Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:48])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=5[F:47])[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:49])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[CH3:51][N:52]1[CH2:57][CH2:56][CH:55]([NH:58][CH3:59])[CH2:54][CH2:53]1>CN(C)C=O>[F:47][C:41]1[CH:42]=[C:43]([F:46])[CH:44]=[CH:45][C:40]=1[NH:39][C:38]([C:35]1([C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][C:23]3[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:58]([CH3:59])[CH:55]4[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]4)=[O:7])[CH:24]=3)=[CH:27][C:28]=2[F:49])=[O:34])[CH2:37][CH2:36]1)=[O:48]
Reactant: CNC1CCN(C)CC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4F)CC3)c(F)c2)ccn1
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5F)CC4)c(F)c3)ccn2)CC1
Reaction time: 8 h
Yield: 14 %

Procedure:
To a solution of [4-(4-{[1-(2,4-Difluorophenylcarbamoyl)cyclopropanecarbonyl]amino}-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (116 mg) in N,N-dimethylformamide (2.0 ml) was added 1-methyl-4-(methylamino)piperidine (0.150 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:1 to the resultant residue. The solid was collected by filtration. The solid was dried under aeration to provide the titled compound as white powder (14.0 mg, 14%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:43]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:16])[F:17])[CH:8]=2)[C:3]=1[C:18]([N:46]1[CH2:45][CH2:44][N:43]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])[CH2:48][CH2:47]1)=[O:20]
Reactant: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Reactant: Oc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 71.2 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(3-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (588 mg, 1.31 mmol, 71%) was obtained.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[CH:28]=[N:27][N:26]=1.[CH:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48][C:47]=1[S:56](Cl)(=[O:58])=[O:57].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[CH:28]=[N:27][N:26]=[C:25]1[CH2:24][NH:23][S:56]([C:47]1[CH:48]=[CH:49][C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:46]=1)(=[O:58])=[O:57])=[O:43]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2cnnc2CN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2cnnc2CNS(=O)(=O)c2ccc3ccccc3c2)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.3 %

