Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:28])[C:14]([O:16][CH2:17][CH2:18][N:19](OC(C)(C)C)[C:20](C)=O)=[O:15])[CH:7]=[CH:6]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:28])[C:14]([O:16][CH2:17][CH2:18][NH:19][CH3:20])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)OCCN(OC(C)(C)C)C(C)=O)ccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCOC(=O)[C@@H](C)c1ccc2cc(OC)ccc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The product of the Example 45b (17.1 g, 50 mmol) was dissolved in CH2Cl2 (400 mL). The solution was cooled to 0° C. and TFA (80 mL) was added drop-wise. The ice bath was removed and the reaction mixture was stirred at room temperature overnight, then the solvent. was evaporated. The residue was treated with aqueous sodium carbonate (10%) and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over sodium sulfate, and the solvent was evaporated. Trituration of the resulting solid with hexane gave the pure product as a white solid. Mp 64-68° C. 1HNMR (300 MHz, CDCl3) δ 7.67 (d, J=8.5 Hz, 2H), 7.66 (d, J=1.3, 1H), 7.4 (dd, J=8.5 and 1.8 Hz, 1H), 7.18-7.08 (m, 2H), 4.18 (t, J=5.4 Hz, 2H), 3.89 (s, 3H), 3.80 (q, J=7.1 Hz, 1H), 2.73 (t, J=5.4 Hz, 2H), 2.31 (s, 3H), 1.56 (d,l J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.5, 157.6, 135.6, 133.6, 129.2, 128.8, 127.1, 126.1, 125.8, 118.9, 105.5, 63.9, 55.2, 50.0, 45.3, 36.0, 18.4.
Reaction SMILES: [CH2:1]([C:3]1([OH:21])[CH2:8][CH2:7][CH:6]([CH2:9][NH:10]C(=O)OCC2C=CC=CC=2)[CH2:5][CH2:4]1)[CH3:2]>O1CCCC1.[Pd]>[NH2:10][CH2:9][CH:6]1[CH2:7][CH2:8][C:3]([CH2:1][CH3:2])([OH:21])[CH2:4][CH2:5]1
Reactant: CCC1(O)CCC(CNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC1(O)CCC(CN)CC1

Procedure:
A mixture of EXAMPLE 358A (500 mg) and 10% Pd/C (100 mg) in tetrahydrofuran (15 mL) was stirred under H2 for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated to provide the title compound.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:17]1[CH:19]2[CH2:20][CH2:21][CH2:22][CH:18]12>>[OH:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: C1CC2OC2C1
Product: O=C(OCc1ccccc1)N1CCN([C@@H]2CCC[C@H]2O)CC1
Temperature: 80 °C
Yield: 44.2 %

Procedure:
A solution of 0.524 g of benzyl piperazine-1-carboxylate is cooled to 0° C., 0.2 g of 1,2-epoxycyclopentane is added and it is heated at 80° C. for four days. The reaction mixture is concentrated under vacuum and the residue is purified by silica gel chromatography, eluting with EtOAc/MeOH mixture. 0.32 g of the expected compound is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C:13]#[N:14])[N:3]=1.CCN(CC)CC.[NH2:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1>CN1C(=O)CCC1>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1)=[N:3][C:4]([C:13]#[N:14])=[CH:5]2
Reactant: N#Cc1cc2cccc(Cl)c2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3cccc(Cl)c23)C1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a suspension of 1,8-dichloroisoquinoline-3-carbonitrile (0.3 g, 1.35 mmol) and Et3N (0.27 g, 2.7 mmol) in NMP (5 mL) was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.3 g, 1.62 mmol) at RT. The resulting mixture was stirred at 160° C. for 30 minutes in a microwave reactor. The reaction was subsequently quenched with water and the mixture was extracted with EtOAc (3×30 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography eluting with ethyl acetate and petroleum ether (EtOAc/PE=1:10-1:2 gradient) on silica gel to give the title compound (0.45 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.90 (d, J=8.0 Hz, 1H), 7.85-7.83 (m, 2H), 7.79-7.77 (d, J=8.0 Hz, 1H), 7.63 (s, 1H), 4.66-4.58 (m, 1H), 3.75-3.72 (t, J=8.0 Hz, 3H), 3.52-3.35 (m, 3H), 2.31-2.30 (br s, 1H), 2.11-2.07 (br s, 1H), 1.47-1.45 (s, 9H).
Reaction SMILES: [H-].[Na+].[O:3]1[C@@H:15]2[C@@:16]34[CH2:18][CH2:19][N:20]([CH3:21])[C@@H:10]([C@@H:11]3[CH:12]=[CH:13][C@@H:14]2[OH:22])[CH2:9][C:8]2=[C:17]4[C:4]1=[C:5]([O:23][CH2:24][O:25][CH3:26])[CH:6]=[CH:7]2.Cl[C:28]1[N:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[O:3]1[C@@H:15]2[C@@:16]34[CH2:18][CH2:19][N:20]([CH3:21])[C@@H:10]([C@@H:11]3[CH:12]=[CH:13][C@@H:14]2[O:22][C:37]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:38]=2)[CH2:9][C:8]2=[C:17]4[C:4]1=[C:5]([O:23][CH2:24][O:25][CH3:26])[CH:6]=[CH:7]2
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(O[C@H]2C=C[C@H]3[C@H]4Cc5ccc(OCOC)c6c5[C@@]3(CCN4C)[C@H]2O6)nc1

