Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH:12]([CH2:13][O:14][C:15]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[O:17][N:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.CC(O)C.Cl>C(Cl)(Cl)Cl.CO>[ClH:24].[NH2:8][CH:12]([CH2:11][OH:10])[CH2:13][O:14][C:15]1[C:19]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=2[O:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1C(COc2noc3ccc(Cl)cc23)COC1(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(CO)COc1noc2ccc(Cl)cc12
Yield: 159.7 %

Procedure:
To a solution of 7.68 g of 3-[(3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)methoxy]-5-chloro-1,2-benzoisoxazole in 77 ml of chloroform and 77 ml of methanol is added 16 ml of a 2-propanol solution (7.5N) of hydrogen chloride at 20°-25° C., and they are subjected to reaction at the same temperature overnight. The crystals precipitated are collected by filtration, to obtain 4.47 g of 3-(2-amino-3-hydroxypropoxy)-5-chloro-1,2-benzoisoxazole hydrochloride.
Reaction SMILES: C[C@H](OC1N=C2C(N=C(OC)N2CCCC[NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=C(N)N=1)CCC.Cl[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:44]([O:45][CH3:46])=[N:43][C:42]2[C:37]1=[N:38][C:39]([O:48][C@@H:49]([CH3:53])[CH2:50][CH2:51][CH3:52])=[N:40][C:41]=2[NH2:47].O1CCC(N)CC1>>[CH3:53][C@H:49]([O:48][C:39]1[N:38]=[C:37]2[C:42]([N:43]=[C:44]([O:45][CH3:46])[N:36]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:41]([NH2:47])[N:40]=1)[CH2:50][CH2:51][CH3:52]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCNC3CCOCC3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Agent: NC1CCOCC1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCNC3CCOCC3)c2n1
Temperature: 70 °C

Procedure:
Prepared similarly to Intermediate 36 from 9-(5-chloropentyl)-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine and tetrahydro-2H-pyran-4-amine but with heating at 70° C. for an additional 20 hours.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([F:20])[CH:19]=1.[NH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1>>[F:13][C:14]1[CH:15]=[C:16]([C:5]2[C:6]3[S:10][C:9]([CH3:11])=[N:8][C:7]=3[C:2]([NH:24][C:25]3[N:26]=[C:27]([CH3:30])[S:28][CH:29]=3)=[N:3][CH:4]=2)[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1nc(N)cs1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Product: Cc1nc(Nc2ncc(-c3cc(F)cc(F)c3)c3sc(C)nc23)cs1

