Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:10]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C.CN(C)C=O>O>[CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]3[NH:34][N:33]=[N:32][N:17]=3)[CH2:15][C@@:9]1([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C@H:10]([O:18][Si:19]([C:22]([CH3:24])([CH3:25])[CH3:23])([CH3:21])[CH3:20])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H]2[C@@H](C#N)C[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H]2[C@@H](c3nnn[nH]3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 99.4 %

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-(tert-butyldimethylsilyloxy)-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Description 42; 43 g), sodium azide (27 g), triethylamine hydrochloride (55 g) and N,N-dimethylformamide (150 ml) was stirred at +130° C. for 7 hours. The reaction mixture was cooled to room temperature, treated with water (500 ml) and extracted into ethyl acetate (4×200 ml). The combined organic extracts were washed with water (3×200 ml) and brine. The combined water layers were extracted again with ethyl acetate (2×200 ml). The organic phase was washed with small amount of water (50 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give crude (1R*,2R*,5S*,6S*)-8-benzyl-2-(tert-butyldimethylsilyloxy)-1-phenyl-6-(tetrazol-5-yl]-8-azabicyclo[3.2.1]octane (47 g), which was mixed with potassium carbonate (25 g) and acetonitrile (220 ml), warmed up to +70° C. and finally treated with 2-methoxyethoxymethyl chloride (20 ml). The reaction mixture was stirred for 15 minutes, cooled to room temperature, then treated with water (500 ml) and extracted into ethyl acetate (3×200 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give a 1:1.5 mixture of isomers A and B, respectively. Regioisomers were separated by chromatography on silica gel (iso-hexane:diethyl ether).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:32]([F:35])([F:34])[F:33])[C:24]([N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH:41]([NH:44][CH3:45])([CH3:43])[CH3:42]>ClCCl.CN(C=O)C>[CH2:28]([N:26]([CH3:27])[C:24]1[C:23]([C:32]([F:34])([F:33])[F:35])=[CH:22][C:17]2[NH:18][C:19](=[O:21])[CH2:20][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:7]4[C:3]([CH2:2][N:44]([CH:41]([CH3:43])[CH3:42])[CH3:45])=[CH:4][N:5]=[N:6]4)[CH:9]=3)=[N:15][C:16]=2[CH:25]=1)[CH:29]([CH3:30])[CH3:31]
Reactant: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: CNC(C)C
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CN(C)C(C)C)c1)=N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 117) (260 mg, 0.53 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with N-isopropyl-methylamine in DMF according to the method described in Example 45. Obtained as a light brown solid (70 mg, 24%).
Reaction SMILES: CC1N2N=NN=C2C2N=C(CCC)N(CCCS(C3C=CC(C(Cl)=O)=CC=3)(=O)=O)C=2C=1C.CNCCCC.N1CCOCC1.[CH2:45]([N:49]([CH3:81])[C:50](=[O:80])[C:51]1[CH:56]=[CH:55][C:54]([S:57]([CH2:60][CH2:61][CH2:62][N:63]2[C:71]3[C:70]([CH3:72])=[C:69]([CH3:73])[N:68]4N=N[N:76]=[C:67]4[C:66]=3[N:65]=[C:64]2[CH2:77][CH2:78][CH3:79])(=[O:59])=[O:58])=[CH:53][CH:52]=1)[CH2:46][CH2:47][CH3:48]>ClCCl>[NH2:76][C:67]1[C:66]2[N:65]=[C:64]([CH2:77][CH2:78][CH3:79])[N:63]([CH2:62][CH2:61][CH2:60][S:57]([C:54]3[CH:55]=[CH:56][C:51]([C:50]([N:49]([CH2:45][CH2:46][CH2:47][CH3:48])[CH3:81])=[O:80])=[CH:52][CH:53]=3)(=[O:59])=[O:58])[C:71]=2[C:70]([CH3:72])=[C:69]([CH3:73])[N:68]=1
Reactant: CCCCN(C)C(=O)c1ccc(S(=O)(=O)CCCn2c(CCC)nc3c2c(C)c(C)n2nnnc32)cc1
Agent: CCCCNC
Agent: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCS(=O)(=O)c1ccc(C(=O)Cl)cc1
Solvent: C1COCCN1
Solvent: ClCCl
Product: CCCCN(C)C(=O)c1ccc(S(=O)(=O)CCCn2c(CCC)nc3c(N)nc(C)c(C)c32)cc1
Reaction time: 8 h
Yield: 76.8 %

