Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][O:7][C:8]3[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1.[CH3:19][NH2:20]>ClCCl.O1CCCC1>[CH3:19][NH:20][C:16]([C:13]1[CH:14]=[CH:15][C:8]2[O:7][CH2:6][C@H:5]3[CH2:1][CH2:2][CH2:3][N:4]3[C:10](=[O:11])[C:9]=2[CH:12]=1)=[O:17]
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)N1CCC[C@@H]1CO2
Reactant: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)C(=O)N1CCC[C@@H]1CO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (R)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzoxazepine-5-one-7-carboxylic acid chloride (0.330 g; 1.24 mmol), prepared as described in Example 17A, starting from the material described in Example 3I, in dichloromethane (3 ml) was added dropwise to a stirred 10% solution of methylamine in tetrahydrofuran. The mixture was stirred at room temperature for a further 1 h and then evaporated to dryness under reduced pressure. The residue was taken up in dichloromethane (20 mL) and washed with 0.5M HCl (2×20 mL). The dichloromethane layer was dried (MgSO4) and solvent evaporated under reduced pressure. Recrystallisation of the crude product from ethylacetate/diethylether gave the title compound (0.262 g) as a white solid. M.p. 186-189° C.; EIMS: m/z=261.0 [M+H]+
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[NH:15][C:16]=2[C:17](=[O:29])[NH:18][C:19]23[CH2:28][CH:23]4[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]4)[CH2:20]2)[CH2:26]3)[CH:5]=1.[OH-].[Na+].Cl>C(O)C.O>[C:19]12([NH:18][C:17]([C:16]3[NH:15][C:14]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[N:13][C:12]=3[CH2:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:37])=[O:2])=[O:29])[CH2:28][CH:23]3[CH2:22][CH:21]([CH2:27][CH:25]([CH2:24]3)[CH2:26]1)[CH2:20]2
Reactant: COC(=O)c1cccc(CCc2nc(-c3ccccc3C)[nH]c2C(=O)NC23CC4CC(CC(C4)C2)C3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1-c1nc(CCc2cccc(C(=O)O)c2)c(C(=O)NC23CC4CC(CC(C4)C2)C3)[nH]1
Yield: 86.2 %

Procedure:
To a solution of the product of step c (232 mg, 0.65 mmol) in ethanol (13 ml) was added 1M sodium hydroxide (1.3 ml, 1.3 mmol). The solution was refluxed for 2 h, diluted with water (10 ml), then acidified (pH=5, 0.01M HCl). The resulting precipitate was collected by filtration, washed with water and dried to give the title compound (271 mg, 86%). 1H NMR (300 MHz, d6-DMSO) 12.40 (1H, br s), 12.2 (1H, br s), 7.80-7.29 (8H, m), 6.98 (1H, br s), 3.23 (2H, m), 3.00 (2H, m), 2.44 (3H, s) 2.03 (9H, s), 1.65 (6H, s). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 58.98; H, 7.83; N, 7.40% C37H50N4O8.4H2O requires: C, 59.18 H, 7.79; N, 7.46%.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11](CC=C)[C:10]([C:18]#[N:19])=[N:9][C:8]=2[N:7]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]>C1COCC1.CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:18]#[N:19])=[N:9][C:8]=2[N:7]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(C#N)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCCn1c(=O)c2[nH]c(C#N)nc2n(CCCC)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
A solution of 1,3-dibutyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carbonitrile (140 mg, 0.43 mmol) in anhydrous THF (4 ml) and anhydrous DMSO (0.4 ml) was treated with Pd(PPh3)4 (74 mg, 0.064 mmol). The mixture was degassed under gentle vacuum, morpholine (371 uL) added, and left to stir at rt under nitrogen for 4 hours. The yellow solution was partitioned between 2M HCl(aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed down and amino-propyl SPE (5 g), eluting with MeOH followed by 5%→50% AcOH/MeOH. The product eluted with a small impurity which was washed out, after concentrating, with cyclohexane to afford the title compound as an off-white solid (30 mg, 24%). NMR δH (400 MHz, d6-DMSO) 0.89 (app. td, 6H, J=7 and 3 Hz), 1.25-1.35 (m, 4H), 12.48-1.55 (m, 2H), 1.58-1.69 (m, 2H), 3.87 (t, 2H, J=7 Hz), 3.95 (t, 2H, J=7 Hz), NH not observed to δH 15; m/z 290.3 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH2:17][C:18](=[C:22]=[O:23])[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2].[C:26]1([NH2:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:23])[NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=1)[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(C1=CC=CC(=C=O)C1)N2