Procedure:
The title compound, MS: m/e=375.1 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B), 3,5-difluorophenylboronic acid and 4-amino-2-methylthiazole (Example C).
Reaction SMILES: N[CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH2:15]=O.[BH3-][C:18]#[N:19].[Na+].O>C(CO)(F)(F)F>[CH3:15][N:19]([CH3:18])[CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: C=O
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: OCC(F)(F)F
Product: CN(C)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 4-amino-1-benzylpiperidine (1.47 g, 7.7 mmol) in CF3CH2OH (14 ml) were added molecular sieve 4 Å (5 g), and paraformaldehyde (0.51 g, 17 mmol). After stirring at RT for 1 h, NaCNBH3 (2.5 g, 39.8 mmol) was added and stirred for 16 h at RT. The reaction was stopped by addition of H2O and the product was extracted with (4:1) (Et2O:CH2Cl2). Organic fractions were combined and washed with brine (2×), dried over MgSO4, filtered and concentrated to give a crude material which was purified by silica flash chromatography to afford 4-dimethylamino-1-benzylpiperidine (80% yield). FAB Mass [M+1]+35Cl 219.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@@H:10]([C:15]([OH:17])=[O:16])[C:11]([SH:14])([CH3:13])[CH3:12].[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(O)C.O>[C:18]([N:9]1[C@@H:10]([C:15]([OH:17])=[O:16])[C:11]([CH3:13])([CH3:12])[S:14][C@H:1]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:20])[CH3:19]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: O=Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Solvent: O
Product: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
A solution of benzaldehyde (102 ml, 1.01 mol) in ethanol (300 ml) was added to a solution of D-penicillamine (150 g, 1.01 mol) in water (900 ml) at room temperature. The mixture was stirred at room temperature for 15 minutes and under ice-cooling for 1.5 hours, and then the precipitated crystals were filtered off and dried. Acetic anhydride (480 ml, 5.05 mol) was added dropwise to a solution of the obtained crystals in water (700 ml) at 60° C. over 15 minutes. The mixture was stirred at the temperature for 15 minutes, then at room temperature for 15 minutes and under ice-cooling for 1.5 hours, and the precipitated crystals were filtered off and dried to give 252.3 g (89%) of the target compound.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][C:28]5[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=5[O:26][CH2:25]4)=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[OH:35][Li].O.[O:38]1[CH2:43]COCC1.O>C(O)(=O)C>[O:29]1[C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[O:26][CH2:25][C@@H:24]1[C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:14]2[CH2:13][CH2:12][N:11]([CH2:10][C:7]3[CH:8]=[C:9]([CH:4]=[CH:5][CH:6]=3)[C:43]([OH:38])=[O:35])[CH2:16][CH2:15]2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(CN2CCN(Cc3ccc([C@H]4COc5ccccc5O4)cc3)CC2)cc1
Reactant: C1COCCO1
Reactant: [Li]O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cccc(CN2CCN(Cc3ccc([C@H]4COc5ccccc5O4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-{4-[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-piperazin-1-ylmethyl}-benzoic acid methyl ester (48 mg, 0.11 mmol), LiOH.H2O (15 mg, 0.37 mmol), dioxane (5 mL), and water (0.5 mL) is stirred at room temperature for 16 h. The reaction mixture is neutralized with acetic acid and concentrated. The residue is triturated with water to give the title compound (LCMS method 4: ES+ m/z 445.2 [M+H]+, Rt=1.31 min)
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][CH2:14][C@H:15]([OH:26])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1)=[O:17])[CH3:12].Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([C:37]3[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=3)[N:35]=[CH:36][C:29]=12>C1COCC1.CCOC(C)=O>[Cl:43][C:42]1[C:37]([N:34]2[C:30]3[N:31]=[CH:32][N:33]=[C:28]([O:26][C@@H:15]([CH2:14][O:13][CH2:11][CH3:12])[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=4)=[O:17])[C:29]=3[CH:36]=[N:35]2)=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOC[C@H](O)C(=O)Nc1ccc(C)cn1
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.9 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (3.26 mL, 3.26 mmol) was added dropwise to a stirred solution of (S)-3-ethoxy-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate G1) (730 mg, 3.26 mmol) in anhydrous THF (15 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes and then a solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (866 mg, 3.26 mmol) in dry THF (3 mL) added dropwise over 1 minute and the reaction heated to 50° C. for 3hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (2×25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography eluting with EtOAc to afford (2S)-2-[1-(3-chloropyridin-2-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-ethoxy-N-(5-methylpyridin-2-yl)propanamide (930 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 1.20 (3H, t), 2.29 (3H, s), 3.59-3.67 (2H, m), 4.06-4.17 (2H, m), 6.06-6.08 (1H, m), 7.47 (1H, dd), 7.53 (1H, dd), 8.00 (1H, dd), 8.09-8.10 (1H, m), 8.13 (1H, d), 8.48 (1H, s), 8.62 (1H, dd), 8.63 (1H, s), 8.65 (1H, s); m/z (ESI+) (M+H)+=454.3; HPLC tR=1.97 min.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:23]([O:25][CH3:26])=[O:24])=[N:9][C:10]([C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH2:19][NH:20]4)=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37](=[O:48])[O:38]C1C=CC([N+]([O-])=O)=CC=1>CC#N>[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37]([N:20]1[C:21]2[C:16](=[CH:15][CH:14]=[C:13]([C:10]3[N:9]=[C:8]([C:23]([OH:25])=[O:24])[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][CH:11]=3)[CH:22]=2)[CH2:17][CH2:18][CH2:19]1)=[O:38].[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37]([N:20]1[C:21]2[C:16](=[CH:15][CH:14]=[C:13]([C:10]3[N:9]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][CH:11]=3)[CH:22]=2)[CH2:17][CH2:18][CH2:19]1)=[O:48]
Reactant: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1-c1ccccc1
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1-c1ccccc1
Product: O=C(O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of methyl 3-phenyl-6-(1,2,3,4-tetrahydroquinolin-7-yl)picolinate (29H) (17 mg, 0.049 mmol) and 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) (15.5 mg, 0.049 mmol) in anhydrous CH3CN (0.8 mL) was heated to reflux for 6 hours, cooled to rt, concentrated under reduced pressure, and the crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 72:28-55:45, to provide the desired product methyl 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-phenylpicolinate (29I): 1H NMR (300 MHz, CDCl3) δ 8.23 (1H, d), 8.13 (1H, d), 7.85-7.76 (3H, m), 7.66 (1H, d), 7.48-7.35 (4H, m), 7.34-7.28 (2H, m), 6.89 (1H, d), 3.98 (2H, t), 3.71 (3H, s), 2.85 (2H, t), 2.09 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])[C:4]=2[CH:3]=1.CN1C[CH2:29][O:28][CH2:27]C1.Cl.C[NH:33]OC>C1COCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([NH:33][CH2:29][O:28][CH3:27])=[O:16])=[O:12])[C:4]=2[CH:3]=1
Reactant: CNOC
Reactant: CN1CCOCC1
Reactant: O=C(O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: Cl
Solvent: C1CCOC1
Product: COCNC(=O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 536.6 %

