Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.[CH:4]([NH2:7])([CH3:6])[CH3:5].Cl[C:9]1[S:10][C:11]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=1>C(OCC)C>[CH3:5][CH:4]([NH:7][C:9]1[S:10][C:11]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[C:12]([C:14]([F:16])([F:15])[F:17])[N:13]=1)[CH3:6]
Reactant: CC(C)N
Reactant: O=C(OCc1ccccc1)c1sc(Cl)nc1C(F)(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)Nc1nc(C(F)(F)F)c(C(=O)OCc2ccccc2)s1
Temperature: 25 °C
Yield: 62 %

Procedure:
A reaction vessel was charged with 25 ml of acetonitrile, 2.94 g (49.8 mmol) of iso-propylamine, and 8 g (24.9 mmol) of benzyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate (prepared as described in U.S. Pat. No. 4,199,506). The reaction mixture was heated at reflux for 16 hours. The mixture was then cooled to ambient temperature, diluted with ethyl ether, washed with large amounts of water, dried over magnesium sulfate, and concentrated under reduced pressure to yield 5.32 g of a gold oil. This oil was subjected - to Kugelrohr distillation (145°-155° C. @ 0.5 mm Hg) to yield 4.97 of a gold oil which was then triturated in hexane to yield 3.99 g of a yellow solid product (m.p.=49°-53° C.) identified in Table I.
Reaction SMILES: [CH2:1]([N:8]([S:18]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[CH2:1]([N:8]([S:18]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)(=[O:19])=[O:20])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(N(Cc2ccccc2)S(=O)(=O)c2cccnc2)c1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1cccc(N(Cc2ccccc2)S(=O)(=O)c2cccnc2)c1

Procedure:
3-[Benzyl-(pyridine-3-sulfonyl)-amino]-N-isopropyl-benzamide was prepared from 3-[benzyl-(pyridine-3-sulfonyl)-amino]-benzoic acid and isopropylamine according to the method described for Example 2. HPLC retention time 5.46 min. Mass spectrum (APCI+) m/z 410 (M+H).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]([CH3:66])[CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]([CH3:66])[CH:60]1[CH2:65][CH2:64][N:63]([C:11](=[O:13])[CH2:10][NH:9][C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:62][CH2:61]1
Reactant: CN(c1ccccc1Cl)C1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(c1ccccc1Cl)C1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.0659 g, 0.00025 mol) in DMF (1 mL), was added DIPEA (0.0911 g, 0.0007 mol), HOBt (0.0318 g, 0.00023 mol) and EDCI.HCl (0.054 g, 0.00028 mol) at ambient temperature. After 2 minutes (2-chloro-phenyl)-methyl-piperidin-4-yl-amine hydrochloride (0.07 g, 0.00023 mol) was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium bicarbonate solution followed by brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue obtained was purified by column chromatography using basic aluminium oxide (10-30% ethyl acetate in hexane) to afford 0.028 g (23%) of biphenyl-4-carboxylic acid (2-{4-[(2-chloro-phenyl)-methyl-amino]-piperidin-1-yl}-2-oxo-ethyl)-amide. LCMS: 462.1 (M+1)+, 96.19%, 1H NMR (DMSO-d6): δ 8.6 (t, 1H), 7.95 (d, 2H), 7.75 (m, 3H), 7.5 (t, 2H), 7.42 (m, 2H), 7.3-7.2 (m, 2H), 7.05 (m, 1H), 4.4 (d, 1H), 4.2 (m, 2H), 3.95 (d, 1H), 3.05 (t, 1H), 2.65 (s, 3H), 1.6 (bs, 3H), 1.6-1.4 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5]>C(#N)C=C>[CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH:5][CH2:7][CH2:6][C:4]#[N:5]
Reactant: COC(=O)[C@@H](N)CC(C)C
Solvent: C=CC#N
Product: COC(=O)[C@H](CC(C)C)NCCC#N