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)Nc3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.3 %

Procedure:
A mixture of 2-(3-carbonyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (720 mg, 2 mmol), phenylamine (224 mg, 2.4 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.14 g, 3 mmol) in dichloromethane (5 mL) and triethyl-amine (0.7 mL, 5 mmol) was stirred at 25° C. for 12 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.8 g, 93%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C27H28N2O3 (M+H)+: 429.54, observed: 429.1.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]1=[O:25])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]1=[O:25]
Reactant: COc1ccc2ncc(=O)n(CCCCO[Si](C)(C)C(C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2ncc(=O)n(CCCCO)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
1-(4-{[Tert-butyl(dimethyl)silyl]oxy}butyl)-7-methoxyquinoxalin-2(1H)-one (363 mg, 1.0 mmol) was dissolved in tetrahydrofuran (10.9 ml). Tetrabutyl ammonium fluoride (1M tetrahydrofuran solution; 1.1 ml, 1.1 mmol) was added to this solution and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 247 mg (100%) of the title compound in the form of a light yellow syrup.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:19]([C:23]([CH3:29])=[C:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1)=[CH:20][CH2:21][CH3:22].C1([Li])C2CC3C(=CC=CC=3)C=2C=CC=1>C1COCC1.CCCCCC.O>[CH:24]1([C:23]([CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)([CH3:29])[CH2:19][CH2:20][CH:21]=[CH2:22])[CH:28]=[CH:27][CH:26]=[CH:25]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CCC=CC(C)=C1C=CC=C1
Agent: [Li]CCCC
Agent: [Li]c1cccc2c1Cc1ccccc1-2
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(C)(C1C=CC=C1)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution was prepared by dissolving 10 g of fluorene in 100 mL of THF and then this was slowly reacted with 37.6 mL of a 1.6 molar solution of n-butyllithium in hexane. This dark red solution was stirred overnight at room temperature. Then a solution was prepared by combining 8.8 g of 6-(butenyl)-6-methylfulvene with 50 mL of THF. This solution was then added dropwise over a period of one half hour to the solution of the fluorenyl lithium salt. That reaction mixture was stirred overnight at room temperature and then 100 mL of water was added. The organic phase was dried overnight over sodium sulfate and the solvent was evaporated in a vacuum. The yellow residue was dissolved in pentane and filtered using silica gel. The solvent was concentrated by means of evaporation. Crystallization took place at about -18° C. to give 5-(cyclopentadienyl)-5-(9-fluorenyl)-1-hexene in the form of a white solid. This compound is also sometimes referred to as 1-(9-fluorenyl)-1-(cyclopentadienyl)-1-(butene-1) methane.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:4][N:3]1[CH2:13][C:14]([O:16]C)=O.[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][NH2:23])[CH3:19]>>[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][NH:23][C:14](=[O:16])[CH2:13][N:3]1[CH2:4][CH:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][C:2]1=[O:1])[CH3:19]
Reactant: CCN(CC)CCN
Reactant: COC(=O)CN1CC(c2ccccc2)CC1=O
Product: CCN(CC)CCNC(=O)CN1CC(c2ccccc2)CC1=O

Procedure:
From 7.0 g. of methyl 2-oxo-4-phenyl-1-pyrrolidineacetate and 5.0 g of 2-(diethylamino)ethylamine, following the procedure of Example 1, there is obtained N-[2-(diethylamino)ethyl]-2-oxo-4-phenyl-1-pyrrolidineacetamide in pure form as an oil, without need for distillation.
