Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]=O.[CH2:9]([N:13]([CH2:35][CH2:36][CH2:37][CH3:38])[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:25])[CH:23]=2)[N:18]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]=1[CH3:34])=[O:15])[CH2:10][CH2:11][CH3:12]>C(O)(=O)C>[CH2:35]([N:13]([CH2:9][CH2:10][CH2:11][CH3:12])[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:25])[C:23]=2[CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:18]([CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:17]=1[CH3:34])=[O:15])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN(CCCC)C(=O)c1c(C)n(CCc2ccccc2)c2ccc(O)cc12
Reactant: C=O
Reactant: C1CCNCC1
Solvent: CC(=O)O
Product: CCCCN(CCCC)C(=O)c1c(C)n(CCc2ccccc2)c2ccc(O)c(CN3CCCCC3)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
Piperidine (11 g) and 11 g of 37% formalin were added to a solution of 44 g of N,N-dibutyl-5-hydroxy-2-methyl-1-(2-phenylethyl)indole-3-carboxamide in 20 m of acetic acid, and the mixture was stirred at 60° C. for 2 hours. The acetic acid was distilled off under reduced pressure. Water was added to the residue, which was made alkaline with potassium carbonate, followed by extraction with ethyl acetate. After the organic layer was washed with water and dried, the solvent was distilled off. Hexane was added to the residue to separate crystals. The crystals were collected by filtration and recrystallized from isopropyl ether to give 31 g of the titled compound as white crystals, m.p. 105°-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:32]2)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:34]=[C:33]4[C:29]([CH:30]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:32]4)=[CH:28][CH:27]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CCOC(=O)c1cc2ccc(N)cc2[nH]1
Product: CCOC(=O)c1cc2ccc(NC(=O)C(CC)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)cc2[nH]1

Procedure:
87 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 56 mg (0.28 mmol, 1.1 eq.) of ethyl 6-amino-1H-indole-2-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 75 mg (55% of theory)
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:21]=[CH:20][C:14]3[S:15](=[O:19])(=[O:18])[CH:16]=[CH:17][C:13]=3[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:21]=[CH:20][C:14]3[S:15](=[O:19])(=[O:18])[CH:16]=[CH:17][C:13]=3[CH:12]=2)[C:8]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)c1ccc2c(c1)C=CS2(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)c2ccc3c(c2)C=CS3(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43.2 %

Procedure:
A solution of 3-cyclopentyl-2-(1,1-dioxo-benzo[b]thiophen-5-yl)-propionic acid (36 mg, 0.12 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 67 μL, 0.14 mmol) which produced gas evolution and it was stirred at 0° C. for 10 min and it was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was concentrated in vacuo to ˜1.5 mL. In a separate flask, a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 20 mg, 0.13 mmol), 2,6-lutidine (20 μL, 0.18 mmol) and methylene chloride (5 mL) was cooled to 0° C. in an ice bath. To this solution was added the solution of the prepared acid chloride, diluted with another portion of methylene chloride (1 mL), dropwise. After addition was complete the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction mixture quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and transferred to a separatory funnel where it was extracted with methylene chloride (3×10 mL). The organic layers were then washed with a 1 N aqueous hydrochloric acid solution (20 mL) and then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 50% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(1,1-dioxo-benzo[b]thiophen-5-yl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (23 mg, 43%) as an off-white foam (as a racemic mixture): ES-HRMS m/e calcd for C23H29N3O4S (M+H)+ 444.1952, observed 444.1949; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (s, 3 H, CH3), 1.05 (s, 3H, CH3), 1.11 (m, 2H, CH2), 1.37-1.78 (m, 8H, 4×CH2), 2.06 m, 1 H, CH), 3.87 (s, 2H, NCH2), 3.93 (t, J=7.5 Hz, 1H, ArCHCO), 4.64 (s, 1H, OH), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.35 (d, J=6.9 Hz, 1H, Ar), 7.51 (d, J=2.1 Hz, 1H, Ar), 7.58 (dd, Jo=7.8 Hz, Jm=1.3 Hz, 1H, Ar), 7.61 (d, Jm=1.3 Hz, 1H, Ar), 7.67 (d, J=6.9 Hz, 1H, Ar), 7.79 (d, Jo=7.8 Hz, 1H, Ar), 10.78 (s, 1H, NH).
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CS(C)=O.[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])(=O)=O>O>[CH2:25]([CH:20]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19][O:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)[CH3:26]
Reactant: OCC1=CCCCC1
Reactant: CCCCC(CC)COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(CC)COCC1C=CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 500 mL round bottom flask equipped with a mechanical stirrer was charged with 33.6g (0.30 mol) cyclohexene-1-methanol, and 260 mL of DMSO. Sodium hydride (8.43 g, 95% in purity; 0.334 mol) was slowly added to above mixture in ice bath over 40 min. After the above mixture was reacted at room temperature for 2 hrs, the reaction mixture was warmed to room temperature. 2-Ethylhexyl tosylate (85.2 g, 0.30 mol) was slowly added to the above mixture over 15 min. The reaction was carried out for another 1 hr at room temperature, then 60° C. for 2 hrs. The reaction mixture was added to water (200 mL), and then extracted with chloroform (3×180 mL), washed with water (2×100 mL). The organic layer was evaporated and the residue distilled to give pure product.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H].[Cl:13][C:14]1[C:18](Cl)=[N:17][S:16][N:15]=1>O1CCCC1>[CH2:3]([O:10][C:18]1[C:14]([Cl:13])=[N:15][S:16][N:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: [H][H]
Reactant: Clc1nsnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nsnc1OCc1ccccc1
Temperature: -50 °C
Yield: 24.2 %