Procedure:
A solution of leucine methyl ester (0.590 mmol) in acrylonitrile (2 ml) was heated at reflux. Evaporation provided a residue which was chromatographed on silica gel to give desired compound.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=O)=[CH:4][C:3]=1[CH3:15].C1COCC1.[OH-].[Na+]>CO>[Br:1][C:2]1[S:6][C:5]([CH2:7][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(C(=O)N2CCOCC2)sc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(CN2CCOCC2)sc1Br
Temperature: 25 °C

Procedure:
(5-Bromo-4-methyl-thiophen-2-yl)-morpholin-4-yl-methanone (1.78 mmol) was added to a flask containing 1M THF.BH3 complex in THF (4.45 mmol). Reaction was stirred at reflux for 2.5 h under N2. Methanol was then added until gas evolution ceased, followed by 10 ml of 1M NaOH and the reaction stirred at reflux for a further 7 h. The mixture was cooled to room temperature and extracted with EtOAc. This extract was concentrated in vacuo and the residue taken up in 1M HCl and washed with EtOAc. The acid layer was then basified with 1M NaOH and extracted back into EtOAc. Removal of solvent gave 4-(5-Bromo-4-methyl-thiophen-2-ylmethyl)-morpholine as a colourless oil: m/z in MS ES+=276, 278 [M+H]+, 0.98 mmol, 55%.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=1[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].[C:33]([C:37]1[N:38]=[C:39]([C:42]2[O:43][C:44]3[CH:50]=[CH:49][C:48]([CH:51]=O)=[CH:47][C:45]=3[CH:46]=2)[S:40][CH:41]=1)([CH3:36])([CH3:35])[CH3:34]>C(#N)C.N12CCCN=C1CCCCC2>[C:33]([C:37]1[N:38]=[C:39]([C:42]2[O:43][C:44]3[CH:50]=[CH:49][C:48]([CH:51]=[CH:9][C:8]4[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=4[C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:47][C:45]=3[CH:46]=2)[S:40][CH:41]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C=O)ccc3o2)n1
Reactant: CCOC(=O)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)c1ccccc1C=Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Yield: 65 %

Procedure:
To a solution of 2-ethoxycarbonylbenzyltriphenylphosphonium bromide (605 mg) and 4-tert-butyl-2-(5-formylbenzofuran-2-yl)thiazole (285 mg) in acetonitrile (5.00 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.317 ml) was added. The resulting solution was heated under reflux for 10 hours. After concentration under reduced pressure, diisopropyl ether was added to the residue. The resulting insoluble material was removed by filtration. After concentration of filtrate under reduced pressure, n-heptane was added to the residue. The resulting insoluble material removed again by filtration. After concentration of filtrate, the residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-[5-{2-(2-ethoxycarbonylphenyl)ethenyl}benzofuran-2-yl]thiazole (280 mg) as a mixture of E and Z isomer as a viscous oil, which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=[O:12])[O:7][CH2:8]2)=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:3]=1[CH2:24][CH:25]=[C:26]([CH3:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30].[C:33]1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(OCC)(=O)C>CO>[OH:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=[O:12])[O:7][CH2:8]2)=[C:4]([O:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:3]=1[CH2:24]/[CH:25]=[C:26](\[CH3:32])/[CH2:27][CH2:28][C:29]([O:31][CH3:33])=[O:30]
Reactant: CC(=CCc1c(O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2)CCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)CC/C(C)=C/Cc1c(O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2

Procedure:
A solution of (E) 6-(1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoic acid (23 g) and p-toluenesulfonic acid (0.8 g) in methanol (150 ml) was stirred for 18 hours then added to water and ethyl acetate. The organc layer was dried and evaporated and the residue was chromatographed on silica gel, eluting with hexane:ethyl acetate: methanol 40:58:2, to afford methyl (E) 6-(1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [CH:1]([C:4]1[CH2:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].N1C[CH2:12][CH2:11][CH2:10]1>CC(C)=O>[CH:1]([C:4]1[CH:8]=[CH:7][C:6](=[C:11]([CH3:12])[CH3:10])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)C1=CC=CC1
Solvent: CC(C)=O
Product: CC(C)=C1C=CC(C(C)C)=C1