Procedure:
NaH (0.72 g, 30 mmol) is stirred with absolute DMF (12 ml) at RT and then 4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (1.9764 g, 6 mmol) in DMF (12 ml) is added. After the development of gas has ceased, a solution of ethyl 2-chloro-nicotinate (5.568 g, 30 mmol) in absolute DMF (8 ml) is added at RT. After 1 hour at RT this reaction mixture is poured onto H2O (100 ml) and extracted 3 times with CH2Cl2 (60 ml). The combined organic phases are dried with Na2SO4, concentrated by rotary evaporation and the residue is purified by flash chromatography (90 g silica gel, CH2Cl2MeOH=9/1). Yield: 2.53 g (5.29 mmol, 88%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:3]=1.[C:17]([O:21][C:22]([CH2:24][CH2:25][CH2:26][S:27]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39](F)(F)F)[CH:38]=1)[C:33](O)=[O:34])(=[O:29])=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18]>CCCCCCC.C(OCC)(=O)C>[C:17]([O:21][C:22](=[O:23])[CH2:24][CH2:25][CH2:26][S:27]([C:30]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:32]([C:33](=[O:34])[N:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH3:9])[CH:31]=1)(=[O:29])=[O:28])([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)CCCS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1nnc(Cl)cc1-c1ccccc1C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N(C)c2nnc(Cl)cc2-c2ccccc2C)cc(S(=O)(=O)CCCC(=O)OC(C)(C)C)c1
Yield: 14 %

Procedure:
The title compound was prepared in analogy to example 1, from (6-chloro-4-o-tolyl-pyridazin-3-yl)-methyl-amine (example 4, intermediate a) and 3-(3-tert-butoxycarbonyl-propane-1-sulfonyl)-5-trifluoromethyl-benzoic acid after a reaction time of 18 hours and using a gradient of n-heptane:ethyl acetate (100:0 to 30:70) for the chromatographic purification. Another purification step using preparative HPLC (Gemini NX column) with a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2) yielded the desired compound as a colorless solid (14%). MS (ESI+): m/z=541.090 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=4[CH:13]=3)=[CH:9][N:10]=2)[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19]([CH3:20])=[O:31])[S:18][C:14]=4[CH:13]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: CSc1nc2ccc(Cc3cnc4ccc(Cl)nn34)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cc3cnc4ccc(Cl)nn34)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a solution of 6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (1.6 g, 4.6 mmol) in DCM (90 mL) was added m-CPBA (1.0 g, 5.8 mmol) at 0° C. The reaction mixture was stirred for 2 h at 0° C., then aq Na2S2O3 (45 mL) was added and the mixture was stirred for 0.5 h. The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole as a yellow solid (1.68 g, 100%). 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J=8.4 Hz, 1H), 7.92 (d, J=3.6 Hz, 1H), 7.89 (s, 1H), 7.58 (s, 1H), 7.53 (dd, J=2.1, 8.7 Hz, 1H), 7.05 (d, J=9.3 Hz, 1H), 4.48 (s, 2H), 3.07 (s, 3H). LCMS (ESI) m/z 363 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]C(COC(=O)NCCCCCCCCCCCCCCCCCC)CN)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][CH2:36][CH2:37][CH2:38][S:39]([NH:42][CH2:43][CH:44](OC)[CH2:45][S:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])(=[O:41])=[O:40]>>[C:1]([O:5][C:6]([NH:8][CH:44]([CH2:43][NH:42][S:39]([CH2:38][CH2:37][CH2:36][Cl:35])(=[O:40])=[O:41])[CH2:45][S:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)NC(=O)OC(C)(C)C
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)NC(=O)OC(C)(C)C

