Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:4][N:3]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)=[N:3][CH:4]=2)=[N:12][N:11]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Cl)nc2)o1
Reactant: C1CSCCN1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCSCC3)nc2)o1
Yield: 59 %

Procedure:
As described for example 136b, 2-chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (400 mg, 1.18 mmol) was converted using thiomorpholine instead of morpholine to the title compound (126 mg, 59%) which was obtained as an off-white solid. MS: m/e=406.3 [M+H]+.
Reaction SMILES: C1(P(=C=[CH:21][C:22]([O:24][CH3:25])=[O:23])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH3:39])[CH:32]=O)[CH3:27]>C1(C)C=CC=CC=1>[CH2:26]([O:28][C:29]1[CH:30]=[C:31](/[CH:32]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH3:39])[CH3:27]
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: COC(=O)C=C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1ccc(/C=C/C(=O)OC)cc1OCC
Reaction time: 1 h

Procedure:
1.81 g (5.40 mmol) of methyl (triphenylphosphoranylidene)acrylate are added, at room temperature, to a solution of 1.0 g (5.15 mmol) of 3,4-diethoxybenzaldehyde and 10 ml of toluene. The reaction is then allowed to proceed for 1 hour at room temperature, the reaction suspension is clarified by filtration over a silica gel bed and the filtrate is evaporated down. Chromatography of the residue over silica gel using toluene/ethyl acetate gives methyl 3(E)-(3,4-diethoxyphenyl)acrylate.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH:12]=[CH2:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:14][OH:15]>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH:12]([O:15][CH3:14])[CH3:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CO
Reactant: C=CCOC1CCN(C(C)=O)CC1
Product: COC(C)COC1CCN(C(C)=O)CC1

Procedure:
This compound was prepared similarly to Example F, starting from N-acetyl-4-allyloxypiperidine and mercuric acetate in methanol. To improve the conversion of starting material to product the mercuric acetate/methanol treatment was repeated twice to give N-acetyl-4-(2-methoxy-n-propoxy)piperidine, which was hydrolyzed in sodium hydroxide and methanol solution to give 4-(2-methoxy-n-propoxy)piperidine. A sample was characterized as the oxalate salt, m.p. 89°-91° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[OH:17])[N:10]=[C:4]2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:24][CH2:25][CH2:26]Br>CN(C=O)C.O>[F:24][CH2:25][CH2:26][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:10]=[C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]2[N:8]=1
Reactant: Nc1ccn2nc(-c3ccccc3O)nc2c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccn2nc(-c3ccccc3OCCF)nc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 111.3 %

Procedure:
To a solution of 2-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-phenol (250 mg, 1.10 mmol) in dry DMF (6 ml), K2CO3 (611 mg, 4.42 mmol) was added under positive nitrogen pressure and the mixture was stirred for 20 min at rt in a sealed tube. A solution of 1-fluoro-2-bromoethane (93 mg, 0.66 mmol) in DMF was added dropwise and the reaction mixture was heated for 8 h at 90° C. On completion of reaction (monitored by TLC), the mixture was cooled, diluted with water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to get the crude product. Purification by silica gel column chromatography using 2% MeOH in DCM as eluent afforded the desired product (200 mg, 66%) as off-white solid. LC-MS: m/z=273.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:4]([N+:20]([O-:22])=[O:21])[C:5](OS(C(F)(F)F)(=O)=O)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([C:32]2[CH:31]=[C:30]([F:29])[CH:35]=[C:34]([F:36])[CH:33]=2)=[C:4]([N+:20]([O-:22])=[O:21])[C:3]=1[C:23]#[C:24][Si:25]([CH3:26])([CH3:27])[CH3:28]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Product: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1-c1cc(F)cc(F)c1
Yield: 82 %