Procedure:
By the method described in Example 5, the title compound of Example 4 (1.2 g, 3.6 mmol) in 40 mL of THF was converted to its mixed anhydride with NMM (0.42 g, 3.6 mmol) and IBCF (0.49 g, 3.6 mmol) and coupled to N,O-dimethylhydroxylamine HCl (0.35 g, 3.6 mmol) using an additional 0.36 mmol (3.6 mmol) of NMM to liberate the free base of N,O-dimethylhydroxylamine HCl. This procedure gave 726 mg of the title compound after HPLC purification on silica gel.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)([O-:3])=[O:2].[Br:20]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C)C=O>[Br:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:11][CH2:12][CH2:13]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccccc1N1CCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1N1CCCc2cc(Br)ccc21
Yield: 82.7 %

Procedure:
A stirred solution, under nitrogen, of 1-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline (76.3 g, 0.30 mole) in dimethylformamide (1000 ml) was cooled to -10° C. A solution of of N-bromosuccinimide (58.7 g, 0.33 mole) in dimethylformamide (250 ml) was added dropwise at such a rate as to keep the reaction temperature below 0° C. (1.5 hours). Half-an hour after the addition was completed, the reaction mixture was poured into 7 liters of 2N-sodium hydroxide solution/ice, with stirring. The product separated as an oil. The quench fluids were decanted and the oil was rinsed several times with water. The oil was dissolved in dichloromethane (1.5 l). The organic solution was extracted once with 2N-sodium hydroxide solution, thrice with water, dried over sodium sulfate and concentrated. The residue was dissolved in 1:1 hexane:toluene (250 ml) and the solution was absorbed on a chromatography column containing 2 kg of silica gel packed in 1:1 hexane:toluene. Elution with this solvent mixture provided 82.7 g (82%) of product, as an oil. For analysis, a sample was Kugelrohr distilled at a vessel temperature of 166°-168° C. (0.2 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].C(O[C:15](=N)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])C.C(O)(=O)C>C(OCC)C>[CH2:20]([O:19][C:17]([CH2:16][C:15]1[NH:11][C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1)=[O:18])[CH3:21]
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: CCOC(=N)CC(=O)OCC
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)Cc1nc2cc(C(=O)O)ccc2[nH]1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A mixture of 3,4-diaminobenzoic acid (9.4 g, 62 mmol), ethyl 3-ethoxy-3-iminopropionate and glacial acetic acid (15 mL) was stirred 30 minutes at 110° C. under nitrogen. The mixture was poured over crushed ice (50 mL) and stirred 30 minutes to give a dark yellow oil. The mixture was stirred while diethyl ether (25 mL) was added to give a gray precipitate. The precipitate was isolated by filtration, washed several times with diethyl ether and dried under vacuum to provide 2-ethoxycarbonylmethyl-1H-benzoimidazole-5-carboxylic acid (12.6 g, 83% yield); 1H-NMR (300 Mhz, DMSO-d6): 12.77 (broad s, 1H), 8.10 (s, 1H), 7.79 (d, 1H, J=8.4 Hz), 7.57 (d, 1H, J=8.4 Hz), 4.11 (q, 2H, J=7.1 Hz), 4.02 (s, 2H), 1.17 (t, 3H, J=7.1 Hz).
Reaction SMILES: [C:1]([CH2:4][S:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:20][C:7]1=2)([OH:3])=O.[C:33]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([S:39]([NH:42][C:1]([CH2:4][S:5][CH:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][O:9][C:8]3[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=4)=[CH:20][C:7]2=3)=[O:3])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)CSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Product: O=C(CSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21)NS(=O)(=O)c1ccccc1