Procedure:
Therefore, 1,3-diisopropylcyclopentadiene was selected as the starting point for the synthesis. Unfortunately, the reported syntheses of 1,3-diisopropylcyclopentadiene gave low yields since the final step was always separation of the 1,3 product from the 1,2 product. A more selective method was found by extension of work by Nile in which he prepared a number of 1,3 disubstituted cyclopentadienes using a fulvene route. Using this method, reaction of isopropylcyclopentadiene with acetone catalyzed by pyrrolidine gave the 3-isopropyl-6,6-dimethylfulvene. Subsequent reduction of the fulvene with LAH and hydrolysis provided 1,3-diisopropylcyclopentadiene, "iPr2Cp." ##STR10##
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:22]([N:25](CC2C=CC(OC)=CC=2OC)[C:26]2[S:30][N:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=1I)#[N:2].[CH3:42][N:43]1[C:47](B2OC(C)(C)C(C)(C)O2)=[CH:46][CH:45]=[N:44]1>>[C:1]([C:3]1[CH:4]=[C:5]([S:22]([NH:25][C:26]2[S:30][N:29]=[CH:28][N:27]=2)(=[O:23])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][C:11]=1[C:47]1[N:43]([CH3:42])[N:44]=[CH:45][CH:46]=1)#[N:2]
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(OC(F)(F)F)cc3I)c(C#N)c2)c(OC)c1
Product: Cn1nccc1-c1cc(OC(F)(F)F)ccc1Oc1ccc(S(=O)(=O)Nc2ncns2)cc1C#N

Procedure:
The title compound was prepared from 3-cyano-N-(2,4-dimethoxybenzyl)-4-[2-iodo-4-(trifluoromethoxy)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 497) and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester using Method E above. Purification afforded the title compound.
Reaction SMILES: [OH:1][CH:2]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)[CH2:3][CH3:4].[Cr](O)(O)(=O)=O>C(O)(=O)C.O>[C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)(=[O:1])[CH2:3][CH3:4]
Reactant: CCC(O)c1cc(-c2ccccc2)no1
Agent: O=[Cr](=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCC(=O)c1cc(-c2ccccc2)no1
Temperature: 60 °C

Procedure:
In 130 ml of acetic acid, 19 g (93.6 mmol) of 5-(1-hydroxypropyl)-3-phenylisoxazole were dissolved. A solution which had been obtained by dissolving 6.4 g (64 mmol) of chromic acid in a mixed solution of 50 ml of acetic acid and 10 ml of water was added dropwise. The reaction mixture was heated at 60° C. for 3 hours and the solvent was distilled off under reduced pressure. The residue thus obtained was poured in ice water. Colorless crystals precipitated were collected by filtration and then dried under reduced pressure. The crystals were purified by chromatography on a silica gel (eluent:2:8 hexane/chloroform), whereby 5-propionyl-3-phenylisoxazole was obtained as colorless crystals. Analytical results of the crystals obtained: Yield: 17.5 g (93.2%). Melting point: 111°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=O)[CH:17]=1)=[CH:5]/[O:6][CH3:7].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:17]=1)=[CH:5]/[O:6][CH3:7]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(C=O)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.9 %

Procedure:
326 mg (1.0 mmol) of the compound obtained in Step 1 was dissolved in 5 ml of methylene chloride, and 297 mg (1.4 mmol) of NaBH(OAc)3 and 87 μl (1.0 mmol) of morpholine were added thereto. After stirring at room temperature for 4 hours, the reaction mixture was treated with a saturated sodium bicarbonate aqueous solution, and the water layer was separated, and extracted twice with 20 ml portions of methylene chloride. The organic layers were combined, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The residue was subjected to column chromatography using 3% methanol/chloroform as an eluent to obtain 385 mg (yield 97%) of (E)-methyl-2-[2-((3-(morpholinomethyl)phenoxy)methyl)phenyl]-3-methoxyacrylate as an oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)CCC>>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12]([C:25]2[CH:30]=[N:29][CH:28]=[CH:27][N:26]=2)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2snc(C)c2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Product: CCCCOC(=O)c1nc(-c2cnccn2)c2snc(C)c2c1O