Procedure:
The general methods described in Example 101 were used with the following modifications. To one-third of the crude solution of 4-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)propane-1-sulfonyl]benzoyl chloride in dichloromethane, described in Part B of Example 101, was added N-methyl butylamine (0.583 mL, 4.92 mmol) in lieu of morpholine, and the reaction was stirred overnight. Additional N-methyl butylamine (0.5 mL) was added, and the reaction was stirred for two hours. The crude product was recrystallized from ethyl acetate:hexane, and the crystals were dried for three hours in a vacuum oven at 90° C. N-Butyl-4-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)propane-1-sulfonyl]N-methyl benzamide (770 mg, 1.46 mmol) was treated as described in Part C of Example 101. The crude product was recrystallized from ethyl acetate:hexane with a couple drops of methanol to provide crystals, which were isolated by filtration, washed with hexane, and dried for four hours under high vacuum at 50° C. to provide 0.56 g of 4-[3-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)propane-1-sulfonyl]-N-butyl-N-methylbenzamide as a white powder, mp 127.0–129.0° C. 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J=8.4, 2H), 7.58 (d, J=8.4, 2H), 4.92 (br s, 2H), 4.42 (dd, J=7.8, 7.8, 2H), 3.55 (dd, J=7.8, 7.8, 1H), 3.21–3.05 (m, 4.5 H), 2.90 (s, 1.5 H), 2.77 (dd, J=7.7, 7.7, 2H), 2.43 (s, 3H), 2.39 (s, 3H), 2.23 (quint, J=7.6, 2H), 1.93–1.36 (m, 5H), 1.15 (quart, J=7.5, 1H), 1.07 (t, J=7.4, 3H), 0.99 (t, J=7.0, 1.5H), 0.81 (t, J=7.4, 1.5H);
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[C:25]([O:28][CH:29]([CH3:33])[C:30](Cl)=[O:31])(=[O:27])[CH3:26]>CN(C=O)C>[C:25]([O:28][CH:29]([CH3:33])[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][CH:7]=1)=[O:31])(=[O:27])[CH3:26]
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: CC(=O)OC(C)C(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)OC(C)C(=O)Nc1ccc(C2=NNC(=O)NC2C)cc1
Yield: 72.5 %

Procedure:
To a stirred mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.0 g) and N,N-dimethylaniline (0.93 ml) in DMF (10 ml) was added dropwise 2-acetoxypropionyl chloride (0.98 g) under ice cooling. The stirring was continued for one night at ambient temperature. The mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate after addition of saline solution. The extract was washed successively with 1N hydrochloric acid, water and saline solution, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (170 ml) with a mixture of chloroform and methanol (10:1) as an eluent. The eluates containing the object compound were evaporated in vacuo to give 1.13 g of 6-[4-(2-acetoxypropionylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one.
Reaction SMILES: [N+:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[O:5]1)([O-])=O.[CH3:14]O>>[CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:14][N:1]=1.[C:6]1([C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][O:5]1)=[O:7]
Reactant: O=C1OC([N+](=O)[O-])c2ccccc21
Reactant: CO
Product: O=C1OCc2ccccc21
Product: c1ccc2cnccc2c1

Procedure:
wherein R4 to R7 are as defined above, in methanol in an amount of 1.5 to 10 times by volume of nitrophthalide and a reaction temperature of 50° to 80° C. for a reaction period of 8 to 36 hours to produce a phthalide isoquinoline represented by the general formula (III): ##STR11##
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:13]=2[N:14]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:13]=2[N:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2sc(C)nc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2sc(CBr)nc2c1

Procedure:
2.58 g (14.5 mmol; 1.3 eq.) of N-bromosuccinimide and a spatula tip's worth of aza-bis-isobutyronitrile are added to 2 g (11.16 mmol) of 2-methyl-5-methoxy-1,3-benzothiazole in solution in 25 ml of anhydrous carbon tetrachloride. The reaction mixture is heated under reflux and under irradiation for 6 hours, with a spatula tip's worth of aza-bis-isobutyronitrile added every 2 hours. After returning to ambient temperature, the insoluble part formed is filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane 1/4). The expected product is obtained in the form of a white solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]([F:18])([F:17])[F:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[NH4+:20]>C(O)C>[NH2:20][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]([F:18])([F:17])[F:16])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1c(OC(F)(F)F)ccc2nc(Cl)sc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc2ccc(OC(F)(F)F)c([N+](=O)[O-])c2s1
Temperature: 110 °C