Procedure:
The desired compound was prepared according to the procedure of Example 16, step E, using methyl 5-chloro-3-nitro-2-{[(trifluoromethyl)sulfonyl]oxy}-4-[(trimethylsilyl)ethynyl]benzoate and (3,5-difluorophenyl)boronic acid as the starting materials in 82% yield. LCMS for C19H17ClF2NO4Si (M+H)+: m/z=424.1; Found: 423.9.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:31]1(=[O:35])[CH2:34][CH2:33][CH2:32]1.[Cl-].[NH4+]>O1CCCC1>[OH:35][C:31]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2(O)CCC2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
To a solution of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (328 mg, 1.00 mmol) in tetrahydrofuran (3 ml) was added 1.6N solution of n-butyllithium in hexane (0.829 ml, 1.33 mmol) at −78° C., and the mixture was stirred at −78° C. for 15 min. At −78° C., a solution of cyclobutanone (0.0747 ml, 1.00 mmol) in tetrahydrofuran (1 ml) was added, and the mixture was stirred at −78° C. for 30 min. Saturated aqueous ammonium chloride solution (3 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (108 mg, 33.8%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([CH2:13][OH:14])[CH2:8]2.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:14][CH2:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[CH:12][C:3]=3[O:2][CH3:1])[CH2:8]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COc1cccc2c1CCC(CO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1cccc2c1CCC(COS(=O)(=O)c1ccc(C)cc1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
To a solution of (5-methoxy-1,2,3,4-tetrahydro-2-naphthyl)methanol (1.00 g) in dry pyridine (10 ml) was added p-toluenesulfonyl chloride (1.15 g) under ice bath cooling. The mixture was stirred for 1 day at room temperature and partitioned between ethyl acetate and water. The organic layer was separated, washed with water (twice), 1N hydrochloric acid and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1) to give (5-methoxy-1,2,3,4-tetrahydro-2-naphthyl)methyl p-toluenesulfonate (1.70 g) as a white powder. mp: 81°-82° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[CH:6][CH:5]=[C:4]([Cl:17])[N:3]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][CH:20]=1.C1COCC1>O1CCOCC1>[Cl:17][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[C:2]([O:25][CH2:24][CH2:23][C:22]2[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=2)[N:3]=1
Reactant: OCCc1ccc(F)cc1
Reactant: O=C(NC1CCCCC1)c1ccc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(NC1CCCCC1)c1ccc(Cl)nc1OCCc1ccc(F)cc1
Temperature: 150 °C
Yield: 40.6 %

Procedure:
2,6-dichloro-N-cyclohexylnicotinamide (Intermediate 1, 273 mg, 1 mmol) was stirred in 1,4-dioxane (4 ml). To this solution was added 4-fluorophenethyl alcohol (154 mg, 1.1 mmol) followed by bis-sodium hexamethyldisilylamide 1.0M in THF (1.1 ml, 1.1 mmol). The tube was sealed and subjected to microwave heating 150° C. (Biotage Initiator 300 W) for 2 hours. The solvent was evaporated and the residue was diluted with water (15 ml) and extracted with dichloromethane (2×20 ml). The combined extract was washed with brine (20 ml) dried over MgSO4, filtered and evaporated. The crude product was purified on SiO2 (40 g) eluting with ethyl acetate/isohexane 0-40% and gave 6-chloro-N-cyclohexyl-2-[2-(4-fluorophenyl)ethoxy]nicotinamide (153 mg, 40%) as a white solid
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[O:13][CH3:14].S(=O)(=O)(O)O.[CH3:20]O>>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:20])=[O:9])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C=CC(=O)O)ccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(O)c(OC)c1

Procedure:
The preparation was effected analogously to Example 1 from 25 g (0.129 mol) of 4-hydroxy-3-methoxy-cinnamic acid and 180 ml of methanol with concentrated sulphuric acid as the catalyst. For purification, it was chromatographed on silica gel with dichloromethane/diethyl ether (19:1). This gave 21.78 g of methyl 4-hydroxy-3-methoxy-cinnamate as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:11])[CH2:9]O)=[CH:4][CH:3]=1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:11])[CH2:9][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])=[CH:4][CH:3]=1
Reactant: C[C@H](CO)c1ccc(F)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](CN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1
Reaction time: 72 h
Yield: 59.4 %