Reaction SMILES: Cl[C:2]([C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:3][C:4]#[N:5].[Se-2:10].[Na+].[Na+].Br[CH2:14][N+:15]([O-:17])=[O:16]>>[NH2:5][C:4]1[CH:3]=[C:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[Se:10][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])CBr
Reactant: CC(C)(C)C(Cl)=CC#N
Reactant: [Se-2]
Agent: [Na+]
Product: CC(C)(C)c1cc(N)c([N+](=O)[O-])[se]1

Procedure:
The reaction of 3-chloro-4,4-dimethylpent-2-enenitrile, sodium selenide and bromonitromethane as described earlier gave the product as a yellow color solid, mp 112-114° C. 1H NMR (400 MHz, DMSO-d6): δ 8.28 (2H, br s), 6.76 (1H, s), 1.28 (9H, s).
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17](=[O:25])[C:16]=1[C:26]#[N:27]>C1(C)C=CC=CC=1>[O:25]=[C:17]1[C:16]([C:26]#[N:27])=[C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[O:8])[CH2:2][CH2:3]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18]1
Reactant: N#Cc1c(Cl)c2ccccc2[nH]c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Solvent: Cc1ccccc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2ccccc2[nH]c1=O
Temperature: 110 °C
Yield: 87.8 %

Procedure:
Piperazine-1-yl-thiophen-2-yl-methanone (8.0 g, 41 mmol) was added to a solution of Compound 115 (4.1 g, 20 mmol) in toluene (50 mL) and heated overnight at 110° C. The solvent was removed under vacuum. The residue was suspended in water, sonicated, and filtered. The crude product was purified by flash chromatography eluting with 0-2% methanol in dichloromethane gradient to yield 6.4 g (88%) of white solids. M.P. 264° C. 1H NMR (DMSO-d6): δ 3.7 (m, 4H), 3.9 (m, 4H), 7.16 (t, J=4.8 Hz, 1H), 7.23 (t, J=5.9 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.49 (d, J=4.0 Hz, 1H), 7.61 (t, J=8.3 Hz, 1H), 7.8 (m, 2H), 11.90 (b, 1H); EIMS: 364 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][C:3]=1[F:11].[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[CH:9]=[CH:10][C:5]2=[CH:4][C:3]=1[F:11]
Reactant: Fc1cc2cc[nH]c2nc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2cc(F)c(Cl)nc21
Temperature: 70 °C
Yield: 28.4 %

Procedure:
To a solution of 6-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (4.15 g, 24.33 mmol) in DMF (50 mL), under a nitrogen atmosphere, is added potassium carbonate (6.73 g, 48.66 mmol), followed by methyl iodide (2.27 mL, 36.49 mmol), and reaction heated to 70° C. for 2 h. The reaction is cooled, poured onto brine (ca. 50 mL) and the product extracted with CHCl3 (ca. 2×30 mL). The combined organic extracts are dried over magnesium sulphate, filtered, and concentrated in vacuo to give a brown solid. This is purified by column chromatography on silica, eluting with 0 to 50% DCM in hexane, to give the title compound as a white solid (1.274 g, 6.90 mmol). MS (m/z): 185/187 (M+1).
