Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:20])[CH3:4].CCN(CC)CC.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:1][CH2:2][CH:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:17])[F:18])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:20])[CH3:4])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
To a solution of 1-(1-hydroxypropan-2-yl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 7) (0.110 g, 0.390 mmol) and Et3N (0.068 mL, 0.487 mmol) in CH2Cl2 (4 mL) was added methanesulfonyl chloride (0.038 mL, 0.487 mmol) dropwise. After stirring at rt for 2 h, the reaction mixture was concentrated to dryness. The residue was partitioned between EtOAc (30 mL) and 0.2N HCl (15 mL). The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using a 25-60% EtOAc-hexane gradient to give 2-(5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl)propyl methanesulfonate (0.145 g, 97% yield) as a colorless oil: MS (ESI): m/z 361 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:27]([C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([OH:33])=O)=[O:28])[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]2=[O:26])[CH2:12][CH2:11]1)([O-:3])=[O:2].C(N1C=CN=C1)([N:40]1C=CN=C1)=O.N>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([C:27]([C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([NH2:40])=[O:33])=[O:28])[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:11][CH2:12][CH:13]([N:16]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]2=[O:26])[CH2:14][CH2:15]1)([O-:3])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c([N+](=O)[O-])c1
Agent: N
Solvent: ClCCl
Product: NC(=O)c1ccccc1C(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A solution of the product from example 1 (0.9 g) and carbonyldiimidazole (1.1 equiv.) in dichloromethane (4 ml) was stirred at room temperature for 1 h, poured onto aqueous ammonia and stirred for a further 1 h. The mixture was extracted with ethyl acetate, the organics washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluting with 2.5% methanol/dichloromethane. Yield 0.01 g as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]2[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[C:4]2=[N:5][N:6]=1.[Li+].[OH-]>C1COCC1.O.CO>[CH3:1][C:2]1[N:3]2[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[C:4]2=[N:5][N:6]=1
Reactant: CCOC(=O)C1CCn2c(C)nnc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nnc2n1CCC2C(=O)O
Temperature: 60 °C

Procedure:
To a solution of ethyl 3-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]-triazole-7-carboxylate (400 mg, 2.05 mmol) from step A in THF/water/MeOH was added LiOH (250 mg, 10.3 mmol) and the resulting solution was heated to 60° C. for 16 h. The solution was cooled to room temperature and concentrated to remove organic solvents. The aqueous layer was then acidified to pH of ˜5 using 2N HCl. The mixture was concentrated to dryness under vacuum, azeotroping with toluene (2×20 mL) to make sure all water was removed. The material was used without further purification with lithium chloride as a by-product. LC-MS: m/z (ES)=168 (MH)+.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:20][CH2:21][CH2:22][OH:23])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCBr
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCCCO
Product: OCCCN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