Procedure:
To a solution of (S)-2-(4-fluorophenyl)propan-1-ol (824 mg, 5.35 mmol, 1.0 equiv), phthalimide (0.824 g, 5.6 mmol, 1.05 equiv), and triphenyl phosphine (2.11 g, 8.03 mmol, 1.5 equiv) in dry THF (18 mL) was added dropwise diethyl azadicarboxylate (DEAD) (3.65 mL, 15% in toluene, 8.03 mmol, 1.5 equiv). The reaction mixture was stirred over 72 h and then concentrated in vacuo. Purification by silica gel chromatography (15-25% EtOAc/Hexanes) provided the title compound (0.9 g, 59%) which was characterized by 1H NMR.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([CH:15]=1)[NH2:14].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:4][CH2:3]1
Reactant: CC1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 100 °C
Yield: 110 %

Procedure:
4-Methylpiperidine (172 mg, 1.738 mmol) was added to a solution of 5-chloro-2-nitroaniline (200 mg, 1.159 mmol) in NMP (5 mL) in the presence of triethylamine (0.404 mL, 2.90 mmol). The reaction mixture was heated via microwave irradiation to 100° C. for 1 h, and. Upon cooling, the solvent was removed by vacuum. Purification by flash column chromatography (5% CH3OH/CH2Cl2) afforded the title compound (300 mg) as a solid. 1H NMR: (400 MHz, CDCl3): δ 7.98 (d, 1H, J=10.0 Hz), 6.26 (dd, 1H, J=2.8 and 10.0 Hz), 6.13 (bs, 2H), 5.92 (d, 1H, J=2.0 Hz), 3.85 (m, 2H), 2.89 (m, 2H), 1.72 (m, 2H), 1.62 (m, 1H), 1.23 (m, 2H), 0.96 (d, 3H, J=6.8 Hz).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[CH2:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCCCCCOCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCCCCOCc1ccccc1
Reaction time: 2 h

Procedure:
Synthesis of [18F]-FCPHA was performed using the following method. PCC (pyridinium chlorochromate; 24.8 g, 115.2 mmol) was slowly added in portions to a solution of 6-benzyloxy-1-hexanol (20 g, 96 mmol) in 200 ml of methylene chloride at room temperature (25° C., RT). The black mixture was stirred for 2 hours, and filtered through 50 g of silica gel. The solvent was removed and the crude oil was separated chromatographically on silica gel using a mixture of hexane:ethyl acetate at a ratio of 90:10. This yielded the aldehyde equivalent, 6-benzyloxy-1-hexanal, at a scale of 14 g (70%).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=[O:5])[CH3:2].S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([Cl:18])=[O:10])=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)Oc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)Oc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
5.9 g (28 mmol) of 2-(ethoxycarbonyloxy)benzoic acid are dissolved in 30 ml of toluene with a few drops of pyridine. 2.15 ml (29 mmol) of thionyl chloride are added dropwise and the mixture is stirred at ambient temperature for 18 h and then concentrated to dryness. The residue is precipitated from pentane. The solid is filtered off and then dried. 5.2 g of 2-(ethoxycarbonyloxy)benzoyl chloride are obtained in the form of a white solid with a yield of 80%.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:8][CH:7]=1)=[O:4].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+].CC#N>O>[CH2:14]([CH:13]([CH2:16][CH3:17])[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[CH:7][CH:8]=1)[N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH3:15]
Reactant: CCC(CC)C(c1ccc(NC(=O)CCl)cc1)n1cncn1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCC(CC)C(c1ccc(NC(=O)CN2CCN(C)CC2)cc1)n1cncn1
Yield: 35.8 %