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazole di-p-toluenesulfonate (5.0 g) was dissolved in dimethylformamide (20 ml). 2-Naphthalenesulfonyl chloride (1.8 g) and triethylamine (5.0 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous citric acid solution and then saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 2.73 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazol-3-ylmethyl)naphthalene-2-sulfonamide.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([C:20]([O:22][CH3:23])=[O:21])[O:8][C@@H:6]1[OH:7])(=[O:3])[CH3:2].[CH3:24][C:25]1([CH3:49])[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[C:31]2[CH:30]=[C:29](/[C:37](/[CH3:48])=[CH:38]/[C:39]3[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=3)[CH:28]=[CH:27][C:26]1=2>N1C=CC=CC=1.CCOCC>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([C:20]([O:22][CH3:23])=[O:21])[O:8][CH:6]1[O:7][C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:39](/[CH:38]=[C:37](/[C:29]2[CH:28]=[CH:27][C:26]3[C:25]([CH3:49])([CH3:24])[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[C:31]=3[CH:30]=2)\[CH3:48])=[CH:40][CH:41]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C/C(=C\c1ccc(C(=O)Cl)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)[C@H]1OC(OC(=O)c2ccc(/C=C(\C)c3ccc4c(c3)C(C)(C)CCC4(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.4 g of methyl 2,3,4-tri-O-acetyl-α-D-glucopyranuronate in 40 ml of pyridine was reacted at 0° C. with a solution of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzoyl chloride in 70 ml of ether. The mixture was stirred at room temperature overnight, evaporated to dryness and the residue was chromatographed on silica gel with hexane/ethyl acetate. There was obtained methyl 2,3,4-tri-O-acetyl-1-O-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzoyl]-D-glucopyranuronate as a mixture of the β- and α-anomers (ca 4:1). Melting point 149°-150° C. (from ethanol); [α]D25 =3° (c=1 in chloroform).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]2=[N:11][C:10]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])C1C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[OH:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH:18]=[C:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:12]2=[N:11][C:10]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC=C2c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCC=C2c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
A solution of intermediate 16, ethyl 3-(benzyloxy)-4-oxo-9-phenyl-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate (0.320 g, 0.80 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (5 ml) and the resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then concentrated in vacuo and the residue was triturated with ether to give 0.189 g (76% yield) of the title material as a white solid; mp 151° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.37 (3H, t, J=7.1 Hz, CH3), 2.67 (2H, m, CH2), 4.34 (2H, t, J=7.1 Hz, CH2), 4.37 (2H, q, J=7.1 Hz, OCH2), 6.70 (1H, t, J=4.8 Hz, CH), 7.38 (3H, m, aromatics), 7.55 (2H, m, aromatics), 10.70 (1H, s, OH). HRMS (ESI+) calculated for C17H17N2O4 [M+H+]: 313.1188; found: 313.1181.
Reaction SMILES: C1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8](CC)=[N:7]2)CCCC1.[CH3:17]N(C)CCOC1C=C(C=CC=1)C=O>>[N:6]1[C:10]2=[N:11][CH:17]=[N:14][C:12](=[O:13])[C:9]2=[CH:8][N:7]=1
Reactant: CN(C)CCOc1cccc(C=O)c1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Product: O=C1N=CN=C2N=NC=C12
Temperature: 160 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.50 g, 15.74 mmol), 3-[2-(dimethylamino)ethoxy]benzaldehyde (3.95 g) and xylenes (10 ml) was heated at 160° C. overnight. The reaction mixture was cooled to room temperature, the solvent was stripped, and the residue was partitioned between chloroform and water. The layers were separated, and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with brine, dried over MgSO4, filtered and stripped to afford, as an oil, 1-cyclopentyl-3-ethyl-6-[3-[2-dimethylamino)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one labelled as [Example 23(b)]. The free base was treated with ethanolic HCl to afford the product as the hydrochloride salt [labelled as Example 23(c)].
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:9]Br.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Br:9][CH2:2][C:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(CBr)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
To a solution of 16.1 g (0.143 mol) of acetylcyclopentane in 175 ml of methanol cooled in an ice bath was added 7.7 ml (0.15 mol) of bromine during 5 min. The reaction mixture was then allowed to warm to 10°-15° and held there by occasional application of the ice bath for 45 min until the reaction mixture became colorless. Then 100 ml of water was added and it was allowed to stir at room temperature for 0.5 hr. It was partially neutralized by the cautious addition of 10 g (72 mmol) of solid potassium carbonate, diluted with 200 ml of water and extracted with 4×150 ml of ether. The combined organic extracts were washed with 2×100 ml of saturated sodium bicarbonate solution and with 3×100 ml of water, dried over magnesium sulfate and concentrated in vacuo at room temperature to leave 30 g (110%) of bromoacetylcyclopentane as an oil whose nmr spectrum indicated that it was mainly the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:33](CC)CC)C.C([O-])(=O)C.[NH4+]>C(O)CCC.C(OCC)(=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:33]=[C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[NH:15][CH:16]=2)=[CH:20][C:21]=1[C:26]([F:29])([F:28])[F:27]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(F)c(C(F)(F)F)c2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.1 %

Procedure:
A mixture of 4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (2900.00 mg; 6.71 mmol; 1.00 eq.), triethylamine (0.94 ml; 6.71 mmol; 1.00 eq.), and ammonium acetate (3618.76 mg; 46.95 mmol; 7.00 eq.) in 20 ml of n-butanol was placed in microwave (150° C.) for 20 min. after cooling to rt, the reaction mixture was diluted with 150 ml of ethyl acetate and washed with water, 5% NaHCO3aq, then brine and concentrated. The residue was treated with ether and collected whit solid as title compound (1500 mg, 54% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](O)=O)=[N:4][C:5]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:12][CH:13]=2)=[CH:6][N:7]=1.[CH3:22][C:23]1[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[CH:27][CH:28]=1.C(OP(C#N)(OCC)=O)C.C(N(CC)CC)C>COCCOC>[CH2:17]([S:14]([N:11]1[CH2:12][CH:13]=[C:8]([C:5]2[N:4]=[C:3]([C:19]3[NH:29][C:26]4[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][C:25]=4[N:30]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15])[CH3:18]
Reactant: Cc1ccc(N)c(N)c1
Reactant: CCS(=O)(=O)N1CC=C(c2cnc(N)c(C(=O)O)n2)CC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(-c3nc4cc(C)ccc4[nH]3)n2)CC1
Temperature: 170 °C
Yield: 36.7 %

