Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].CC(C)=O>C(O)C>[O:14]=[C:12]1[CH2:11][CH2:10][CH:9]2[N:13]1[CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2
Reactant: CCOC(=O)C1CCC2CCC(=O)N21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: O=C(O)C1CCC2CCC(=O)N21
Reaction time: 72 h

Procedure:
A solution of hexahydro-5-oxo-1H-pyrrolizine 3-carboxylic acid ethyl ester (12.6 g, 0.064 mol) in ethanol (35 ml) is treated with a 2N sodium hydroxide solution (35 ml, 0.07 mol) with stirring for 72 hours. The solution is concentrated at reduced pressure and treated with concentrated hydrochloric acid (6 ml) dropwise. The solution is extracted with dichloromethane. The extracts are dried (MgSO4), filtered, and concentrated to yield an oil. Trituration of the oil with acetone yields hexahydro-5-oxo-1H-pyrrolizine 3-carboxylic acid as a white solid with mp 145°-148° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][CH:14]=[C:15]([N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[N:16]=3)[CH:9]=2)[NH:4][N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][CH:14]=[C:15]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[N:16]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c2ccc(-c3nncc(N4CCN(C(=O)OC(C)(C)C)CC4)n3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2ccc(-c3nncc(N4CCNCC4)n3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To 3-(3-methylindazol-5-yl)-5-(4-Boc-piperazin-1-yl)-[1,2,4]triazine 153 (5.1 mg, 0.013 mmol.) was added a 20% solution of trifluoroacetic acid in DCM. The reaction mixture was stirred at room temperature for 1 hour. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 3-(3-methylindazol-5-yl)-5-(piperazin-1-yl)-[1,2,4]triazine 46 (2.6 mg, 0.0088 mmol.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4(CC)[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][CH:17]4[O:23][CH:24]([C:27]([OH:29])=O)[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[NH2:42][CH2:43][C@H:44]([OH:47])[CH2:45][OH:46].CN(C(ON1N=N[C:58]2C=CC=N[C:57]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:25][CH3:26])([C:27](=[O:29])[NH:42][CH2:43][C@H:44]([OH:47])[CH2:45][OH:46])[CH2:57][CH3:58])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(OC1C=CC(Cl)=CC1(CC)C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: NC[C@H](O)CO
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NC[C@H](O)CO
Reaction time: 5 h
Yield: 70.8 %

Procedure:
At room temperature, a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[1-ethyl-5-chloro-2-(1-hydroxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.084 mmol), (S)-3-amino-1,2-propanediol (27 mg, 0.3 mmol), HATU (114 mg, 0.30 mmol) and DMAP (72 mg, 0.59 mmol) in DMF (2 mL) was stirred for 5 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic phase was washed with saturated NaCl solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (40 mg).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:21][CH:22]=O)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[NH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[C:16]([O:15][C:14]([N:13]([CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10]1)[CH2:21][CH2:22][NH:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:20])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N(CC=O)C1CCc2ccc(C#N)cc2C1
Reactant: COC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)CNCCN(C(=O)OC(C)(C)C)C1CCc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-Butyl (7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)(2-oxoethyl)carbamate (260 mg, 0.83 mmol) in 10 mL of anhydrous DCM was added Gly-OMe (150 mg, 1.7 mmol), 2 drops of HOAc and NaBH(OAc)3 (180 mg, 0.83 mmol) and the mixture was stirred at ambient temperature overnight. Then DCM was added, and the mixture was washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to the title compound. MS m/z: 388 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([S:27][C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])=[CH:4][N:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCOCC1
Reactant: Sc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cnc(Sc2cccc(Cl)c2)nc1C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
A mixture of 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}morpholine (167 mg), 3-chlorobenzenethiol (98 mg), cesium carbonate (221 mg), and N,N-dimethyl formamide (2 mL) was stirred at room temperature for 15 hours, and then at 70° C. for 10 hours. To the reaction liquid was added ethyl acetate (30 mL), followed by washing with saturated brine (20 mL) and a saturated aqueous ammonium chloride solution (20 mL) in this order, the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-ethyl acetate) to obtain 4-({2-[(3-chlorophenyl)sulfanyl]-4-(trifluoromethyl)pyrimidin-5-yl}carbonyl)morpholine (183 mg) as a colorless solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.[NH:30]1[CH:38]=[C:36]([CH3:37])[C:34](=O)[NH:33][C:31]1=[O:32]>C(#N)C.CO>[CH3:37][C:36]1[C:38]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[N:30][C:31](=[O:32])[NH:33][CH:34]=1
Reactant: c1nc[nH]n1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC#N
Product: Cc1c[nH]c(=O)nc1-n1cncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.3 %