Reaction SMILES: CC(C)(O)[C:3]#[N:4].[NH3:7].Cl[CH2:9][CH2:10][CH2:11][C:12](=O)[CH2:13][CH2:14][CH2:15]Cl.[OH-].[Na+]>>[C:3]([C:12]12[CH2:13][CH2:14][CH2:15][N:7]1[CH2:9][CH2:10][CH2:11]2)#[N:4]
Reactant: N
Reactant: CC(C)(O)C#N
Reactant: O=C(CCCCl)CCCCl
Agent: [Na+]
Agent: [OH-]
Product: N#CC12CCCN1CCC2
Temperature: 20 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
To a solution of aceton cyanohydrin (2.3 g, 27 mmol) saturated with ammonia, 1,7-dichloro-4-heptanone (0.50 g, 2.7 mmol) was added dropwise at 20° C. The resulting solution was stirred for 48 hours at 20° C. under ammonia gas atmosphere. To the reaction mixture, 0.1N-NaOH was added to extract with methylene chloride. The extract was dried over anhydrous sodium sulfate, concentrated and distilled in vacuo to afford 0.33 g of the desired compound (Yield: 89%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]1([CH2:13][CH2:14][NH2:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1>C(Cl)Cl>[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]=1[CH2:13][CH2:14][NH:15][CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: NCCC1=CCCCC1
Reactant: COC(=O)CBr
Solvent: ClCCl
Product: COC(=O)CNCCC1=CCCCC1
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a solution of methyl bromoacetate (5 g, 32.7 mmol) in DCM (150 mL) was added 2-(1-cyclohexenyl)ethylamine (11.4 ml, 81.71 mmol) over 5 min. After 2 h, the solvent was removed and the residue purified on silica gel (Merck 60; (1:9) ethyl acetate/hexane) to afford methyl 2-[N-(2-cyclohex-1-enyl)ethylamino]acetate (5.0 g, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[CH:22]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:27]N1C(=O)CCC1=O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[Br:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4cc(C)no4)cc3)cc2)CC1
Solvent: CC(=O)O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Br)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[4′-(3-Methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (1.00 g, 2.88 mmol) was dissolved in acetic acid (12 mL) and N-bromosuccinimide (0.563 g, 3.2 mmol) was added. After stirring at room temperature for 1 hour, the reaction mixture was submitted to standard aqueous workup to give the title compound, which was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:7]=1[O:8][CH:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH3:10]>C(OC(=O)C)C>[Cl:5][C:6]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:7]=1[O:8][CH:9]([C:11]1[S:15][C:14]([N:16]=[C:1]=[O:2])=[N:13][N:12]=1)[CH3:10]
Reactant: O=C(Cl)Cl
Reactant: CC(Oc1ccc(Cl)cc1Cl)c1nnc(N)s1
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(Cl)cc1Cl)c1nnc(N=C=O)s1
Reaction time: 17 h

Procedure:
A 500 milliliter, neck flask equipped with a magnetic stirrer, thermometer, dry ice condenser/drying tube and inlet from a phosgene (COCl2) tank via a calibrated rotameter was charged with 50 milliliters of ethyl acetate saturated with phosgene at 20° C. (approximately 0.5 mole of phosgene). An additional 100 milliliters of ethylacetate was added and 10.0 grams of 5-[1-(2,4-dichlorophenoxy)ethyl]-2-amino-1,3,4-thiadiazole, (prepared above) was added. The resulting emulsion was stirred for 17 hours; and the flask was purged with nitrogen until no COCl2 was detected and a suspension formed. The solid was removed by filtration and dried in a vacuum oven at 80° C. to 5.9 grams of white crystals of 5-[1-(2,4-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer. (Melting point 176°-179° C.).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:45]3[CH2:46][CH2:47][N:42]([CH2:41][CH2:40][O:39][CH3:38])[CH2:43][CH2:44]3)=[O:36])[C@@:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCCN1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCOC)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-(2-methoxy-ethyl)-piperazine (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C35H45N6O3Cl2 [(M+H)+] 667.2925, observed 667.2919.