Procedure:
A mixture of 3-amino-6-(1-ethylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylic acid (100 mg, 0.320 mmol), 4-methylbenzene-1,2-diamine (39.12 mg, 0.320 mmol), diethoxyphosphorylformonitrile (47.83 uL, 0.320 mmol) and triethylamine (44.63 uL, 0.320 mmol) in DME (1 mL) were heated in a microwave at 170° C. for 90 min. After this time the reaction mixture was filtered and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried to give the title compound (46.8 mg, 21% Yield). 1H NMR (400.0 MHz, DMSO) d 8.34 (s, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.46 (s, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.78 (s, 1H), 4.00 (d, J=2.8 Hz, 2H), 3.50 (t, J=5.7 Hz, 2H), 3.16 (q, J=7.4 Hz, 2H), 2.78 (s, 2H), 2.46 (s, 3H) and 1.25 (t, J=7.4 Hz, 3H) ppm; MS (ES+) 399
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[C:21]([O:25][C:26]([N:28]1[CH2:32][C:31]([F:34])([F:33])[CH2:30][C@H:29]1[C:35]([OH:37])=[O:36])=[O:27])([CH3:24])([CH3:23])[CH3:22].CI>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:32][C:31]([F:33])([F:34])[CH2:30][C:29]1([CH3:1])[C:35]([OH:37])=[O:36])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(F)CC1(C)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a cooled (−78° C.) solution of diisopropylamine (4.9 mL, 0.032 mol) in dry THF (15 mL), n-BuLi (0.030 mol) was added dropwise under argon atmosphere, stirred the reaction mixture for 30 min at −78° C., then for one hour at −20° C. The resulting LDA solution was transferred to a solution of (S)-4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.7 g, 0.010 mol) in THF (15 mL), via cannula and then stirred for 30 minutes at −78° C., then at 0° C. for one hour. The reaction mixture was once again cooled to −78° C., and methyl iodide (0.54 mL, 0.010 mol) was added over 10 min and then warmed to RT over 2 h. After completion of the reaction, the reaction mixture was quenched with 1N HCl (20 mL) and extracted with DCM. The organic layer was concentrated under reduced pressure using a rotary evaporator to give a crude gum, which was purified through column chromatography (10-20% ethyl acetate:hexane, basic alumina, diameter of column—2.5 cm, Height of alumina—approx. 7 inch) to give the desired (rac)-4,4-difluoro-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.1 g) as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[CH3:23].O>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH3:23])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
1-Acetyl-4-hydroxypiperidine (9.2 g) was dissolved in dimethylformamide (20 ml) and to the solution was added sodium hydride (oily, 60%, 2.6 g). The mixture was stirred at room temperature for 30 minutes, followed by adding dropwise 2-fluoro-5-nitrotoluene (10 g). The mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added water (50 ml) which was extracted with methylene chloride (50 ml×3). The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography (developing solvent: methylene chloride/methanol=20/1 (v/v)) to obtain 1-acetyl-4-(4-nitro-2-methylphenyloxy)piperidine (12.6 g) as yellow crystals, m.p. 139°-141° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:6]([NH:8][CH2:9][C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)=O)=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:37]2)=CC=1.ClCCl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[S:37][C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)=[CH:9][N:8]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(C(=O)NCC(=O)c2ccc3c(c2)CCC(=O)N3)cc1OC
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2ncc(-c3ccc4c(c3)CCC(=O)N4)s2)cc1OC
Reaction time: 3 h

Procedure:
There were mixed, each in a powdery state, 500 mg of 6-[2-(3,4-dimethoxybenzoylamino)acetyl]-3,4-dihydrocarbostyril and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent), The mixture was stirred at 200° C. with heating. After 3 hours, the reaction was completed. The residue was subjected to silica gel column chromatography (dichloromethane:methanol=49:1 by v/v), A solid obtained from the eluate was recrystallized from ethanol to obtain 98 mg of 2-(3,4-dimethoxyphenyl)-5-(3,4-dihydrocarbostyril-6-yl) thiazole as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][NH:6][C:7]1[C:12]([NH2:13])=[CH:11][N:10]=[C:9]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:15]=2)[N:8]=1.[S:38](N)(N)(=[O:40])=[O:39].N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][N:6]1[C:7]2[N:8]=[C:9]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=4)[N:16]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[N:15]=3)[N:10]=[CH:11][C:12]=2[NH:13][S:38]1(=[O:40])=[O:39]
Reactant: NS(N)(=O)=O
Reactant: COc1ccc(CNc2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)ncc2N)c(OC)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CN2c3nc(-c4nn(Cc5ccccc5F)c5ncc(F)cc45)ncc3NS2(=O)=O)c(OC)c1
Temperature: 160 °C