Procedure:
3-Hexadecylthio-2-tert-butoxycarbonylaminopropylamine IV e4 is allowed to react and worked up by the same procedure as described in (4). m.p. 100.5°-101.5° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.[BH4-].[Na+]>C1COCC1.CO>[N:1]1[N:2]([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:12][CH:13]=2)[N:3]=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(-n2nccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(-n2nccn2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 42.26 g (244 mmol) of 4-[1,2,3]-triazol-2-yl-benzaldehyde in 140 ml of THF and 420 ml of MeOH, 9.23 g (244 mmol) of NaBH4 are added portionwise at 0-5° C. and the mixture is stirred for 30 min. at the same temperature. The reaction is quenched with sat. NH4Cl at 0-5° C. and the mixture is extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[CH:38]12[O:45][CH:42]([CH2:43][CH2:44]1)[CH2:41][NH:40][CH2:39]2.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:40]3[CH2:39][C@@H:38]4[O:45][C@@H:42]([CH2:43][CH2:44]4)[CH2:41]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CC2CNCC1O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2C[C@H]3CC[C@@H](C2)O3)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 18.7 %

Procedure:
A mixture of 0.15 g (0.28 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.13 g (0.84 mmol) 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride and 0.20 g (1.4 mmol) potassium carbonate in 1 ml dimethyl sulfoxide was heated at 150° C. under microwave irradiation in a sealed tube for 30 min. Another portion of 0.06 g (0.4 mmol) 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride was added and the reaction mixture was heated at 150° C. under microwave irradiation in a sealed tube for 30 more minutes. After cooling to room temperature the reaction mixture was diluted with water and extracted with four portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate and concentrated. Flash column chromatography gave 32 mg (18%) of the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:15][NH:16][C:17]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)=[O:18])[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(=O)(=O)(O)O.[CH3:35]O>>[CH3:35][O:13][C:12](=[O:14])[CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:15][NH:16][C:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)=[O:18]
Reactant: COc1ccc(CC(=O)NCC(C(=O)O)c2ccc(OC)c(OC)c2)cc1OC
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(CNC(=O)Cc1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1

Procedure:
A solution of 23.3 g of 2-(3,4-dimethoxyphenyl)-3-{{[(3,4-dimethoxyphenyl)methyl]carbonyl}amino}propanoic acid and 15.5 ml of concentrated sulfuric acid in 300 ml of methanol was refluxed for 6 hours and evaporated to dryness. The residue was partitioned between ethyl acetate and dilute sodium bicarbonate solution and the organic layer was dried and evaporated to give 15.5 g of crude 2-(3,4-dimethoxyphenyl)-3-{{[(3,4-dimethoxyphenyl)methyl]carbonyl}amino}propanoic acid methyl ester. Crystallization from ethyl acetate provided the analytical sample, mp 92°-93°.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([NH2:14])[C:9]([NH2:13])=[CH:10][C:11]=1[F:12].[N+:16]([C:19]1[C:20]([CH:30]=O)=[N:21][N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:23]=1)([O-:18])=[O:17]>CO>[F:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])=[CH:7][C:8]2[NH:14][C:30]([C:20]3[C:19]([N+:16]([O-:18])=[O:17])=[CH:23][N:22]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[N:21]=3)=[N:13][C:9]=2[CH:10]=1
Reactant: CN(C)CCNc1cc(N)c(N)cc1F
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Solvent: CO
Product: CN(C)CCNc1cc2[nH]c(-c3nn(C4CCCCO4)cc3[N+](=O)[O-])nc2cc1F
Yield: 17.8 %

Procedure:
A solution of 1 g of N4-(2-dimethylaminoethyl)-5-fluorobenzene-1,2,4-triamine in 30 mL of methanol with 1.06 g of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde is stirred at ambient temperature for 72 hours. After evaporation of the solvent under vacuum in a rotary evaporator, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-90 cartridge with an eluent of 100% dichloromethane to 85/15 dichloromethane/methanol. 350 mg of N1-{6-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-3H-benzimidazol-5-yl}-N2,N2-dimethylethane-1,2-diamine are isolated in the form of an orange foam. ES mass spectrum: 418(+)=(M+H)(+); 334(+)=(M+H)(+)-THP+H, 209.6=(M+2H)(2+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1.Cl>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.5 %