Procedure:
A mixture of (±)-2-chloro-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]acetamide (0.0218 mol), 1-methylpiperazine (0.0436 mol) and K2CO3 (0.0436 mol) in CH3CN (150 mol) was stirred and refluxed for 4 hours. The mixture was cooled, poured out into water and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (8.13 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/410.5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 3 g (35.8%) (±)-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-4-methyl-1-piperazineacetamide (compound 15).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[N:12]=[N:13][C:14]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)=[CH:15][CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:24].O1CCOCC1>C(Cl)Cl>[ClH:24].[ClH:24].[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[N:13]=[N:12][C:11]([C:8]3([NH2:7])[CH2:10][CH2:9]3)=[CH:16][CH:15]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2ccc(C3(NC(=O)OC(C)(C)C)CC3)nn2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(-c2ccc(C3(N)CC3)nn2)cn1
Reaction time: 2 h

Procedure:
{1-[6-(1-Methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-cyclopropyl}-carbamic acid tert-butyl ester (51 mg, 0.16 mmol) was dissolved in CH2Cl2 (1 mL) and 4M HCl in dioxane (2 mL, 4 mmol) was added. After 2 h, the solvents removed under a stream of N2 to give the title compound as an orange solid, m/z=216.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[O:27][C:28]=2[CH3:29])=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[O:27][C:28]=3[CH3:29])=[CH:35][CH:36]=2)[N:5]=1)[CH3:2]
Reactant: Cc1oc(-c2cccs2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4cccs4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl]propionate (300 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-(2-thienyl)oxazole (450 mg), and N,N-dimethylformamide (5 ml), sodium hydride (60%, oily, 70.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the obtained colorless oily substances, 1 N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature overnight, diluted with 1 N hydrochloric acid (5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionic acid (460 mg, yield: 70%) was obtained. This was recrystallized from acetone-hexane. Melting point: 156–157° C.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=O.[N+]([O-])(O)=O.[F:17][C:18]([F:33])([O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH2:32])=[NH:31])[CH:26]=[CH:27][CH:28]=1)[CH:19]([F:21])[F:20]>>[F:17][C:18]([F:33])([O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[N:32]=[C:5]([C:7]3[S:8][CH:9]=[CH:10][CH:11]=3)[CH:4]=[CH:3][N:31]=2)[CH:26]=[CH:27][CH:28]=1)[CH:19]([F:20])[F:21]
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: CN(C)C=CC(=O)c1cccs1
Solvent: O=[N+]([O-])O
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3cccs3)n2)c1

Procedure:
In accordance with the eneral procedure described in Example 1, reaction of 100 mg (0.55 mmol) of 3-dimethylamino-1-(2-thienyl)-2-propen-1-one [described in EP-A-0 233 461] and 173 mg (0.55 mmol) of 3-(1,1,2,2-tetrafluoroethoxy)phenylguanidine nitrate gives N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-(2-thienyl)-2-pyrimidine-amine; FAB-MS:370 (M+ +1), m.p. 115°-116°, Rf =0.95 (ethyl acetate).
Reaction SMILES: [CH2:1]([CH:3]1[C:9]2[CH:10]=[C:11]([O:17][CH3:18])[C:12]([N+:14]([O-])=O)=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH2:19][CH3:20])[C:4]1=[O:21])[CH3:2].[H][H]>[Pd].CCO>[NH2:14][C:12]1[C:11]([O:17][CH3:18])=[CH:10][C:9]2[CH:3]([CH2:1][CH3:2])[C:4](=[O:21])[N:5]([CH2:19][CH3:20])[CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: [H][H]
Reactant: CCC1C(=O)N(CC)CCc2cc([N+](=O)[O-])c(OC)cc21
Agent: [Pd]
Solvent: CCO
Product: CCC1C(=O)N(CC)CCc2cc(N)c(OC)cc21
Yield: 92.6 %