Reaction SMILES: O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][SH:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].Br[N:25]1[C:29](=[O:30])[CH2:28][CH2:27][C:26]1=[O:31]>CO>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][S:21][N:25]2[C:29](=[O:30])[CH2:28][CH2:27][C:26]2=[O:31])=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccc(CS)cc1
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: O
Solvent: CO
Product: O=C1CCC(=O)N1SCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
Lead (II) acetate trihydrate (0.759 g, 2.0 mmol) and 4-nitrobenzyl mercaptan (0.745 g, 4.4 mmol) were stirred together in methanol (24 cm3) solution at room temperature. After 1 h, the products were filtered and the residue was washed with a small volume of cold methanol. The residue was dried in vacuo over calcium chloride and then suspended in dry acetonitrile (20 cm3). Following the evaporation of the solvent under reduced pressure, the residue was suspended in dry benzene (20 cm3) and the solvent was again evaporated under reduced pressure. Finally, the residue was re-suspended in dry benzene (64 cm3) and N-bromosuccinimide (0.783 g, 4.4 mmol) was added in three portions over a period of 45 min to the stirred suspension at room temperature. The reactants were then heated at 50° C., under an atmosphere of argon, for 14 h. The cooled products were filtered and the filtrate was evaporated under reduced pressure to give a solid. The latter material was crystallized from ethyl acetate--hexane to give N-(4-nitrobenzylmercapto)succinimide 18 (0.76 g, 65%) (Found: C, 49.85; H, 3.8; N, 10.4. C11H10N2O4S requires: C, 49.6; H, 3.8; N, 10.5%), m.p. 146°-148° C.; δH [CDCl3 ] 2.73 (4 H, s), 4.18 (2 H, s), 7.50 (2 H, m), 8.17 (2 H, m); δC [CDCl3 ] 28.4, 40.5, 123.8, 130.3, 141.9, 147.5, 176.2.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11]=O)=[N:7][O:8][C:4]=2[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[NH2:27])=[CH:22][CH:21]=1.S([O-])([O-])(=O)=O.[Mg+2]>ClCCl>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3/[CH:11]=[N:27]/[CH:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=Cc1ccccc1-c1noc2cc(Br)ccc12
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: Fc1ccc(C(/N=C/c2ccccc2-c2noc3cc(Br)ccc23)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a stirred solution of 2-(6-bromobenzo[d]isoxazol-3-yl)benzaldehyde (compound 7) (2 g) in dichloromethane (33 mL) was added bis(4-fluorophenyl)methanamine (1.74 g) and anhydrous magnesium sulfate and stirred under nitrogen at room temperature for 18 h. Filtration and evaporation of the filtrate and crystallisation from dichloromethane-methanol gave the title compound (2.4 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([OH:29])[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2].[CH3:32][CH:33]([CH3:36])[CH2:34]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:32][CH:33]([CH3:36])[CH3:34])[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#CCN3CCOCC3)c2)cc1C
Reactant: CC(C)CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C
Reaction time: 16 h

Procedure:
{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methylphenoxy}-acetic acid ethyl ester (250 mg; 0.57 mmol), 2-methyl-propan-1-ol (0.078 mL; 0.85 mmol) and tributylphosphine (0.31 mL; 1.25 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (0.31 g; 1.25 mmol) was dissolved in THF (10 mL) and added to the reaction mixture. After stirring for 16 h the reaction mixture was evaporated to dryness and purified by prep. HPLC (method B). Yield: 200 mg. HPLC-MS: m/z: 498.1 (M+); Rt: 2.03 min
Reaction SMILES: [H-].[Na+].[CH3:3][C@H:4]1[CH2:9][C@@H:8]([OH:10])[C@H:7]([CH:11]([CH3:13])[CH3:12])[CH2:6][CH2:5]1.[C:14](#[N:17])[CH:15]=[CH2:16].C(O)(=O)C>ClCCl.O>[CH3:3][C@@H:4]1[CH2:5][CH2:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C@H:8]([O:10][CH:15]([CH3:16])[C:14]#[N:17])[CH2:9]1
Reactant: C=CC#N
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CC(C#N)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1 g of a sodium hydride suspension (50% strength) in paraffin oil was added at a temperature of 0° C. to a solution of 30 g of L-menthol in 300 ml of dichloromethane. A solution of 12.5 ml acrylonitrile in 50 ml dichloromethane was slowly added dropwise, and the reaction mixture was then stirred at room temperature for a further 5 hours. The reaction mixture was worked up by cautiously adding 10 ml of glacial acetic acid, followed by 200 ml of water, and then extracting the mixture with dichloromethane. The dichloromethane extract was dried over sodium sulfate, filtered and concentrated. After chromatographic purification of the residue on silica gel using n-hexane/dichloromethane as the eluent, 25.03 g of crude 2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)propionitrile were obtained and used for the next reaction step without further purification.