Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH3:11].Cl.[H][H]>CO.[Pd]>[CH2:10]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[F:1])[CH3:11]
Reactant: [H][H]
Reactant: COc1ccc(C(C)=O)c(F)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCc1ccc(OC)cc1F
Temperature: 25 °C
Yield: 66.1 %

Procedure:
To a solution of 1-(2-fluoro-4-methoxyphenyl)ethanone (FMAP) (13.46 g, 80 mmol) in MeOH (100 mL), 37% HCl (7.0 mL, 85 mmol) diluted with MeOH (5 mL) was added, followed by 5% Pd/C (340 mg, 0.4 mol %). The mixture was placed under 3 bar hydrogen at rt until the reaction was complete based on HPLC analysis. The mixture was cooled to room temperature and the catalyst was removed by filtration. The solvent was removed under reduced pressure, and water (100 mL) and petroleum ether were added. The organic layer was cut and washed with water (50 mL) and dried over Na2SO4. The solvent was removed under the reduced pressure. The oily residue was distilled using 8×1 cm distillation column with Raschig rings at 95-97° C. and 45 mbar to yield 1-ethyl-2-fluoro-4-methoxybenzene (MET) as a colorless oil (8.15 g, 66%). 1H NMR (CDCl3) δ 1.19 (t, J=7.6, 3H), 2.60 (q, J=7.6, 2H), 3.77 (s, 3H), 6.52-6.68 (m, 2H), 7.08 (t, J=8.6, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>CS(C)=O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:30])[N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1nnc2ccc(CN3CCOCC3)cc2c1O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: CS(C)=O
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reaction time: 0.25 h
Yield: 39 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-cinnolinecarboxamide [Preparation 12] (200 mg) in dry DMSO (15 mL) is added lithium bis(trimethylsilyl)amide (0.51 mL of a 1 M solution in hexanes). The mixture is stirred for 15 min over which time everything dissolves. Methyl iodide (0.032 mL) is then added and the reaction is stirred for an additional 2 h. The mixture is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc (3×). The combined organic layers are washed with brine, dried and condensed. The crude product is chromatographed on silica (gradient CH2Cl2, 1% MeOH/CH2Cl2, 2% MeOH/CH2Cl2, 3% MeOH/CH2Cl2). Fractions homogeneous by TLC are combined and concentrated. The residue from the column is dissolved in CH2Cl2. Hexanes are added to precipitate the product. The resulting solid is collected and dried to yield 0.079 g (39%) of the title compound as a white solid. Physical characteristics are the same as reported above.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[N:11]([OH:21])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][N:14]=1.C(N(CC)CC)C.Cl.[NH2:30][CH2:31][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)[OH:33]>CN(C)C=O>[Cl:40][C:36]1[CH:35]=[C:34]([CH:32]([OH:33])[CH2:31][NH:30][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:10]2[N:11]([OH:21])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: COc1nccc(I)c1-c1ncc(-c2ccccc2)n1O
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]ccc(NCC(O)c2cccc(Cl)c2)c1-c1ncc(-c2ccccc2)n1O
Temperature: 65 °C
Yield: 26.8 %