Procedure:
550 mg (1.093 mmol) of the compound from example 92A were divided between 11 microwave vessels. 50 mg of the substance in each were admixed with 48 mg (0.496 mmol) of sulfamide and 2.5 ml of pyridine and then heated at 160° C. under microwave radiation for 30 min. Subsequently, all batches were combined and freed of the solvent under reduced pressure. The residue was taken up in dichloromethane and extracted three times with water. The phases were separated and the organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). This gave 0.130 g (12% of theory, purity 50%) of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]1([CH2:16][CH2:17][N:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]([CH3:23])[CH2:20][CH2:21][NH2:22])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([CH2:16][CH2:17][N:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:19]([CH3:23])[CH2:20][CH2:21][NH:22][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(CCN)N(CCC1CCCC1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CC(CCNc1ccc([N+](=O)[O-])cc1)N(CCC1CCCC1)c1ccccc1

Procedure:
In a manner similar to Preparation 1 react 4-fluoro1-nitrobenzene with N-[2-(cyclopentyl)ethyl]-N-phenyl-methyl-1,3-propanediamine to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH3:36])[CH:30]=2)[C:9]#[C:10][C:11]2[CH:27]=[CH:26][C:14]([CH2:15][NH:16][CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH3:36])[CH:30]=2)[C:9]#[C:10][C:11]2[CH:27]=[CH:26][C:14]([CH2:15][NH:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(CC(C#Cc2ccc(CNCCC(=O)OC(C)(C)C)cc2)c2cccc(Cl)c2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(CC(C#Cc2ccc(CNCCC(=O)O)cc2)c2cccc(Cl)c2)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 3-((4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)but-1-yn-1-yl)benzyl)amino)propanoate in CH2Cl2 (10 mL) was added TFA (1 mL) at room temperature and the mixture was stirred at room temperature for 16 h. The mixture was evaporated under reduced pressure. The residue was diluted with CH2Cl2:MeOH and the mixture was neutralized with NH3:MeOH silica gel was added, concentrated to dryness, then purified by MPLC using MeOH:CH2Cl2 and Compound 3 (129 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH:13]=O)=[CH:7]2)([O-:3])=[O:2].[Cl-].[Cl:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH:19]=[CH:13][C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2
Reactant: Clc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Cl-]
Product: O=[N+]([O-])c1ccc2[nH]c(C=Cc3ccccc3Cl)cc2c1

Procedure:
Reaction of the aldehyde (904) prepared as described in example 454 with 2-chlorobenzyltriphenylphosphonium chloride using the procedure described in example 37(at room temperature) gave the diene (905) as a mixture of E/Z isomers as a yellow solid (95%). Crystallisation from aqueous methanol yielded the pure E-isomer as yellow needles (80%), mp 230–232° C. 1H NMR δ [(CD3)2SO] 12.28 (br s, 1H), 8.55 (d, J=2.3 Hz, 1H), 8.03 (dd, J=9.1, 2.3 Hz, 1H), 7.91 (dd, J=7.8, 1.5 Hz, 1H), 7.32–7.61 (m, 6H), 6.92 (s, 1H). Found: C, 64.59; H, 5.68; N, 9.49. C16H11ClN2O2 requires C, 64.33; H, 5.68; N, 9.49.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:18][CH:17]=2)=[C:9]([CH2:11][C:12]#[N:13])[CH:10]=1.S(=O)(=O)(O)O.O1CCCC1>O>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[O:27][C:28]=3[CH3:29])=[CH:20][CH:21]=2)=[C:9]([CH2:11][C:12]#[N:13])[CH:10]=1
Reactant: COCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CC#N)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(O)cc2CC#N)cc1
Yield: 68.1 %

Procedure:
A mixture of 2-[5-methoxymethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile (1.83 g), 10% sulfuric acid (5 mL) and tetrahydrofuran (50 mL) was heated under reflux for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (1.13 g, 68%) of 2-[5-hydroxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 185-186° C.