Procedure:
To a mixture of 24 g of sodium hydride and 500 ml of tetrahydrofuran, 65 g of benzyl alcohol was added dropwise at room temperature. The mixture was stirred until the evolution of hydrogen stopped, cooled to −50° C., then, 100 g of 3,4-dichloro-1,2,5-thiadiazole was added to the mixture. The mixture was stirred over night at room temperature, and for 3 hours at reflux temperature. The mixture was concentrated, then poured into dilute hydrochloric acid, extracted with t-butyl methyl ether. The organic layer was washed with water, then, saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 33 g of 4-benzyloxy-3-chloro-1,2,5-thiadiazole (purity: 72%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[NH2:16]>C(OCC)(=O)C>[CH3:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(Nc2cc(O)ccc2[N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
5.4 g of 3-fluoro-4-nitrophenol and 4.3 ml of 3,5-dimethylaniline were mixed and stirred for 6 hours at 120° C. After cooling, it was taken up in ethyl acetate and water and extracted three times with 1N aqueous hydrochloric acid. The combined aqueous phases were extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was crystallized.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[NH:26][C:27](=[O:35])[C:28]2[CH:33]=[C:32]([CH3:34])[S:31][C:29]=2[N:30]=1.[H-].[Na+]>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:24][C:25]4[NH:26][C:27](=[O:35])[CH:28]5[CH:33]=[C:32]([CH3:34])[S:31][CH:29]5[N:30]=4)[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1
Reactant: Cc1cc2c(=O)[nH]c(CCl)nc2s1
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC4=NC5SC(C)=CC5C(=O)N4)C3=O)CC2)cc1
Temperature: 70 °C
Yield: 88.5 %

Procedure:
To a solution of 3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (0.165 mmol, 50 mg) and 2-chloromethyl-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one (0.165 mmol, 33 mg) in THF (2 mL) was added sodium hydride (60%, 0.331 mmol, 23 mg) and heated to 70° C. for 1 hour. The reaction was allowed to cool to ambient temperature, diluted with 10 mL of ether, and the resulting solid in suspension was filtered and dried under vacuum provided the title compound as an off-white solid (70.5 mg, 95.4% yield). HRMS calculated for C25H28N4O4S 480.5903. found (ESI, [M+H]+) 481.1907. 1H NMR (400 MHz, MeOD) δ ppm 1.66-1.93 (m, 4H) 2.05-2.30 (m, 2H) 2.51-2.63 (m, 1H) 2.79-2.90 (m, 1H) 2.90-2.98 (m, 1H) 3.03-3.18 (m, 1H) 3.33-3.54 (m, 4H) 3.65-3.75 (m, 1H) 3.87 (s, 3H) 4.20-4.31 (m, 1H) 4.51-4.62 (m, 1H) 6.94-7.06 (m, 3H) 7.98 (d, J=9.03 Hz, 2H), analytical RP-HPLC retention time=3.22 min
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:35]=[O:36].O>O1CCCC1>[C:8]1([N:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([CH:35]=[O:36])=[CH:3][CH:4]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(CN(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=Cc1ccc(CN(c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
In an argon atmosphere, the thus obtained N-(4-bromobenzyl)diphenylamine (440 mg, 1.30 mmol) was dissolved in tetrahydrofuran (6 mL) and cooled to −78° C. A 1.6 M n-butyl lithium hexane solution (1.3 mL, 2.0 mmol) was added thereto, and, 5 minutes thereafter, dimethylformamide (0.20 mL, 2.6 mmol) was further added thereto, followed by stirring for 5 minutes. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (9:1 hexane/ethyl acetate) to obtain 4-(N,N-diphenylaminomethyl)benzaldehyde (213 mg, 57%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:42]=[CH:41][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28]([C:37](OC)=[O:38])=[CH:27]2)=[CH:23][CH:22]=1.C(OCC)C.O1CCCC1>O>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:42]=[CH:41][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:28]([CH2:37][OH:38])=[CH:27]2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)c(-c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
Lithium aluminium hydride (232 mg) was added to a mixture of methyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenylpyrrole-3-carboxylate (2.92 g), diethyl ether (50 ml), and tetrahydrofuran (25 ml) at 0° C., and the mixture was stirred at 0° C. for 3 hours. After water was added to the reaction mixture, the precipitate was removed by filtration. The filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]methanol (2.37 g, yield: 86%) was obtained as a colorless amorphous substance from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8](=[O:27])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([C:24](O)=[O:25])C=CN=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[S:30]1[C:39]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34][C:33]=2[N:32]=[CH:31]1.CCN(C(C)C)C(C)C.C[N:50]([C:52](ON1N=NC2C=CC=CC1=2)=[N+:53](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8](=[O:27])[N:9]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]4[CH:23]=[C:22]([C:24]([N:36]5[CH2:37][CH2:38][C:39]6[S:30][CH:31]=[N:32][C:33]=6[CH2:34][CH2:35]5)=[O:25])[N:53]=[CH:52][N:50]=4)[CH2:16][CH2:17]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ccn3)CC1)C(=O)N2
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: c1nc2c(s1)CCNCC2
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5ncsc5CC4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
83 mg (0.21 mmol) 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylic acid and 37 mg (0.24 mmol) 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine in 0.13 mL (0.72 mmol) DIPEA and 1.0 mL DMF were combined with 77 mg (0.24 mmol) TBTU and the mixture was stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCC([O:13][C:14](=[O:17])[CH2:15][Cl:16])=O>C(Cl)(Cl)(Cl)Cl>[Cl:16][CH2:15][C:14]([O:8][CH:1]([O:17][C:14](=[O:13])[CH2:15][Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: O=C(CCl)OC(=O)CCl
Reactant: O=Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CCl)OC(OC(=O)CCl)c1ccccc1
Temperature: 35 °C