Procedure:
2-(4-Iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol (0.020 g, 0.053 mmol) was dissolved in N,N-dimethylformamide (4 mL) and treated with triethylamine (20 μL, 0.159 mmol) and the hydrochloric acid salt of (S)-2-amino-1-[3-chlorophenyl]ethanol (0.017 g, 0.0795 mmol). This mixture was heated at 65° C. for 3 hours, then the solvent was evaporated. The residue was purified by Prep HPLC (ammonium acetate/water/acetonitrile) to give the title material (0.006 g, 27%) as a beige solid. HPLC 87.9% (220 nm), LCMS (+ESI, M+H+) m/z 423; IR ν (cm−1): 2923, 2853, 1637; HRMS calcd for C22H20N4O3Cl (M+H)+=423.1224, found: 423.1221; 1H NMR (400 MHz, methanol-d4) δ (ppm): 3.56 (1H, dd, J=13.2 and 7.0 Hz), 3.69 (1H, dd, J=13.2 and 4.6 Hz), 4.96 (1H, m), 6.36 (1H, d, J=7.4 Hz), 7.22-7.79 (11H, m).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:59])([CH3:58])[CH3:57])[C:53](O)=[O:54])[C:48]1=[O:60])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:58])([CH3:57])[CH3:59])[C:53]([NH:1][C@@H:2]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:8]=2)=[O:54])[C:48]1=[O:60])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
A solution containing the product from Example 1H (0.040 g, 0.075 mmol) in THF (0.6 mL) was treated with the product from Example 70A (0.027 g, 0.092 mmol), DEPBT (0.034 g, 0.114 mmol), and N,N-diisopropylethylamine (0.066 mL, 0.379 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by elution with 0-5% methanol in ethyl acetate to give the title compound (0.045 g, 73% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.87 (s, 9 H), 1.38 (t, J=11.58 Hz, 1 H), 1.54 (m, 1 H), 2.41 (m, 1 H), 2.64 (m, 3 H), 2.87 (m, 3 H), 3.19 (m, 1 H), 3.53 (m, 4 H), 3.84 (d, J=9.56 Hz, 1 H), 3.95 (m, 1 H), 4.04 (s, 1 H), 4.18 (m, 1 H), 4.29 (m, 2 H), 4.45 (d, J=7.35 Hz, 1 H), 6.88 (d, J=9.56 Hz, 1 H), 7.05 (m, 5 H), 7.30 (m, 8 H), 7.53 (d, J=9.56 Hz, 1 H), 7.90 (m, 5 H), 8.65 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[OH-].[Na+].[CH2:12]([CH:14]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH3:13]>O.C(O)C>[CH2:12]([CH:14]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]=[C:2]2[C:3](=[O:9])[CH:4]3[CH2:7][CH2:8][N:1]2[CH2:6][CH2:5]3)=[CH:23][CH:24]=1)[CH3:13]
Reactant: CCCCC(CC)COc1ccc(C=O)cc1
Reactant: O=C1CN2CCC1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCC(CC)COc1ccc(C=C2C(=O)C3CCN2CC3)cc1

Procedure:
A solution of 16.0 g of 3-quinuclidinone (hydrochloride) in 100 ml of water is treated with 100 ml of a 32% sodium hydroxide solution. 36.0 g of 4-(2-ethylhexyloxy)benzaldehyde [can be prepared from p-hydroxybenzaldehyde by reaction with 1-chloro-2-ethylhexane], dissolved in 250 ml of ethanol, is then added with stirring and the mixture is heated under reflux for 3 hours. After the reaction is complete, it is worked up in the customary manner. 2-[4-(2-ethylhexyloxy)benzylidene]quinuclidin-3-one is obtained in the form of a pale yellow solid; m.p. 37°, λmax =331 nm, E=0.8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:8]2([CH3:24])[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[N:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([OH:35])=[C:30](B(O)O)[CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.C(O)(C)(C)C.[Pd]>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]([C@:8]3([CH3:24])[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[N:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[NH:9]3)[CH:5]=[CH:6][CH:7]=2)[C:29]([OH:35])=[CH:28][CH:27]=1
Reactant: CN1C(=O)C[C@@](C)(c2cccc(Br)c2)NC1=NC(=O)OC(C)(C)C
Reactant: OB(O)c1cc(Cl)ccc1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: CN1C(=O)C[C@@](C)(c2cccc(-c3cc(Cl)ccc3O)c2)NC1=NC(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 50 %