Procedure:
The title compound was synthesized in analogy Example 3 from 7-bromo-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and 2-(tributylstannyl)pyrazine: MS (m/z) 345.2 (M+1).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[NH:13][C:12]1=[O:19])[CH2:8]2.[H-].[Na+].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1.[Na+].[Cl-]>CN(C=O)C>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]([CH3:17])[CH3:18])[N:13]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:12]1=[O:19])[CH2:10]2
Reactant: BrCC1CC1
Reactant: CC(C)c1cn(C2C3CC4CC(C3)CC2C4)c(=O)[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cn(C2C3CC4CC(C3)CC2C4)c(=O)n1CC1CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1-Adamantan-2-yl-4-isopropyl-1,3-dihydro-imidazol-2-one (obtained in example 8, 100 mg) was dissolved in dry DMF under argon and sodium hydride (55% in mineral oil) was added. The mixture was allowed to stir for 45 minutes and then bromomethylcyclopropane (0.04 ml) was added drop by drop. Stirring was continued at RT for another 4 hours. The reaction mixture was poured into ice/water, saturated with NaCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated to give a residue that was purified by flash chromatography using a gradient of 10 to 80% ethyl acetate in heptane as an eluent. Fractions containing the desired material were combined and evaporated to give 1-adamantan-2-yl-3-cyclopropylmethyl-4-isopropyl-1,3-dihydro-imidazol-2-one as a colorless oil (87 mg). MS (ESI): 315.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[N:29]=[C:30]=[O:31]>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:30]([NH:29][C:20]4[CH:21]=[C:22]([C:25]([F:26])([F:28])[F:27])[CH:23]=[CH:24][C:19]=4[F:18])=[O:31])=[CH:7][CH:6]=3)=[CH:9][S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Nc1ccc(-c2csc3ncnc(N)c23)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: ClCCl
Product: Nc1ncnc2scc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
A suspension of Example 58D (0.04 g, 0.165 mmol) in dichloromethane (3 mL) under nitrogen was cooled to 0° C., treated with 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (0.024 mL, 0.165 mmol), and stirred overnight while gradually warming to room temperature. The suspension was filtered and the filter cake was dried in a vacuum oven to provide 0.056 g of the desired product. MS(ESI(+)) m/e 448 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.40 (s, 1H); 8.98 (d, J=2.7 Hz, 1H); 8.63 (dd, J=7.2 Hz, 2.1 Hz, 1H); 8.35 (s, 1H); 7.63 (d, J=8.7 Hz, 2H); 7.55-7.39 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12](Cl)=[O:13])=[CH:7][CH:6]=1)=[O:4].[CH3:20][C:21]1([CH3:34])[CH2:30][CH2:29][C:28]([CH3:32])([CH3:31])[C:27]2[CH:26]=[C:25]([NH2:33])[CH:24]=[CH:23][C:22]1=2>N1C=CC=CC=1>[CH2:15]([N:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)[C:12]([NH:33][C:25]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:34])([CH3:20])[CH2:30][CH2:29][C:28]([CH3:32])([CH3:31])[C:27]=2[CH:26]=1)=[O:13])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCN(C(=O)Cl)c1ccc(C(=O)OC)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Solvent: c1ccncc1
Product: CCCCCN(C(=O)Nc1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C(=O)OC)cc1
Temperature: 40 °C
Reaction time: 15 h
Yield: 66.9 %