Procedure:
Benzaldehyde (10.0 g, 0.094 mol) and chloroacetic acid anhydride (16.1 g, 0.094 mol) were dissolved in carbontetrachloride (50 ml) under N2 atmosphere. Nafion NR 50 (240 mg) was added and the reaction mixture stirred at 35° C. over night. An additional amount of benzaldehyde (5.0 g) and catalyst (120 mg) was added and the reaction continued for several days. The catalyst was filtered off and the filtrate evaporated. The residue was distilled under reduced pressure (B.p. 123-125° C./0.1 mbar) giving a slightly yellow oil, which solidified upon standing. The yield was 7.9 g, 30% of the theoretical. 1H NMR (CDCl3), d (ppm) rel. to TMS: 7.75 (s, 1H, CH(OCO--)2), 7.57-7.41 (m, 2+3H, Ar-H) and 4.14 (d, 4H CH2Cl).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13](I)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].I[C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25]N(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:23]2>>[F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([C:23]#[C:22][CH2:21][CH2:20][CH2:28][CH2:27][CH2:26][CH3:25])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2ccc(I)cc2CC1)C(F)(F)F
Reactant: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CCCCCCC#Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Yield: 73 %

Procedure:
When the product of Step B was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 73% yield, as a pale oil. 1H-NMR (CDCl3) 0.9 (tr, 3H), 1.28-1.33 (m, 10H); 1.42-1.46 (m, 2H); 2.88-2.96 (m, 4H); 3.64-3.67 (m, 2H); 3.71-3.75 (m, 2H); 7.05 (tr, 1H, J=7.92 Hz), 7.13-7.2 (m, 2H).
Reaction SMILES: [N:1]#[C:2][NH2:3].CC(C)([O-])C.[K+].[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[CH:26][CH:25]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].Br[CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=1)=[O:36]>C(#N)C.C(O)(C)(C)C.O>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]2[S:32][C:34]([C:35](=[O:36])[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=3)=[C:2]([NH2:3])[N:1]=2)=[CH:26][CH:25]=1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(N=C=S)cc1
Reactant: N#CN
Reactant: O=C(CBr)c1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Nc2nc(N)c(C(=O)c3cccc(F)c3)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyanamide (46.2 mg, 1.1 mmol) was suspended in acetonitrile (5 mL). To the stirred suspension, potassium tert-butoxide (123 mg, 1.1 mmol) in 2 mL of tert-butanol was added followed by isothiocyanate (Example 1, 334 mg, 1 mmol). The mixture was stirred for 30 minutes at room temperature followed by the addition of 2-bromo-1-(3-fluoro-phenyl)-ethanone (TCI, 261 mg, 1 mmol). After being stirred for 2 hours at room temperature, the mixture was poured into water and the new mixture was extracted with ether. The extract was dried(Na2SO4) and concentrated to give the desired product as a yellow solid, 510 mg, 99%. MS (ES) MH+=513.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.[H-].[Na+].[CH2:21](I)[CH3:22].CN(C=O)C.[CH2:29]1COC[CH2:30]1>O>[CH2:29]([O:9][C:8](=[O:10])[C:7]([C:4]1[CH:5]=[CH:6][C:1]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:2][CH:3]=1)([O:12][CH2:21][CH3:22])[CH3:11])[CH3:30]
Reactant: C1CCOC1
Reactant: CC(O)(C(=O)O)c1ccc(-c2ccccc2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(OCC)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-biphenyl-4-yl-2-hydroxy-propionic acid (CAS-6244-54-8, 943 mg) in THF (10 ml), stirred at 0° C. was added NaH (60% in mineral oil, 342 mg). After 50 min, ethyl iodide (0.69 ml) was added and the mixture was stirred at rt for 14 h. DMF (10 ml) was added. After 2 days, 47 mg NaH and 0.16 ml ethyl iodide were added subsequently. In the course of three weeks, a total of 653 mg NaH and 1.32 ml ethyl iodide were added. Water was added and the mixture was extracted with EtOAc (2×). The organic phase was washed with water, dried, filtered and evaporated. The crude product was purified by flash chromatography (EtOAc/cyclohexane 5:95=>1:4) to give (RS)-2-biphenyl-4-yl-2-ethoxy-propionic acid ethyl ester (276 mg) as a light yellow oil. MS 298.1 ([M]+)