Procedure:
A mixture of (S)-tert-butyl 4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF2; R1═R6=Me) (0.25 g, 0.6 mmol), 5-chloro-2-hydroxyphenylboronic acid (R21=5-chloro-2-hydroxyphenyl; 0.2 g, 1.2 mmol, 2 eq), Fibrecat (4.26% of Pd, 0.7 g) and 1N aq. K2CO3 (0.5 mL) in dimethoxyethane (DME, 10 mL) or tert-butanol (10 mL) in a 20 mL Smith process vial equipped with stir a bar was sealed and heated in an Emrys optimizer at 110° C. for 15 min. After cooling, the reaction mixture was transferred to a pre-packed Si-Carbonate column and eluted with MeOH/CH2Cl2 (1:1). The eluant was collected and concentrated under reduced pressure to give 0.32 g of the crude product as an oil. The crude product was purified by silica gel chromatography (20-50% EtOAc/hexanes gradient) to yield 0.13 g (0.3 mmol, 48%) of (S)-tert-butyl 4-(3-(3-chloro-6-hydroxyphenyl)-phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF3; R1═R6=Me, R21=3-chloro-6-hydroxyphenyl) as a white solid. 1HNMR (CDCl3, 300 MHz): δ 7.48-4.32 (m, 2H), 7.20 (m, 3H), 6.84 (m, 2H), 5.68 (br s, 1H), 3.28 (d, J=15.7 Hz, 1H), 3.21 (s, 3H), 2.96 (d, J=15.3 Hz, 1H), 1.68 (s, 3H), 1.53 (s, 9H). MS (ESI): MH+=443.7, 445.7; M+−56=388.0. HPLC Rt (A)=6.99 min.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=1.C>[OH-].[Na+]>[F:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][CH:17]=1)[NH:18][C:1](=[O:8])[C:2](=[O:4])[NH:19]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1ccc(F)cc1N
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2ccc(F)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound (Sarges, R. et al., J. Med. Chem. 33:2240 (1990)) was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (17.4 g, 0.100 mol) and 4-fluoro-1,2-diaminobenzene (1.00 g, 7.93 mmol) was heated to reflux with stirring under N2 for 2 h. The reaction was cooled to room temperature and the solid was collected by vacuum filtration and rinsed with EtOH (50 mL) to give a gray-brown solid which was further dried under vacuum (0.1 torr, 25° C.) to yield 1.06 g (74.4%) which was >98% pure by NMR. An analytically pure sample was prepared by dissolution of 60 mg of the solid in 1.0N NaOH and treatment of this solution with activated charcoal. Filtration of this mixture through a pad of Celite and acidification with 1N HCl gave fine white needles which were collected by vacuum filtration, rinsed with H2O and further dried under vacuum (0.1 torr, 25° C.) to give 25.5 mg of white needles, mp 375°-380° C. (dec) (lit.>300° C. (Sarges, R., et al., J. Med. Chem. 33:2240 (1990)). 1H NMR (d6 -DMSO) δ6.90 (m, 2H, ArH), 7.09 (dd, J=9, J=5.4), 11.9 (s, 1H, NH), 11.96 (s, 1H, NH). EIMS m/z180(100,M+), 152(44), 124(63), 97(43), 28(53). EIHRMS calc. for C8H5FN2N2O2 180.0334, found 180.0337.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[C:11]([CH3:19])=[N:10]2)=[C:4]([F:20])[CH:3]=1.[CH2:21](Br)[C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH2:23][C:22]#[CH:21])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[C:11]([CH3:19])=[N:10]2)=[C:4]([F:20])[CH:3]=1
Reactant: C#CCBr
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1CCCF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2nc(C)n(CCCF)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 61.5 %

Procedure:
A stirred solution of 0.5 g (0.002 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-(3-fluoropropyl)-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 0.43 g (0.004 mole) of propargyl bromide and 0.33 g (0.002 mole) of potassium carbonate in 20 mL of acetone was heated under reflux for 5 hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The residual oil was subjected to column chromatography on silica gel using 4:1 methylene chloride:heptane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure to give 0.42 g of 1-(4-chloro-2-fluoro-5-propargyloxyphenyl)-4-(3-fluoropropyl)-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as an oil.
Reaction SMILES: [OH:1][C@H:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.CCOCC>[Si:17]([O:1][C@H:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)CCCC[C@@H](C)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CCCC[C@@H](C)O[Si](C)(C)C(C)(C)C
Yield: 71.3 %