40 g of 4,4-diphenylpiperidine, 24.7 g of 3-bromopropanol, 116.4 g of powdered potassium carbonate and about 1 g of potassium iodide are heated at the boiling point under reflux and with vigorous stirring in 500 ml of a 1:1 mixture of dioxane and 1-butanol for about 48 hours. After cooling, the mixture is filtered and the filtrate is concentrated. The oily residue is taken up in ethyl acetate, and the solution is filtered again. After the filtrate has been concentrated to dryness, the title product is obtained as a yellowish oily residue which slowly solidifies as a wax. Yield: 44.8 g. With ethereal hydrochloric acid, the hydrochloride is obtained, and is recrystallized from 2-propanol. m.p.: 226°-227° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][C:30]([F:32])([F:31])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([CH:25]=O)=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:9][CH2:8]3.Cl.[NH2:34][OH:35].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][C:30]([F:31])([F:32])[C:4]=2[CH:3]=1)[CH2:8][CH2:9][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([CH:25]=[N:34][OH:35])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:11][CH2:12]3
Reactant: Cc1nn(-c2ncccc2C=O)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(-c2ncccc2C=NO)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Yield: 50.8 %

Procedure:
To a solution of 2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carbaldehyde (0.210 g, 0.438 mmol) in ethanol (3 mL) are added hydroxylamine hydrochloride (0.038 g, 0.526 mmol) and sodium ethanoate (0.044 g, 0.526 mmol) and the mixture is stirred at reflux for 1 h. The solvent is evaporated and the residue is extracted with ethyl acetate and water. The organic layer is separated, dried over magnesium sulfate, filtered and the solvent is evaporated in vacuo. The residue is purified by basic reverse phase HPLC to yield 0.110 g of 2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carbaldehyde oxime. MS (m/z): 494 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:27]=[C:11]3[N:12]=[C:13]([CH3:26])[C:14]([C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22])=[C:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.[B]1OC2C(=CC=CC=2)O1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:27]=[C:11]3[N:12]=[C:13]([CH3:26])[C:14]([C@H:20]([OH:25])[C:21]([O:23][CH3:24])=[O:22])=[C:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1CC(C)C
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [B]1Oc2ccccc2O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1CC(C)C
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a stirred solution of methyl 2-(2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (0.077 g, 0.170 mmol) in toluene (3 mL) was added 1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (0.034 ml, 0.034 mmol) at rt and cooled to −35° C. To this was added dropwise 1M catecholborane/THF (0.237 ml, 0.237 mmol) over 10 min. After stirring 30 min, the reaction mixture was slowly warm to −15° C. over 30 min and diluted with EtOAc (15 mL). Then, the mixture was vigorously stirred with sat Na2CO3 (2 mL) for 45 min. The aqueous layer separated and organic layer washed with sat sat Na2CO3 (2×5 mL), dried (Na2SO4), filtered, concentrated and the resulting yellow residue purified by prep-HPLC to afford (S)-methyl 2-(2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (0.0592 g, 0.153 mmol, 90% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ: 7.98 (t, J=1.7 Hz, 1H), 7.85 (dt, J=7.3, 1.5 Hz, 1H), 7.40-7.32 (m, 2H), 6.80 (s, 1H), 5.52 (s, 1H), 3.81 (s, 3H), 3.66 (br. s., 1H), 3.34-3.23 (m, 2H), 2.51 (s, 3H), 2.43 (dt, J=13.6, 6.9 Hz, 1H), 1.05 (d, J=6.7 Hz, 6H). LCMS (M+H) calcd for C20H23ClN3O3: 388.14. found: 388.3.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:18](=[N:19][OH:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2].[C:21](Cl)(=[O:23])[CH3:22].O>N1C=CC=CC=1>[C:1]([C:3]1[N:4]=[C:5]2[C:18](=[N:19][O:20][C:21](=[O:23])[CH3:22])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2]