Procedure:
A mixture of 0.4 g of 2-chloro-7-nitro-6-trifluoromethoxybenzothiazole and 10 cm3 of 33% aqueous ammonium hydroxide solution in 30 cm3 of ethanol is heated at 110° C. in an autoclave for 5 hours. The mixture is cooled and the solvent is evaporated off under reduced pressure (2.7 kPa). After purification by flash chromatography on silica with a cyclohexane/ethyl acetate mixture (4/6 by volume) as eluent, 0.22 g of 2-amino-7-nitro-6-trifluoromethoxybenzothiazole is obtained, melting at 180° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:18][C:19]([F:22])([F:21])[F:20])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]2)([O-:3])=[O:2].[H-].[Na+].CN(C)C=O.[CH3:30][O:31][CH2:32]Cl>O1CCCC1.C(OCC)(=O)C>[CH3:30][O:31][CH2:32][N:11]1[C:12]2[C:8](=[CH:7][C:6]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH:9]=[C:10]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: COCCl
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc([N+](=O)[O-])c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)cc([N+](=O)[O-])c2n1COC
Temperature: 4 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
A mixture of ethyl 7-nitro-5-(trifluoromethoxy)-1H-indole-2-carboxylate (1.19 g), 60% sodium hydride (0.18 g) and N,N-dimethylformamide (20 mL) was stirred at 4° C. for 20 min. A solution (5 mL) of chloromethyl methyl ether (0.33 mL) in tetrahydrofuran was added dropwise. After stirring at 4° C. for 3 hr, the reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=5:95-20:80) to give the title compound (1.0 g, yield 74%) as pale-yellow prism crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][O:17][CH2:16][CH2:15][NH:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][O:17][CH2:16][CH2:15][N:14]3[CH2:24][C:20]3[S:19][CH:23]=[CH:22][N:21]=3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1nccs1
Reactant: Clc1cccc(-c2noc(C3COCCN3)n2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Clc1cccc(-c2noc(C3COCCN3Cc3nccs3)n2)c1

Procedure:
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-pyridin-2-ylmethyl-morpholine was obtained as described in Example 43 from (48 mg, 44%) 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine (80 mg, 0.30 mmol) with 2-thiazolecarboxaldehyde (68 mg, 0.60) and sodium triacetoxyborohydride (89 mg, 0.42 mmol). The product was purified by SPE chromatography on silica gel using 20–60% ethyl acetate in hexanes. 1H NMR (CDCl3), δ(ppm): 8.13 (s, 1H), 8.01 (d, 1H), 7.75 (d, 1H), 7.47 (m, 2H), 7.33 (d, 1H), 4.29 (m, 1H), 4.15 (m, 4H), 3.88 (m, 2H), 3.30 (m, 1H), 2.70 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([CH3:11])[CH:3]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[NH2:27][CH2:28][CH:29]1[CH2:31][CH2:30]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[O:10])[CH:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: NCC1CC1
Reactant: Cc1cc(Cl)nc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc(C(=O)NCC2CC2)c1
Reaction time: 3 h
Yield: 89.4 %