Procedure:
A solution of alcohol 25 (2.53 g, 15.89 mmol), imidazole (1.9 g, 27.9 mmol), and tert-butyldimethylsilyl chloride (2.4 g, 15.89 mmol) in DMF (32 mL) was stirred at 23° C. After 16 h the reaction was diluted with Et2O and then washed with 1N HCl, saturated aqueous NaHCO3 and brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9:1 hex/EtOAc) afforded 3.11 g (71%) of silyl ether 26 (see scheme 4).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CS(C)=O>[CH2:1]([O:8][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
Benzyl alcohol (2.22 g, 20 mmol) was added to a slurry of hexane-washed NaH (60% oil suspension, 820 mg, 20.5 mmol) in DMSO (20 mL), stirred under nitrogen at 20° C., producing strong gas evolution. After 30 minutes, 1-fluoro-4-nitrobenzene (2.826 g, 20 mmol) was added dropwise to the light grey slurry. The reaction mixture became a bright orange red and quite strongly exothermic, and a lot of gas was evolved. After 2 hours, the reaction mixture was poured onto ice-water (200 mL), and the solid was collected by Buchner filtration, rinsed with water (2×50 mL), and air dried to give 1-benzyloxy-4-nitrobenzene (4.188 g, 91.3%) as canary yellow crystals.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].C(N1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])(OCC)=O>O>[OH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([N:1]2[C:24](=[O:25])[C:23]3[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]2=[O:30])[CH2:3][CH2:4]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Reaction time: 16 h

Procedure:
Trans 4-aminocyclohexanol (25 g, 0.22 mol) dissolved in water (350 mL) was added potassium carbonate (3.0 g, 0.022 mol) and N-carbethoxyphthalimide (47.6 g, 0.22 mol) and the reaction mixture was stirred for 16 hours. The white precipitate was filtered off, washed with water and dried to give 37.7 g (71%) of trans-2-(4-hydroxycyclohexyl)-isoindole-1,3-dione (J. Med. Chem. 1996, 39, 314-322).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[Na].Cl[CH2:8][C:9]1([CH2:13]Cl)[CH2:12][O:11][CH2:10]1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:8][C:9]1([CH2:13][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:12][O:11][CH2:10]1
Reactant: ClCC1(CCl)COC1
Reactant: COCCO
Agent: [Na]
Product: COCCOCC1(COCCOC)COC1
Temperature: 25 °C

Procedure:
To a 5 liter, three-neck flask, fitted with a reflux condenser, a stirrer and a thermometer, were added 1824 g (24 mole) of 2-methoxyethanol followed by 139 g (6 mole) of sodium metal. The flask temperature was then raised to mild reflux and thus maintained until all the sodium had dissolved. At this time, 465 g (3 mole) of 3,3-bis(chloromethyl)oxetane was added and heating was maintained for a further 24 hr. The mixture was then cooled to room temperature and the precipitated sodium chloride was removed by filtration. The filtrate was dissolved in an excess offwater, extracted with four portions of 500 ml methylene chloride, and then the combined organic layers were dried over magnesium sulfate. The solvent was then removed by evaporation and the required monomer isolated by fractional distillation, the fraction boiling at 85° C. and 0.1-mm pressure being collected. Redistillation from calcium hydride yielded 487 g of polymerizable grade monomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[CH:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.I[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][CH:15]=1>C1COCC1.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][Si:22]([C:21]#[C:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]#[C:11][C:5]2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:15][CH:16]=1)([CH3:24])[CH3:25]
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Reactant: C#Cc1cc(OC)cc(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 90.5 %

Procedure:
Into a 100 ml round bottom flask was placed a mixture of 1.31 g (0.0081 mole) of 3.5-dimethoxyphenylacetylene, 2.25 g (0.0075 mole) of 4-iodophenyl-trimethylsilylacetylene, 0.016 g (0.084 mmole) of CuI, 0.155 g (0.22 mmole) of bis(triphenylphosphine)palladium(II) dichloride in 15 ml of THF and 15 ml of triethylamine. The light brown solution turned to a suspension within a minute. After ˜40 min, the reaction mixture turned to an orange solution with some white ppt. The reaction was followed by TLC. The mixture was stirred at room temperature under nitrogen overnight. TLC showed presence of staring material still. The reaction was stirred continuously overnight at room temp. Not much further reaction had occurred. It was then stirred overnight at 50° C. TLC indicated that only a trace of starting material was present. The reaction was then terminated and the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was redissolved in 15 ml of chloroform and the solution was washed two times with water (15 ml each) and dried over anhydrous MgSO4, filtered and concentrated. 2.27 g (90.4% yield) of solid was obtained. 1HNMR: 0.26 ppm (s, 9H); 3.83 ppm (s, 6H); 6.49 ppm (s, 1H); 6.70 ppm (s, 2H); 7.47 ppm (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[O:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[CH:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[O:23][C:15]([CH3:14])=[CH:16][C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1cc2c(o1)CCNC2C
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: Cc1cc2c(o1)CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C
Yield: 10 %