Procedure:
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (440 mg; 2.2 mmol), triethylamine (420 μL; 3.0 mmol) and 2-chloro-4-methyl-5-nitro-pyridine (346 mg; 2.0 mmol) is irradiated in a mono-mode microwave oven for 10 hours at 120° C. The mixture is then cooled to room temperature, water is added (5 mL) and the pH is adjusted to pH 4-5 by addition of aq. 1N hydrochloric acid. After extraction with dichloromethane (2×10 mL), the combined organic layers are dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue obtained is finally purified by column chromatography on silica gel (dichloromethane:ethyl acetate 1:0; 12:1; 2:1) to afford the desired product (480 mg; 1.43 mmol).
Reaction SMILES: [CH3:1][CH:2]1[CH:13]=[C:12]([CH3:14])[CH2:11][CH2:10][C:3]21[CH:8]([OH:9])[O:7][CH2:6][CH2:5][CH2:4]2.[CH3:15]C1C=CC(S(O)(=O)=O)=CC=1>CO.CC(OC)(C)C>[CH3:15][O:9][CH:8]1[C:3]2([CH2:10][CH2:11][C:12]([CH3:14])=[CH:13][CH:2]2[CH3:1])[CH2:4][CH2:5][CH2:6][O:7]1
Reactant: CC1=CC(C)C2(CCCOC2O)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: COC(C)(C)C
Product: COC1OCCCC12CCC(C)=CC2C
Yield: 7041.6 %

Procedure:
A solution of 7,9-dimethyl-2-oxaspiro[5.5]undec-8-en-1-ol (5.0 g, 26 mmol) and p-TsOH (50 mg) in methanol (20 ml) was stirred at reflux temperature for 0.5 hours. The mixture was diluted with MTBE, washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was distilled bulb-to-bulb to yield a colorless oil (4.3 g, 80%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.CN(C)[CH:22]=[O:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH:12]=[CH:13][C:14]=1[CH:22]=[O:23])([O-:3])=[O:2]
Reactant: CCN(CC)c1cccc([N+](=O)[O-])c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 27 %