Procedure:
11-Carboxymethylthio-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and benzensulfonamide were used and reacted in the same manner as in Example 39 to obtain the title compound.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[CH2:16]([C:18]1[N:19]=[N+:20]([O-:38])[C:21]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:24][C:22]=2[N:23]=1)[CH3:17].FC(F)(F)C(O)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[CH2:16]([C:18]1[N:19]=[N+:20]([O-:38])[C:21]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:24][C:22]=2[N+:23]=1[O-:6])[CH3:17]
Reactant: CCc1nc2cc(OCCCN3CCOCC3)ccc2[n+]([O-])n1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCc1n[n+]([O-])c2ccc(OCCCN3CCOCC3)cc2[n+]1[O-]
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 25.9 %

Procedure:
Hydrogen peroxide (70%; 0.53 mL, ca. 10.43 mmol) was added dropwise to a stirred solution of trifluoroacetic anhydride (1.45 mL, 10.43 mmol) in DCM (20 mL) at 5° C. The solution was stirred at 20° C. for 10 min, then cooled to 5° C., added to a solution of 1-oxide 31 (260 mg, 1.04 mmol) and trifluoroactic acid (0.17 mL, 2.23 mmol) in CHCl3 (20 mL) at 5° C. The solution was stirred at 20° C. for 24 h, diluted with dilute aqueous NH3 solution (50 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by column chromatography, eluting with 5% MeOH/DCM to give 1,4-dioxide 32 (90 mg, 32%) as a bright yellow solid, mp 123-126° C.; 1H NMR δ 8.36 (d, J=9.5 Hz, 1 H, H-8), 7.77 (d, J=2.6 Hz, 1 H, H-5), 7.36 (dd, J=9.5, 2.6 Hz, 1 H, H-7), 4.29 (t, J=6.4 Hz, 2 H, CH2), 3.72 (t, J=4.6 Hz, 4 H, 2×CH2O), 3.21 (q, J=7.5 Hz, 2 H, CH2), 2.54 (t, J=7.0 Hz, 2 H, CH2), 2.47 (t, J=4.6 Hz, 4 H, 2×CH2N), 2.10-2.04 (m, 2 H, CH2), 1.44 (t, J=7.5 Hz, 3 H, CH3); 13C NMR δ 165.1, 157.1, 141.5, 129.6, 124.4, 123.4, 98.0, 68.1, 66.9 (2), 55.0, 53.7 (2), 25.9, 24.1, 9.3. Anal. Calcd for C16H22N4O4: C, 57.5; H, 6.3; N, 16.8. Found: C, 57.2; H, 6.5; N, 16.5%.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.Br[CH2:19][CH2:20][CH:21]1[O:23][CH2:22]1>CN(C=O)C.CCOC(C)=O>[Br:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:19][CH2:20][CH:21]3[CH2:22][O:23]3)[C:7]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:4]([Br:3])=[CH:5][CH:6]=3
Reactant: BrCCC1CO1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2CCC1CO1
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Crushed KOH (0.0054 g, 0.0954 mmol, 1.2 equiv) was added to 3,6-dibromocarbazole (0.0258 g, 0.0795 mmol, 1 equiv.) in 0.5 mL DMF solution and the mixture was stirred for 30 min. 1-Bromo-3,4-epoxybutane (0.0300 g, 0.199 mmol) in 0.5 mL DMF solution was dropwise added into the mixture and it was stirred at room temperature for overnight. Reaction crude was diluted with 20 mL EtOAc and washed with water 5×10 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford 31.2 mg white solid as product, yield 97.9%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([CH3:22])([CH3:21])[CH2:11][C@:12]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH2:13][C:14]#[CH:15])=[C:6]([CH:9]=1)[CH:7]=[O:8].CC(=CC)C.Cl([O-])=[O:29].[Na+].P([O-])([O-])(O)=O.[Na+].[Na+]>C(O)(C)(C)C.C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([CH3:22])([CH3:21])[CH2:11][C@:12]([OH:20])([C:16]([F:18])([F:19])[F:17])[CH2:13][C:14]#[CH:15])=[C:6]([CH:9]=1)[C:7]([OH:29])=[O:8]
Reactant: [O-][Cl+][O-]
Reactant: C#CC[C@](O)(CC(C)(C)c1ccc(F)cc1C=O)C(F)(F)F
Agent: CC=C(C)C
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: C#CC[C@](O)(CC(C)(C)c1ccc(F)cc1C(=O)O)C(F)(F)F
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a solution of 15 g (0.031 mol) of 5-fluoro-2-((S)-3-hydroxy-1,1-dimethyl-3-trifluoromethylhex-5-ynyl)benzaldehyde in 240 mL of tert-BuOH was added a solution of the 62 mL (0.124 mol) of 2-methyl-2-butene in THF (2 M). To this solution was added a solution of the 17.5 g of sodium chlorite (0.150 mol) and 42.8 g of sodium hydrogen phosphate (0.138 mol) in water. The reaction mixture was stirred overnight. The volatiles were removed in vacuo. The aqueous mixture was then acidified to pH=1 with 1 M HCl, extracted with 1200 mL of ethyl acetate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture was chromatographed on silica gel using 10-100% ethyl acetate/hexanes to afford 10.6 g (103%) of 5-fluoro-2-((S)-3-hydroxy-1,1-dimethyl-3-trifluoromethylhex-5-ynyl)benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13](=[CH:16][O:17]C)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C1(C)C=CC=CC=1.C(O)=O.[OH-].[K+]>CO>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH:16]=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: COC=C1CCC(c2ccc(C(=O)OC)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 123 g of 4-[4-(methoxymethylidene)cyclohexyl]benzoic acid methyl ester 1000 ml of toluene and 500 ml of formic acid was stirred vigorously at room temperature overnight. The formic acid phase was separated. The toluene phase was washed neutral with water, dried over sodium sulfate, filtered and concentrated. The crude trans/cis-mixture obtained was dissolved in 600 ml of methanol. The solution was added dropwise at 3° C. within 10 minutes to 1.2 1 of 0.1N methanolic potassium hydroxide solution while gassing with nitrogen. The reaction mixture was stirred at 3° C. for a further 1 hour, then poured on to ice/water and extracted with diethyl ether. The organic phases were washed neutral with water, dried over sodium sulfate, filtered and concentrated. Recrystallization of the residue from tert. butyl methyl ether yielded 88.5 g of 4-(trans-4-formylcyclohexyl)benzoic acid methyl ester with m.p. 84°-85° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27]C1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1>>[F:27][C:25]1[CH:26]=[C:21]([CH:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:12]=3)[O:17]2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cccc(F)c2)O3)nc1

