4-1.9 (7H, m), 2.1-2.3 (1H, m), 2.8-2.9 (1H, m), 4.1-4.4 (3H, m), 6.56 (1H, t, J=76.6 Hz), 7.15 (2H, d, J=8.7 Hz)
Reaction SMILES: [OH:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][CH2:5][N:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:7](=[O:9])[CH3:8].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(OCC)C>[C:24]([O:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][CH2:5][N:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:7](=[O:9])[CH3:8])(=[O:26])[CH3:25]
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CCCCCC(CCCN(CCCCCCC(=O)O)C(C)=O)OC(C)=O
Temperature: 60 °C

Procedure:
A mixture of 7-[N-(4-hydroxynonyl)acetamido]-heptanoic acid (9.8 g., 0.03 mole) (Example 1, Step C) and acetic anhydride (6.1 g., 0.06 mole) is heated at 60° C. for 18 hours. The mixture is cooled and taken up in 80 ml. of ethyl ether. The solution is extracted with and ice-cold solution of 8 g. of sodium hydroxide in 150 ml. of water. The basic solution is separated and acidified with concentrated hydrochloric acid. The crude product that separates is extracted into ether, washed with water and dried over sodium sulfate. The ether is evaporated and the residual oil is purified by chromatoraphy on slica gel using 2% methanol in chloroform as the eluting solvent. There is obtained 7-[N-(4-acetoxynonyl)acetamido]heptanoic acid as a viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[NH:5][C:6]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][CH2:22]O)=[C:15]([CH3:24])[CH:14]=1)=[N:7]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:46]>CN(C=O)C>[Br:46][CH2:22][CH2:21][O:20][C:16]1[C:17]([CH3:19])=[CH:18][C:13]([C:6]2[NH:5][C:4](=[O:25])[C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[N:7]=2)=[CH:14][C:15]=1[CH3:24]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)c1OCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)c1OCCBr
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 5,7-difluoro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-3H-quinazolin-4-one (1.54 g, 4.44 mmol), PPh3 (1.52 g, 5.78 mmol), and CBr4 (1.92 g, 5.78 mmol) in anhydrous DMF (30 mL) was stirred at room temperature for 36 hours. DMF was evaporated under vacuum, water (100 mL) was added, and stirred for 30 minutes. The solid separated was filtered, washed with water, then ether, and dried under vacuum to give 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-difluoro-3H-quinazolin-4-one as pale yellow solid. Yield: 1.38 g (crude). This product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[C:6](\[NH:8][CH2:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[F:17])/[CH3:7])[CH3:2].CC1(C)[O:25][C:24](=O)[CH:23]=[C:22]([CH3:27])O1>C1(C)C=CC=CC=1>[F:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([F:17])[C:10]=1[CH2:9][N:8]1[C:22]([CH3:27])=[CH:23][C:24](=[O:25])[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])=[C:6]1[CH3:7]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: CCOC(=O)/C=C(/C)NCc1c(F)cccc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)n(Cc2c(F)cccc2F)c(C)cc1=O
Yield: 43 %

Procedure:
A mixture of ethyl-3-(2,6-difluorobenzylamino)crotonate (2.55 g, 10.0 mmol) and 2,2,6-trimethyl-1,3-dioxin-4-one (1.85 g, 13.0 mmol) in toluene (100 mL) was heated at reflux for 3 hours. The reaction progress was monitored by LC/MS. An additional aliquot of 2,2,6-trimethyl-1,3-dioxin-4-one (2.0 mL) was added and the reaction mixture was refluxed for another 2 hours. LC/MS indicated complete conversion to product. The mixture was cooled down and the solvent was removed in vacuo. The solid residue was triturated with diethyl ether to yield the product as a tan solid (1.37 g, 4.3 mmol, 43%). 1H NMR (CDCl3, 300 MHz): 7.40-7.30 (m, 1H), 7.00-6.91 (m, 2H), 6.30 (s, 1H), 5.20 (s, 2H), 4.37 (q, J=6.9 Hz, 2H), 2.37 (s, 3H), 2.31 (s, 3H), 1.35 (t, J=6.9 Hz, 3H); LRMS m/z 322.1 (M++1).
Reaction SMILES: [N:1]1([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+]>C1COCC1.CO>[N:1]1([C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(-n2cnc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-n2cnc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.1 %