Procedure:
1,3-Diethyl-8-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (205 mg, 0.70 mmol) was charged to 10 ml EtOH in a Parr bottle and then 50 mg of 10% Pd/C was also charged. The resulting suspension was shaken under 40 psi hydrogen (g) for 2 h. The resulting suspension was filtered through celite and evaporated to yield 7-amino-1,3-diethyl-8-methoxy-1,3,4,5-tetrahydro-3-benzazepin-2-one (170 mg, 93%) which was used crude in the next reaction. 1H-NMR (CDCl3) δ 6.58 (s, 1H), 6.44 (s, 1H), 3.92-3.77 (m, 5H), 3.70-3.40 (br s, 1H), 3.58-3.38 (m, 3H), 3.09 (p, J=7 Hz, 1H), 2.95 (p, J=7 Hz, 1H), 2.20 (p, J=7 Hz, 1H), 1.90 (p, J=7 Hz, 1H), 1.10 (t, J=7 Hz, 3H), 1.04 (t, J=7 Hz, 3H); LC/Ms (ESI+): 263 (M+H).
Reaction SMILES: [CH3:1][CH:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH:9][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:1]
Reactant: COC(CBr)OC
Reactant: CC(N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(CNC(C)c1ccccc1)OC

Procedure:
A solution of α-methylbenzylamine (8.37 g, 0.07 mol) and bromoacetaldehyde dimethylacetal (11.67 g, 0.07 mol) in acetonitrile (150 ml) containing potassium carbonate (12.39 g, 0.09 mol) was heated at reflux for 2d and cooled. The solid was filtered off and the filtrate was concentrated under reduced pressure to leave an oil. Chromatography on silica gel eluting with ethyl acetate afforded the title compound as an oil.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]([OH:27])[N:11]([C:18]([CH3:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:12]2=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.[I:47]I>C1COCC1>[O:1]([C:8]1[CH:16]=[CH:15][C:14]([I:47])=[C:13]2[C:9]=1[CH:10]([OH:27])[N:11]([C:18]([CH3:19])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:26])[C:12]2=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccccc1)N1C(=O)c2cccc(Oc3ccccc3)c2C1O
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(c1ccccc1)N1C(=O)c2c(I)ccc(Oc3ccccc3)c2C1O
Yield: 74.8 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-phenoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (700 mg, 1.95 mmol) was dissolved in THF (28 mL), and the solution was treated with TMEDA (0.94 mL, 6.2 mmol), sec-butyllithium-hexane solution (1.01 mol/L, 6.20 mL, 6.24 mmol) and iodine (594 mg, 2.34 mmol), followed by purification by flash column chromatography (chloroform/methanol=100/0, 99/1) to obtain 4-phenoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (708 mg, yield 75%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[C:12]([O:16][C:17](=[O:46])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:35]2[C:34]3[CH:33]=[CH:32][C:31]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:30][C:29]=3[N:28]=[CH:27][C:26]=2[N:25]=[C:24]1[CH2:44][CH3:45])([CH3:15])([CH3:14])[CH3:13].[OH-].[NH4+:48].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[C:12]([O:16][C:17](=[O:46])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:35]2[C:34]3[CH:33]=[CH:32][C:31]([O:36][CH2:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:30][C:29]=3[N:28]=[C:27]([NH2:48])[C:26]=2[N:25]=[C:24]1[CH2:44][CH3:45])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
mCPBA (10.6 g, 33.7 mmol) was added in one portion to a solution of tert-butyl[4-(7-benzyloxy-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (16.0 g, 33.7 mmol) in chloroform (270 mL). After the reaction was stirred for 1.5 hours, ammonium hydroxide (270 mL) was added. The mixture was stirred for 15 minutes, and p-toluenesulfonyl chloride (6.42 g, 33.7 mmol) was added in three portions. The reaction was stirred for 18 hours. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic fractions were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to afford 9.73 g of tert-butyl[4-(4-amino-7-benzyloxy-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a gray powder.