Procedure:
38 parts of m-nitrodiethylaniline is introduced into a mixture of 48 parts of phosphorus oxychloride in 120 parts of dimethylformamide. After having been stirred for six hours at 60°C the mixture is poured into ice-water and the precipitate is suction filtered, washed free from acid and recrystallized from acetone. 12 parts (27% of theory) of 2-nitro-4-diethylaminobenzaldehyde having a melting point of 75° to 77°C is obtained. ##SPC15##
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:8]2[CH:9]=[CH:10][CH2:11][O:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)=[O:6]>CO.O>[O:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:7]([C:5]([OH:6])=[O:4])[C:8]=2[CH:9]=[CH:10][CH2:11]1
Reactant: COC(=O)c1cccc2c1C=CCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc2c1C=CCO2
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A solution of NaOH (7.26 mmol) in a mixture of MeOH (5.4 mL) and water (12.1 mL) is added to 2H-chromene-5-carboxylic acid methyl ester (4.84 mmol). The mixture is stirred at 55° C. for 3 h, partially concentrated in vacuo to remove MeOH and made acidic by addition of hydrochloric acid (1.0M). The desired carboxylic acid precipitates and is collected by filtration. 1H-NMR (DMSO-d6): δ=4.75 (bs, 2H); 5.99-6.05 (m, 1H); 6.98 (d, J=7.78 Hz, 1H); 7.19 (t, J=7.78 Hz, 1H); 7.25 (d, J=10.3 Hz, 1H); 7.40 (d, J=7.78 Hz, 1H); 13.0 (bs, 1H).
Reaction SMILES: CS(O)(=O)=O.[OH:6][N:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH:10]([OH:15])[CH2:9][C:8]1([CH3:17])[CH3:16].[C:18](#N)[CH3:19].OO>O.CS(O)(=O)=O.C1CCCCC1>[CH:19]1([O:6][N:7]2[C:12]([CH3:13])([CH3:14])[CH2:11][CH:10]([OH:15])[CH2:9][C:8]2([CH3:17])[CH3:16])[CH2:18][CH2:10][CH2:9][CH2:8][CH2:16]1
Reactant: CC#N
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: CS(=O)(=O)O
Agent: OO
Solvent: C1CCCCC1
Solvent: O
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Temperature: 62 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A solution of 0.234 g (0.842 mmol) of ferrous sulfate heptahydrate, 3 ml of water, and 0.293 g (3.05 mmol) of methanesulfonic acid is added to a mixture of 5.00 g (29.0 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol, 45 ml of acetonitrile, and 32 ml of cyclohexane, which has been heated to 62° C. A solution of 8.07 g (119 mmol) of 50% aqueous hydrogen peroxide is added dropwise over 2.25 hours to the reaction mixture while the temperature is maintained at reflux. A solution of 0.069 g of ferrous sulfate heptahydrate and 0.188 g of methanesulfonic acid in 2 ml of water is added to the reaction mixture 2 hours after the peroxide addition is started. A solution of 0.065 g of ferrous sulfate heptahydrate and 0.108 g of methanesulfonic acid in 1 ml of water is added to the reaction mixture 3.5 hours after the peroxide addition is started. After a total reaction time of 4.5 hours at reflux, the reaction mixture is allowed to cool. Excess peroxide is quenched with aqueous sodium sulfite solution. The aqueous layer is extracted with a 2:1 mixture of acetonitrile and cyclohexane, and the combined organic layers are washed with sodium hydroxide solution. To the organic layer are added 6 ml of t-butyl alcohol, 6 ml of water, 0.4 g of sodium hydroxide, and 0.70 g of sodium borohydride. The mixture is stirred for 3 hours, and the aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with aqueous citric acid, aqueous sodium bicarbonate, and then concentrated. Purification by flash chromatography with 1:1 heptane-ethyl acetate affords 5.10 g (69% yield) of the title compound as a light yellow syrup, GC assay 93%.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH2:3][CH3:4].[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[Cl:18])=[CH:11][CH:10]=[CH:9][C:8]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cccc(C(=O)OC)c2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1[nH]c2c(C(=O)OC)cccc2c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-(n-butyl)indole-7-carboxylate (P) (0.3 g) in 6 ml of dimethylformamide at room temperature was added N-chlorosuccinimide (0.17 g). The solution was stirred at room temperature for 16 hours, then water was added, and the mixture extracted with ether. The extract was separated and solvent evaporated under reduced pressure, to give methyl 2-(n-butyl)-3-chloroindole-7-carboxylate, a compound of Formula (Q) where X is chloro, as an oil.
Reaction SMILES: I[C:2]1[C:3]([O:24]C)=[CH:4][C:5]([O:22]C)=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-])=O)[N:11]=[CH:10][CH:9]=2)[CH:7]=1.[C:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:28])=[CH2:27]>CCOCC>[C:29]1([CH:26]([CH3:28])[CH2:27][C:2]2[C:3]([OH:24])=[CH:4][C:5]([OH:22])=[C:6]([C:8]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[NH2:19])[N:11]=[CH:10][CH:9]=3)[CH:7]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C=C(C)c1ccccc1
Reactant: COc1cc(OC)c(-c2ccnn2-c2ccccc2[N+](=O)[O-])cc1I
Solvent: CCOCC
Product: CC(Cc1cc(-c2ccnn2-c2ccccc2N)c(O)cc1O)c1ccccc1

Procedure:
12.8 Analogous reaction of 5-[5-iodo-2,4-dimethoxyphenyl]1-(2-nitrophenyl)-1H-pyrazole with isopropenylbenzene, hydrogenation and ether cleavage gives the compound 5-{5-(2-phenylpropyl)-2,4-dihydroxyphenyl}-1-(2-aminophenyl)-1H-pyrazole.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([N:16]=[C:14]([CH:5]2[CH:6]([C:11]([OH:13])=[O:12])[CH:7]3[CH2:10][C:4]2([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]3)[OH:15])=[CH:18][CH:19]=1
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: Nc1ccc(O)cc1
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=Nc1ccc(O)cc1
Reaction time: 1 h

Procedure:
408 g of an isomeric mixture of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride are heated with 238.26 g of 4-aminophenol to 200° C.; the pressure is lowered to 2.7 Pa and the mixture is held for 1 hour under these conditions. There are thus obtained 535 g of a red solid resin (87.7% of theory) having a glass transition temperature of 58° C.