Procedure:
6-Chloro-4-methylpyridine-2-carboxylic acid (422 mg, 2.46 mmol) was dissolved in DCM (10 mL) and oxalyl chloride (422 μL, 4.92 mmol) and DMF (100 μL) were added. The reaction mixture was stirred for 3 h, the solvents were removed in vacuo and the residue was azeotroped with DCM. The residue was dissolved in DCM (10 mL), DIPEA (1.63 mL, 9.84 mmol) and aminomethylcyclopropane (427 μL, 4.92 mmol) were added and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with DCM (40 mL), washed with sat aq NaHCO3 (50 mL), 1 M aq HCl (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (494 mg, 69%) as a yellow liquid. LCMS (ES+): 225.5 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]C([O-])=O)=O)([CH3:4])([CH3:3])[CH3:2].[NH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C([Li])CCC.Br[CH2:25][CH:26]=[CH:27][CH2:28][O:29][CH2:30][O:31][CH3:32].[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6]([NH:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH2:25][CH:26]=[CH:27][CH2:28][O:29][CH2:30][O:31][CH3:32])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCOCC=CCBr
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: Nc1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCOCC=CCc1cnccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
To a solution of t-butyldicarbonate (9.59 g) in THF (40 ml), 4-aminopyridine (3.76 g) was added. The mixture was stirred for 1 hour at room temperature. The solvent was distilled off from the reaction mixture. The obtained solid was washed with hexane/ethyl acetate (1:2), and the solid was obtained by filtration. To a solution of the obtained solid in THF (35 ml), 1.6M n-butyl lithium (9.6 ml) was added at −78° C., and then the mixture was stirred for 2 hours at 0° C. The mixture was cooled −78° C., and a solution of 4-bromo-1-methoxymethoxy-2-butene (1.5 g) in THF (4.0 ml) was dropped into the mixture slowly. The mixture was warmed until 10° C. under stirring for 2 hours. A saturated aqueous solution of ammonium chloride was added to the mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (394 mg) having the following physical data and 4-t-butoxycarbonylaminopyridine.
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[O:13]1[CH2:17][CH2:16][CH:15]([CH:18]=[CH:19][C:20](=[O:22])[CH3:21])[CH2:14]1.[OH-].[Na+]>C(O)C.C(O)(C)C>[O:13]1[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:2][C:3](=[O:4])[CH2:21][C:20](=[O:22])[CH2:19]2)[CH2:14]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=CC1CCOC1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)O
Product: O=C1CC(=O)CC(C2CCOC2)C1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Diethyl malonate (6.50 ml, 43 mmol) is added dropwise to a cooled (ice-bath) solution of sodium (1.07 g, 46 mmol) in anhydrous ethanol (60 ml) and once the addition is complete the cooling bath is removed and the reaction mixture is stirred at room temperature for 25 minutes. The mixture is cooled in an ice bath and a solution of 4-(tetrahydrofuran-3-yl)-3-buten-2-one (5.0 g, 36 mmol) in ethanol (30 ml) is added dropwise. Once the addition is complete the cooling bath is removed and the reaction mixture is stirred at room temperature for 19 hours. The reaction mixture is acidified to pH 3 by dropwise addition of 2M aqueous hydrochloric acid, water added to dissolve any precipitate formed and the reaction mixture is extracted into dichloromethane. The organic extracts are dried over anhydrous magnesium sulphate, filtered and the filtrate is concentrated in vacuo to afford a yellow oil which is taken up in isopropanol (35 ml) and a 2M aqueous solution of sodium hydroxide (100 ml) is added. The reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is concentrated in vacuo to remove isopropanol then heated to 70° C. A solution of 2M aqueous hydrochloric acid is added carefully until the reaction mixture reached pH 1. The reaction mixture is heated for 1½ hours at 70° C., then cooled to room temperature, diluted with water and the product is extracted into ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and the filtrate is concentrated in vacuo to give 5-(tetrahydrofuran-3-yl)cyclohexane-1,3-dione as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][C:10]1([CH3:19])[CH2:15][CH:14]([NH2:16])[CH2:13][C:12]([CH3:18])([CH3:17])[NH:11]1.C(O)CCC>O.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:16][CH:14]2[CH2:15][C:10]([CH3:19])([CH3:9])[NH:11][C:12]([CH3:18])([CH3:17])[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: Clc1ccc(Cl)nn1
Solvent: O
Solvent: ClCCl
Solvent: CCCCO
Product: CC1(C)CC(Nc2ccc(Cl)nn2)CC(C)(C)N1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of 3,6-dichloropyridazine (6.26 g, 42 mmol) and 2,2,6,6-tetramethylpiperidin-4-amine (14.7 mL, 84 mmol) was stirred at 120° C. for 1 h, neat. To this crude mixture was added n-butanol (40 mL), and the reaction was stirred at 120° C. for 1 h. The crude reaction mixture was cooled to room temperature and diluted in water and CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was recrystallized from CH3CN to give 6-chloro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine, Intermediate 1-2 (7.3 g) as an off-white solid. LCMS Rt=1.10 min (condition B), MS (M+1)=269.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.08 (d, J=9.3 Hz, 1H), 6.54 (d, J=9.3 Hz, 1H), 4.53 (d, J=7.6 Hz, 1H), 4.05-4.26 (m, 1H), 1.98 (dd, J=12.6, 3.8 Hz, 2H), 1.22 (s, 6H), 1.08 (s, 6H), 0.93 (apparent t, J=12.1 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[C:9]([CH3:15])=[C:8]4[CH:16]=[CH:17][N:18]=[CH:19][C:7]4=[C:6]([CH3:20])[C:5]=3[C:4]=2[CH:3]=1.C([O-])(O)=O.[Na+].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)(=O)C>[C:26]([O:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[C:9]([CH3:15])=[C:8]4[CH:16]=[CH:17][N:18]=[CH:19][C:7]4=[C:6]([CH3:20])[C:5]=3[C:4]=2[CH:3]=1)(=[O:28])[CH3:27]
Reactant: Cc1c2ccncc2c(C)c2c1[nH]c1ccc(O)cc12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Product: CC(=O)Oc1ccc2[nH]c3c(C)c4ccncc4c(C)c3c2c1
Reaction time: 0.17 h
Yield: 75 %