Reactant: CC(=O)Cl
Reactant: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=NO
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)ON=C1c2ccccc2-c2nc(C(N)=O)c(C#N)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.7 %

Procedure:
To a solution of 33 (1.0 g, 3.77 mmol) in dry pyridine (30 ml) cooled at 0° C., acetyl chloride (0.8 ml, 11.3 mmol) was added dropwise and the mixture was stirred 16 h at room temperature. Water (40 ml) was added and the precipitate was collected by filtration. The crude was purified by flash chromatography (CH2Cl2/acetone/MeOH 8:2:0.5) and triturated with Et2O/CH2Cl2/MeOH, affording 35 (251 mg, 21%) as yellow solid as single isomer. 1H NMR (300 MHz, DMSO d6): δ 8.12 (d, 1H), 7.91 (m, 2H), 7.77 (ddd, 1H), 7.43 (bs, 2H), 2.27 (s, 3H). ESI+MS: calcd for C15H9N5O3: 307.27; found: 308.1 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=2)=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1)[CH3:23]
Reactant: CCc1ccc(O)c(Oc2ccccc2)c1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Product: CCc1ccc(Oc2cccc(Oc3ccc(CCC(=O)O)c(C)c3)c2)c(Oc2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-ethyl-2-phenoxy-phenol as in Example 18 to afford 0.200 g (35%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C30H28O5 468, found 469 (M+1, 100%).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][CH:10]=[N:11][O:12][CH3:13])=[O:8])=[C:5]([CH3:16])[CH:4]=1)=O.Cl.[OH:18][NH2:19]>CO.O>[OH:18][N:19]=[CH:1][C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][CH:10]=[N:11][O:12][CH3:13])=[O:8])=[C:5]([CH3:16])[CH:4]=1
Reactant: CON=CNC(=O)c1ccc(C=O)cc1C
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: CON=CNC(=O)c1ccc(C=NO)cc1C
Yield: 102.4 %

Procedure:
In a solution of 64 mg of 4-formyl-N-(methoxyiminomethyl)-2-methyl benzoic acid amide in 4 mL of methanol and 1 mL of water, 30 mg of hydroxyamine hydrochloride was added at room temperature with stirring, and continued to stir at the same temperature for 1.5 hour. After the completion of the reaction, 10 mL of water was added in the reaction mixture, and extracted with ethyl acetate (10 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (1:1) to obtain 70 mg of the aimed product as white crystal.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.O[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:40])[CH:25]([N:27]2[CH2:32][CH2:31][C:30]([OH:39])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:29][CH2:28]2)[CH3:26])=[CH:20][CH:19]=1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[OH:39][C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:31][CH2:32][N:27]([CH:25]([CH3:26])[C:24]([C:21]2[CH:20]=[CH:19][C:18]([O:13][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][C:8]([CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:9][CH:10]=3)=[CH:23][CH:22]=2)=[O:40])[CH2:28][CH2:29]1
Reactant: O=C(O)c1ccc(CN2CCOCC2)cc1
Reactant: CC(C(=O)c1ccc(O)cc1)N1CCC(O)(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C(=O)c1ccc(OC(=O)c2ccc(CN3CCOCC3)cc2)cc1)N1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a mixture of 4-(morpholinomethyl)benzoic acid (3.17 g, 12.3 mmol), 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanone (4.0 g, 12.29 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (2.36 g, 12.31 mmol) in methylene chloride (75 mL) was added 4-dimethylaminopyridine (1.88 g, 15.39 mmol). The heterogeneous mixture was allowed to stir overnight under a nitrogen atmosphere at ambient temperature. The mixture was washed with saturated aqueous bicarbonate (2×50 mL), dried by filtration through phase separating filter paper, and concentrated to a glassy yellow