Procedure:
In close analogy to the procedure described in Example 11, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,4-Dimethyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[C:14]([C:18]4[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:23])=[CH:20][CH:19]=4)[NH:15]3)=[CH:11][CH:10]=2)=[O:8])=[CH:4][C:3]=1[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].Br[CH2:41][CH2:42][CH2:43][CH2:44][N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].[F-].[Cs+]>CC#N>[Br:1][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[C:14]([C:18]4[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:23])=[CH:20][CH:19]=4)[N:15]3[CH2:41][CH2:42][CH2:43][CH2:44][N:45]3[C:49](=[O:50])[C:48]4[C:47](=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:46]3=[O:55])=[CH:11][CH:10]=2)=[O:8])=[CH:4][C:3]=1[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)[nH]c3c2)sc1Br
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Yield: 57.4 %

Procedure:
To a stirred solution of 4 (76 mg, 0.13 mmol), N-(4-bromobutyl)-phthalimide (71 mg, 0.25 mmol) in 10 mL CH3CN, CsF (96 mg, 0.63 mmol) was added. The resulting mixture was refluxed for 5 hours and then concentrated in vacuo. MPLC purification (Hex:EtOAc/4:1) of the residue gave 5 as a yellow amorphous solid (60 mg, 69%). 1H NMR (400 MHZ, CDCl3) δ 8.13 (d, J=8.4 Hz, 2H), 7.96 (s, 1H), 7.74-7.35 (m, 14H), 6.62 (s, 1H), 5.39 (s, 2H), 4.30 (t, J=7.2 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 3.66 (s, 2H), 3.49 (t, J=6.8 Hz, 2H), 1.70-1.66 (m, 2H), 1.48-1.45 (m, 2H), and 1.26 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 187.27, 169.94, 168.47, 166.11, 144.12, 143.76, 137.30, 137.13, 136.11, 135.81, 135.11, 134.22, 132.06, 131.88, 131.24, 130.37, 130.20, 129.31, 128.90, 128.61, 128.53, 123.43, 121.63, 120.86, 112.60, 104.17, 67.17, 61.49, 43.90, 37.22, 35.32, 27.38, 25.80, and 14.43.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=S)[NH2:19])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].IC.C([O-])(=O)C.[NH4+:28]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[NH:28])[NH2:19])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(C(N)=S)cc1
Agent: CC(=O)[O-]
Solvent: CI
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCc1ccc(C(=N)N)cc1
Reaction time: 8 h
Yield: 29.4 %

Procedure:
[4-(4-Thiocarbamoylphenyl)butyl]carbamic acid tert-butyl ester (58) (500 mg, 1.6 mmol) and iodomethane (4 mL, 64 mmol) were combined in methylene chloride (8 mL). The solution was stirred at reflux for 3 h, and allowed to stand overnight. The volatiles were removed by evaporation, and the residue was dried under vacuum for 3 h. The resulting crystalline solid was dissolved in ethanol (5 mL), and ammonium acetate (1.1 g, 14.4 mmol) was added. The resulting solution was stirred at reflux for 2 h, and the solvent was evaporated. The residue was taken up in a mixture of methanol and concentrated ammonium hydroxide (20 mL, 10:1), and the solvent was then evaporated. To this residue were added water (20 mL) and concentrated ammonium hydroxide (3 mL). The resulting mixture was stirred for 1 h, cooled in an ice bath, and suction filtered to collect a solid. The solid was dried under vacuum overnight to afford the product 59 (137 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ 1.37 (s, 9H), 1.38 (m, 2H), 1.55 (m, 2H), 2.64 (t, 2H), 2.93 (m, 2H), 6.80 (br s, 1H), 7.35 (d, 2H), 7.70 (d, 2H), 9.62 (br s, 3H).