Procedure:
2-[2-(3-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 210 mg of 2-(3-fluorophenyl)chroman-6-ol. The product was recrystallised from 2-propanol. 1H NMR (400 MHz, CDCl3) δ: 9.07 (d, 1H, J 2.8 Hz), 8.46 (dd, 1H, J 9.0, 2.8 Hz), 7.36 (m, 1H), 7.21-7.15 (m, 2H), 7.03 (m, 1H), 7.01 (d, 1H, J 9.0 Hz), 6.98 (d, 1H, J 8.6 Hz), 6.92 (dd, 1H, J 8.6, 2.7 Hz), 6.90 (d, 1H, J 2.7 Hz), 5.09 (dd, 1H, J 10.3, 2.4 Hz), 3.01 (ddd, 1H, J −16.9, 11.4, 6.0 Hz), 2.82 (ddd, 1H, J −16.9, 5.1, 3.2 Hz), 2.24 (m, 1H), 2.09 (m, 1H).
Reaction SMILES: N1C=CN=CC=1C=[C:8]1[CH2:24][N:11]2[C:12]3[CH2:23][C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:13]=3[NH:14][C:15](=[O:16])[C:10]2=[N:9]1.C[N:26]([CH3:29])[CH:27]=O.CO.[H][H]>[Pd].C(O)(=O)C>[N:9]1[CH:10]=[CH:29][N:26]=[CH:27][C:8]=1[CH2:24][CH:23]1[C:12]2[N:11]3[CH:24]=[CH:8][N:9]=[C:10]3[C:15](=[O:16])[NH:14][C:13]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]1=2
Reactant: [H][H]
Reactant: O=C1NC2=C(Cc3ccccc32)N2CC(=Cc3cnccn3)N=C12
Reactant: CN(C)C=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1cnccn1)c1ccccc1-2

Procedure:
A mixture of 3.2 g of 10-(2-pyrazinylmethylene-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 250 ml of dimethylformamide, 50 ml of methanol and 5 ml of acetic acid is hydrogenated at a temperature in the region of 20° C. and a pressure of 1.8 bar of hydrogen, in the presence of 10% palladium on charcoal for 18 hours. The catalyst is filtered off under inert atmosphere and the filtrate is concentrated on a rotary evaporator. On addition of 200 ml of methanol a precipitate is formed which, after trituration in dichloromethane (100 ml), filtration and drying at 60° C. under vacuum (1 mmHg; 0.13 kPa), gives 1.4 g of 10-(2-pyrazinylmethyl)-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one in the form of a beige solid melting above 260° C. (Analysis % calculated C: 68.56, H: 4.16, N: 22.21, O: 5.07, % found C: 68.3, H: 3.9, N: 21.9).