solid. Trituration with ether and hexane yielded 5.17 g, 80% of a light yellow solid product which was suitable for further reaction without additional purification. A sample recrystallized from ethyl acetate/hexane had: m.p. 126°-126.5° C.; NMR (CDCl3) 8.22 (d, J=8.6 Hz, 2 H), 8.13 (d, J=7.8 Hz, 2 H), 7.47 (t, J=7.3 Hz, 4 H), 7.34-7.19 (m, 5 H), 4.13 (q, J=6.6 Hz, 1 H), 3.70 (t, J=4.4 Hz, 4 H), 3.57 (s, 2 H), 2.97-2.79 (m, 2 H), 2.67-2.60 (m, 2 H), 2.44 (t, J=4.5 Hz, 4 H), 2.18-1.98 (m, 2 H), 1.78-1.67 (m, 3 H), 1.31 (d, J=6.6 Hz, 3 H). IR (KBr) 3270, 2960, 2942, 2912, 2830, 2821, 1743, 1682, 1596, 1390, 1273, 1199.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][NH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.Br[CH2:44][C:45]1[CH:46]=[C:47]([CH:55]=[CH:56][CH:57]=1)[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>CN(C)C=O.C(OCC)(=O)C>[C:51]([O:50][C:48]([C:47]1[CH:46]=[C:45]([CH:57]=[CH:56][CH:55]=1)[CH2:44][N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:10][CH2:11]2)[N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4]1)=[O:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)c1cccc(CBr)c1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Yield: 100 %

Procedure:
A mixture of benzyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (12.5 g, 34.21 mmol, 1 equiv), sodium bis(trimethylsilyl)amide, 1M in tetrahydrofuran (37.63 ml, 37.63 mmol, 1.1 equiv), and tert-butyl 3-(bromomethyl)benzoate (9.27 g, 34.21 mmol, 1 equiv) in N,N-dimethylformamide was stirred for 16 h at ambient temperature. Reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.6, 10%-50% ethyl acetate in hexanes) to afford benzyl 3-(3-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (19 g, quant) as a cream solid; 1H NMR (400 MHz, DMSO-d6): δ 1.53 (s, 9H); 1.71 (d, 2H, J=13.6 Hz); 2.37-2.42 (m, 2H); 3.6 (bs, 2H); 4.01-4.03 (m, 2H); 4.61 (s, 2H); 4.64 (s, 2H); 5.14 (d, 2H, J=7.2 Hz); 6.69 (d, 2H, J=8 Hz); 6.79 (t, 2H, J=7.2 Hz); 7.16-7.2 (m, 2H); 7.32-7.39 (m, 5H); 7.49-7.56 (m, 2H); 7.81-7.85 (m, 2H); MS for C33H37N3O5 m/z 556.28 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.[CH3:18][O:19][C:20]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21]>C1(C)C=CC=CC=1>[CH3:18][O:19][C:20](=[O:21])/[CH:22]=[CH:6]/[C:5]1[CH:8]=[C:9]([O:10][CH2:11][CH2:12][O:13][CH3:14])[C:2]([Cl:1])=[CH:3][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: COCCOc1cc(C=O)c([N+](=O)[O-])cc1Cl
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COCCOc1cc(/C=C/C(=O)OC)c([N+](=O)[O-])cc1Cl

Procedure:
1-Chloro-2-(2-methoxyethoxy)-4-methyl-5-nitrobenzene (300 mg; 1.22 mmol) in DMF (3 ml) was treated with tert.butoxy-bis(dimethylamino)methan (1.06 ml; 5.1 mmol) in DMF (13 ml) at 160° C. for 20 min. The reaction mixture was evaporated to dryness and taken up in THF (6 ml). NalO4 (1.6 g; 7.3 mmol) in water (25 ml) was added at room temperature within 0.5 h and after stirring for another 1 h, the reaction mixture was extracted with EtOAc twice. The combined organic phases were dried over Na2SO4 and evaporated to dryness to yield the intermediate 4-chloro-5-(2-methoxyethoxy)-2-nitrobenzaldehyde as brown solid (360 mg; quant.). 4-chloro-5-(2-methoxyethoxy)-2-nitrobenzaldehyde (360 mg; 1.22 mmol) and (methoxycarbonylmethylen)triphenylphosphoran (449 mg; 1.34 mmol) were refluxed for 1 h in toluene (20 ml). After cooling the reaction mixture, toluene (100 ml) was added and the resulting crystals filtered off and purified via chromatography (SiO2, TBME/hexanes 1/1) to yield the title compound as a cis-trans mixture (290 mg). Recrystallisation from hot TBME rendered the pure trans isomer (180 mg; 47%) as slightly yellow crystals.