Procedure:
A solution of 9-hydroxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (10 g.) in acetic anhydride (75 ml.) and acetyl chloride (25 ml.) was stirred at room temperature for 2 hours. The reaction mixture was poured into excess NaHCO3 solution and stirred for 10 minutes. The resulting precipitate was removed by filtration and was washed well with water. The dried solids (10 g.; 86%) were dissolved in tetrahydrofuran and the solution was charcoaled. Crystallization from tetrahydrofuran-ethyl acetate mixture afforded 9-acetoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (8.3 g.; 75%), m.p. 303°-304°.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:5]=1[O:6][CH2:7][CH:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:5]=1[O:6][CH2:7][CH:8]1[CH2:12][O:11][C:10]([CH3:13])([CH3:14])[O:9]1
Reactant: CC1(C)OCC(COc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)OCC(COc2ccc(N)cc2N)O1
Temperature: 5 °C

Procedure:
215 ml of methanol are introduced into a 0.7 l autoclave, 85.3 g (0.3 mole) of 4-(2,4-dinitrophenoxymethyl)-2,2-dimethyl-1,3-dioxolane (step a) are dissolved therein and 0.6 g of palladium on active carbon 10% (Degussa) is added. After the autoclave has been closed and blanketed with nitrogen, hydrogenation is carried out under a pressure of 4 bar and at a temperature of 35 to 40° C. until no more hydrogen is taken up. 1.3 g of active carbon is added under nitrogen to the warm solution and the catalyst is filtered off. 42 g of 70% sulfuric acid are added dropwise to the solution while cooling with ice at 5° C. The product precipitated is filtered off under suction, washed with methanol and dried.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:10])[CH:8]=2)[CH:3]=[N:2]1.CN(C=O)C.N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])[CH3:23]>C(OCC)(=O)C.O>[Si:25]([O:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[N:2][NH:1]2)=[CH:5][CH:6]=1)([C:22]([CH3:24])([CH3:23])[CH3:21])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc2cn[nH]c2c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2cn[nH]c2c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Indazol-6-ol (4.029 g) which can be prepared according to the method described in Reference example 35, etc. was dissolved dehydrated DMF (60 mL; manufactured by Kanto Chemical Co., Inc.), and added with imidazole (4.49 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) and TBDPSCl (17.1 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.). The mixture was stirred overnight at room temperature. The reaction solution was added to water and extraction was carried out three times with ethyl acetate. The organic layer was washed three times with water and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=92:8→71:29) to obtain the title compound (9.214 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1.ClC1C=C(C2C(CO[C:38]3[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=CN=3)=C(C)ON=2)C=CC=1.[NH2:48]C1CCOCC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH2:48])=[O:21])=[C:17]([CH:45]4[CH2:46][CH2:38][O:43][CH2:42][CH2:41]4)[N:16]=3)=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(F)cn2)nc1
Product: NC(=O)c1ccc(OCc2conc2-c2ccc(F)cn2)nc1C1CCOCC1
Yield: 79 %

Procedure:
As described for example 98b, 6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinic acid (79 mg, 0.25 mmol) was converted, instead of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (79 mg, 79%) which was obtained as an off white solid. MS: m/e=399.1 [M+H]+.