Procedure:
To a solution of (2.3 g, 19.46 mmol) 1H-benzimidazole in DMF (80 mL) at 0° C. was added sodium hydride (0.78 g, 19.46 mol, 60 wt. %) and the reaction mixture was stirred at 0° C. for 30 minutes, then at room temperature for 1 hour. Methyl 4-fluorobenzoate (3.0 g, 19.46 mmol) was then added and the reaction mixture was heated at 85° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with water (300 mL) and extracted with dichloromethane (4×250 mL). The combined organic layers were washed with water (2×250 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:10) provided 3.7 g (76%) of methyl 4-(1H-benzimidazol-1-yl)benzoate as a white solid. To a solution of methyl 4-(1H-benzimidazol-1-yl)benzoate (3.7 g, 14.7 mmol) dissolved in THF/MeOH (1:1, 90 mL) was added 1.0 M aqueous NaOH (0.587 g, 14.67 mmol) and the reaction mixture was allowed to stir for 12 h at room temperature and the solvent removed in vacuo. The residue was diluted with water (100 mL), cooled to 0° C., and the pH was adjusted to 6.0 with 1.0 N aqueous HCl. The resulting precipitate was filtered and dried to afford 3.4 g (96%) of 4-(1H-benzimidazol-1-yl)benzoic acid as a white solid. MS [239.0 m/e (M+H)].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.O>C1COCC1>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(CCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(CCCn2ccnc2)cc1
Temperature: 50 °C
Reaction time: 60 h
Yield: 44.3 %

Procedure:
Imidazole (1.3 g) was dissolved in. THF (15.5 ml), potassium carbonate (5.3 g) was added to the mixture, and a solution of 1-(3-bromopropyl)-4-nitrobenzene (3.1 g) in THF (15.5 ml) was added dropwise to the mixture. The mixture was stirred for 60 hours at 50° C., and cooled to room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 1-[3-(4-nitrophenyl)propyl]imidazole (1.3 g).
Reaction SMILES: [CH3:1][SiH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:1][Si:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=CCCCCCCCC
Reactant: CCCCCCCCCC[SiH2]C
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCCC[Si](C)(CCCCCCCCCC)CCCCCCCCCC
Yield: 80 %

Procedure:
A mixture of 75 grams of methyldecylsilane and 202 grams 1-decene was reacted in the presence of 0.0040 grams of chlorotris(triphenylphosphine)rhodium(I) at 87°-95° C. for one hour. The unreacted decene was stripped off under high vacuum and the residue hydrogenated as above. Distillation gave an 80 percent yield of methyltri(decyl)silane having a boiling point of 230°-233° C. (0.95 mm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=O)=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17][CH:16]=1.[Li+].CC([N-]C(C)C)C>C1COCC1>[NH2:23][C:22]1[C:5]2[C:6](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:7](=[O:9])[C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(OC)cc1
Reactant: COc1ccc(CC#N)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C2=C(N)c3cc(OC)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of methyl 4-methoxybenzoate (1.47 g, 7.47 mmole) and 4-methoxy phenylacetonitrile (1.00 g, 6.79 mmole) in dry THF (15 mL) was slowly added to 20 ml of 2.0 M of LDA at −10° C. The mixture was gradually allowed to warm to room temperature and left to stir overnight. The reaction was quenched with water and most of the THF was removed via vacuum. The crude aminoindenone was then filtered, dried and recrystallized from isopropanol to give a red orange solid (65% yield, m.p. 213° C.); MS m/e 281 (M+)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C@H:25]([OH:47])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:30]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:29]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH2:71]([O:73][C:74](=[O:84])[C@H:75]([CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[NH2:76])[CH3:72]>ClCCl.C(N(CC)CC)C>[CH2:1]([N:8]([CH2:24][C@H:25]([OH:47])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:30]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:29]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:76][C@H:75]([C:74]([O:73][CH2:71][CH3:72])=[O:84])[CH2:77][C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)=[O:20])=[CH:22][CH:23]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)O)cc3)CC2)ccc1OCc1ccccc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
A solution of 0.3 g (0.45 mmol) of trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoic acid (preparation 3), of 0.78 g (0.91 mmol) of 1-hydroxybenzotriazole, of 0.175 g (0.91 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, of 0.19 ml of triethylamine and of 0.165 g (0.91 mmol) of L-phenylalanine ethyl ester hydrochloride in 5 ml of dichloromethane is stirred for 24 h. The solvents are evaporated under reduced pressure. Dichloromethane and water are added and the organic phase is washed three times with water. The organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The product is obtained in the form of a white solid (0.350 g, 92%) after purification on silica gel (eluent: dichloromethane/methanol 100/00 to 90/10 gradient in 35 min). [M+H+]=835