Procedure:
A solution of 4-methoxycarbonylphenyl-pentyl-carbamoyl chloride (45) (180 mg, 0.63 mmole) in 5 mL pyridine was treated with 130 mg of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1.05 eq.) and stirred at 40° C. for 15 hours. The reaction mixture was concentrated in vacuo to give an orange oil which was purified by flash chromatography (SiO2, 10%-20% ethyl acetate/hexanes) to provide 190 mg (67%) of methyl 4-[1-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (47) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2OCC[O:18]2)=[CH:13][CH:12]=1)O.Cl[Si](C)(C)C.[I-].[Na+].C(#N)C>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1cccc(C)c1C(O)c1ccc(C2OCCO2)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cccc(C)c1Cc1ccc(C=O)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of (2,6-dimethylphenyl)[4-(1,3-dioxolan-2-yl)phenyl]methanol (7.10 g), chlorotrimethylsilane (10.8 g), sodium iodide (15.0 g) and acetonitrile (50 mL) was stirred at 50° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 10% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate-hexane (gradient of 1:9 to 7:3 by volume ratio) to give 4-(2,6-dimethylbenzyl)benzaldehyde as pale-yellow crystals.
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][CH:8]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([NH:17]C(=O)CC)=[C:12]([Cl:22])[CH:11]=1)[OH:9])([CH3:5])([CH3:4])[CH3:3]>>[NH2:17][C:13]1[C:14]([F:16])=[CH:15][C:10]([CH:8]([OH:9])[CH2:7][NH:6][C:2]([CH3:3])([CH3:5])[CH3:4])=[CH:11][C:12]=1[Cl:22]
Reactant: CCC(=O)Nc1c(F)cc(C(O)CNC(C)(C)C)cc1Cl
Agent: Cl
Product: CC(C)(C)NCC(O)c1cc(F)c(N)c(Cl)c1

Procedure:
m.p. of the hydrochloride: 206°-208° C. (decomp.), was prepared from 2-tert.butylamino-1-(3'-chloro-5'-fluoro-4'-propionylamino-phenyl)-ethanol analogous to Example 4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=1)([O-:3])=[O:2].C(O[C:18]1(O[Si](C)(C)C)[CH2:20][CH2:19]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:18]1([N:12]2[CH2:13][CH2:14][CH:9]([N:7]3[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]3)[CH2:10][CH2:11]2)[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1cnn(C2CCNCC2)c1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1cnn(C2CCN(C3CC3)CC2)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A mixture of 4-(4-nitro-1H-pyrazol-1-yl)piperidine (100 mg), (1-ethoxycyclopropoxy) trimethylsilane (267 mg), acetic acid (292 μL), Molecular Sieve 3 A (100 mg), and sodium cyanoborohydride (96 mg), and methanol (3 mL) was stirred at 65° C. for 8 hours. After leaving to be cooled, the insoluble matter was separated by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=100:0-95:5) to obtain 1-cyclopropyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine (110 mg) as a colorless solid.
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#[N:14])[C:9](=[O:15])[C:8]=2[CH:16]=1)[CH3:3].[C:17]([O-:20])(=[O:19])[CH3:18].[Na+].CN(C)C=O>O>[C:17]([O:20][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#[N:14])[C:9](=[O:15])[C:8]=2[CH:16]=1)[CH3:3])(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: CC(Br)c1ccc2occ(C#N)c(=O)c2c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC(C)c1ccc2occ(C#N)c(=O)c2c1
Temperature: 70 °C
Reaction time: 0.83 h

Procedure:
A mixture of 5.56 parts of 6-(1-bromoethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile, 1.640 parts of anhydrous sodium acetate and 8 parts by volume of dimethylformamide is heated at 70° C under stirring for 50 minutes. After cooling, the reaction mixture is poured into 100 parts by volume of water to give precipitates, which are collected and recrystallized from ethanol and subsequently ethyl acetate. The procedure yields 2.90 parts of 6-(1-acetoxy-ethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile. Melting point: 148°-149° C
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O[N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:13]([O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][O:27][N:31]2[C:32](=[O:41])[C:33]3=[CH:40][CH:39]=[CH:38][CH:37]=[C:34]3[C:35]2=[O:36])=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCOc1ccc(CO)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
Diethyl azodicarboxylate (18.4 g) was added dropwise to a suspension of 4-octyloxybenzyl alcohol (25 g), N-hydroxyphthalimide (17.15 g) and triphenylphosphine (27.74 g) in tetrahydrofuran (250 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours, and evaporated in vacuo. The residue was purified by chromatography on silica gel to give N-(4-octyloxybenzyloxy)phthalimide (33.45 g) as crystals.