Reaction SMILES: O.[NH2:2][NH2:3].Br[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11]>C(O)C>[CH3:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:2][NH2:3]
Reactant: NN
Reactant: COCCOCCBr
Solvent: CCO
Solvent: O
Product: COCCOCCNN
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.7 %

Procedure:
To a solution of hydrazine monohydrate (44.0 mL, 1.00 mol) in ethanol (75 mL) at 0° C. in an ice-water bath was added 1-(2-bromoethoxy)-2-methoxyethane (13.6 mL, 0.100 mol) drop-wise over 20 minutes. The reaction was then allowed to warm to room temperature and stir for 5 minutes and then heated to 40° C. in a preheated oil bath for 12 hours. The reaction was then cooled to room temperature and concentrated to remove the ethanol. The remaining aqueous layer was extracted with methylene chloride (2×100 mL) and diethyl ether (2×100 mL). The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated to provide [2-(2-methoxyethoxy)-ethyl]-hydrazine as a light yellow oil (10.29 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(CCN)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)Cc1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
8.3 g 4-Chlorobenzoyl chloride are added dropwise at 5°-10° C., within the course of 10 minutes, to a solution of 11.0 g ethyl 4-(2-aminoethyl)-phenylacetate in 90 ml anhydrous pyridine. The reaction mixture is then stirred for 90 minutes at 10° C., subsequently allowed to warm up to 20° C. and thereafter warmed to 40°-45° C. for 30 minutes. The reaction mixture is then cooled and stirred into 900 ml ice water, a solid precipitate thereby being obtained. This is filtered off with suction and washed with water. There are obtained 14.5 g (94% of theory) of crude product which is recrystallized from isopropanol to give 10.9 g (70% of theory) ethyl 4-[2-(4-chlorobenzamido)-ethyl]-phenylacetate; m.p. 118°-119° C.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23](I)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg+].[Br-].[CH2:29]([C:31]1[S:32][CH:33]=[CH:34][C:35]=1[CH:36]=[O:37])[CH3:30]>C(Cl)Cl.C(OCC)C.ClCl>[CH2:29]([C:31]1[S:32][CH:33]=[CH:34][C:35]=1[CH:36]([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)[OH:37])[CH3:30]
Reactant: CCc1sccc1C=O
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C[Mg+]
Agent: ClCl
Agent: [Br-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCc1sccc1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 3 h

Procedure:
To a solution of N-trityl-4-iodo-imidazole (4.1 g, 0.0095 mol) in dry CH2Cl2 (75 mL) was added a solution of MeMgBr (4.0 mL, 3.0M) in diethyl ether and the solution was stirred for 3 hrs. Then a solution of 2-ethylthiophene-3-carboxaldehyde, B7, (1.66 g, 0.0087 mol) in CH2 Cl2 (20 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with aqueous NH4Cl and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with a second portion of CH2Cl2. The extracts were combined and washed with a small portion of water, dried (Na2 SO4), and filtered. The solvent was evaporated in vacuo, and the residue was triturated with Et2O to give (2-ethylthien-3-yl)-1-trityl-imidazol-4-yl-methanol, C7, as a beige solid which was taken on to the next step directly. ##STR56##