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[C:16]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O>[ClH:1].[CH2:26]([O:25][C:16]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[CH2:12][CH2:11]1)=[O:15])=[O:24])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Nc1ccccc1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Nc2ccccc2C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (3.0 g, 0.013 mole) (which is prepared by the method as disclosed in Japanese Patent First Publication No. 19694/1977, C.A., 87, 53269x) and benzyl anthranilate (3.4 g, 0.015 mole) are added to pyridine (25 ml), and thereto is added dicyclohexylcarbodiimide (3.1 g, 0.015 mole), and the mixture is stirred at room temperature for 72 hours. After the completion of the reaction, water (10 ml) is added to the reaction mixture, and the mixture is stirred for 30 minutes, and the undissolved materials are filtered off. The filtrate is concentrated to driness. The resulting residue is washed with ethyl acetate (100 ml) and recrystallized from water to give N-(o-benzyloxycarbonylphenyl)-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride (3.2 g) as white crystals. m.p. 93°-95° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:37][C:38]1[C:46]2[C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([NH2:53])[CH:48]=3)=[N:44][C:43]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[N:42][C:41]=2[S:40][C:39]=1[C:60](O)=[O:61]>C(Cl)Cl.CN(C=O)C>[C:10]([NH:14][C:60]([C:39]1[S:40][C:41]2[N:42]=[C:43]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[N:44]=[C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([NH2:53])[CH:48]=3)[C:46]=2[C:38]=1[NH2:37])=[O:61])([CH3:13])([CH3:12])[CH3:11]
Reactant: Nc1cccc(-c2nc(-c3ccccc3)nc3sc(C(=O)O)c(N)c23)c1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(N)c3)c2c1N
Reaction time: 3 h

Procedure:
DIPEA (15.3 ml), tert-butylamine (9.3 ml) and TBTU (14.1 g) were added to a mixture of 5-amino-4-(3-aminophenyl)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (example 31(f), 13.3 g) in a mixture of DCM (250 ml) and DMF (50 ml) under a nitrogen atmosphere. After 3 h at room temperature, the mixture was diluted with DCM and washed with sat. aq. NaHCO3, 0.1N aq. HCl and sat. aq. NaCl. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, using heptane/EtOAc=3/7 to 1/1 (v/v) as eluent.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[C:49]([CH3:56])=[C:50]([CH:53]=[CH:54][CH:55]=1)[CH2:51][NH2:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:52][CH2:51][C:50]4[CH:53]=[CH:54][CH:55]=[C:48]([F:47])[C:49]=4[CH3:56])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(F)cccc1CN
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2cccc(F)c2C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-(3-fluoro-2-methyl-benzyl)-amine (Alfa) to give the title compound. LC-MS (ES+) 786 [(M+H)+].
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[CH2:3][CH2:4][OH:5].O[CH:8]1[CH2:13][CH:12]([CH3:14])[CH2:11][CH2:10][O:9]1>CCCCCC>[CH3:6][C:2](=[CH2:1])[CH2:3][CH2:4][O:5][CH:8]1[CH2:13][CH:12]([CH3:14])[CH2:11][CH2:10][O:9]1
Reactant: C=C(C)CCO
Reactant: CC1CCOC(O)C1
Solvent: CCCCCC
Product: C=C(C)CCOC1CC(C)CCO1
Temperature: 60 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A 300-ml three-necked flask equipped with condensor, stirrer and thermometer was charged with 70 g (0.60 mole) of 2-hydroxy-4-methyltetrahydropgran, 52.46 g (0.61 mole) of 3-methyl-3-buten-1-ol, 150 ml of hexane and 3 g of active clay, and the mixture was stirred at 60° C. for 1 hour. Thereafter, the reaction mixture was analyzed by gas chromatography. The chromatogram showed no peak for 2-hydroxy-4-methyltetrahydropyran but showed a new peak. The active clay was filtered off from the reaction mixture, then, the hexane was distilled off and the residue was distilled under reduced pressure to give 105 g (98% yield) of tetrahydro-2-(3-methyl-3-butenoxy)-4-methyl-2H-pyran as a fraction boiling at 89.5°-90.0° C./10 mm Hg. A nuclear magnetic resonance (NMR) spectrum (in CDCl3) and an infrared absorption spectrum (liquid film-NaCl method) each obtained with the above product are shown in FIG. 1 and FIG. 2, respectively. The NMR spectrum suggested this product was a mixture of 70% of ##STR16## and 30% of ##STR17## Field desorption ionization (FD) mass spectrometry of this product gave M+ =184.