Procedure:
69 g (1 mol) of 1,2,4-triazole are suspended in 800 ml of dry acetonitrile under a protecting gas (argon). 251 g (0.95 mol) of diphenyl chlorophosphate are added to the suspension at 0°-10° C. Subsequently, in the course of 1 hour, 151.79 g (1.5 mol) of triethylamine are added dropwise before 63 g (0.5 mol) of thymine are added. The resulting suspension is stirred for 12 hours at room temperature. Finally, the mixture is heated for 5 hours at 60°-80° C. 40 ml of methanol are added to the cooled suspension and the mixture is stirred for 2 hours at room temperature. The suspension is filtered; the residue is stirred with one liter of diisopropyl ether, filtered off again by suction and stirred with 800 ml of water. The aqueous suspension is filtered and the solid residue is recrystallized from 1300 ml of dimethylformamide. 28.6 g of 5-methyl-4-(1,2,4 -triazol-1-yl)pyrimdin-2(1H)-one are obtained with melting point 275°-280° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][C:16]([CH3:18])=[CH2:17])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C=C>ClCCl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:18][C:16]1[CH2:15][N:4]([C:5]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:14])[CH2:1][CH:17]=1
Reactant: C=CCN(CC(=C)C)C(=O)OCc1ccccc1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CC1=CCN(C(=O)OCc2ccccc2)C1
Yield: 90.9 %

Procedure:
A solution of benzyl allyl(2-methylallyl)carbamate (20.2 g, 82 mmol) in dichloromethane (500 mL) was purged with argon for 5 min. Grubbs I catalyst (1.694 g, 2.059 mmol) was added and the resulting purple solution was warmed to a gentle reflux under argon for 24 h. The mixture was concentrated and purified by silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes, to give benzyl 3-methyl-2,5-dihydro-1H-pyrrole-1-carboxylate (16.2 g, 91% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.65-7.28 (m, 5H), 5.69-5.27 (m, 2H), 4.30-3.91 (m, 5H), 1.84-1.68 (m, 3H); MS (ES+) m/z: 218.2 (M+H).
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[C:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH:13]3O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:17]1[CH:21]=[C:20]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[N:19]=[CH:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O>C1COCC1>[CH:25]([O:24][C:22]([C:20]1[N:19]([CH:13]2[C:14]3[C:9](=[CH:8][CH:7]=[C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:15]=3)[CH2:10][CH2:11][CH2:12]2)[CH:18]=[N:17][CH:21]=1)=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)OC(=O)c1c[nH]cn1
Reactant: OC1CCCc2ccc(N3CCCC3)cc21
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1cncn1C1CCCc2ccc(N3CCCC3)cc21
Reaction time: 0.17 h

Procedure:
To a suspension of 7-pyrrolidin-1-yl-3,4-dihydro-2H-naphthalen-1-ol (0.300 g, 1.382 mmol), and isopropyl 4-imidazolecarboxylate (0.149 g, 0.967 mmol), which can be prepared as described in Example 1, in THF (10 mL) at 0° C. is added triphenylphosphine (0.293 g, 1.382 mmol) and dimethyl azodicarboxylate (40% wt. in toluene, 0.505 g, 1.382 mmol). After 10 minutes, the cooling bath is removed and the mixture is stirred for another 30 minutes. Water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The resulting residue is purified by silica gel chromatography (elution with hexanes-ethyl acetate mixtures) to give 3-(7-pyrrolidin-1-yl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 354.2 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.40 (d, J=6.3 Hz, 3 H), 1.41 (d, J=6.3 Hz, 3 H), 1.66-1.75 (m, 1 H), 1.79-1.87 (m, 1 H), 1.98-2.01 (m, 4 H), 2.13-2.25 (m, 2 H), 2.77 (ddd, J=16.7, 8.8, 5.3 Hz, 1 H), 2.88 (dt, J=16.7, 5.6 Hz, 1H), 3.12-3.24 (m, 4 H), 5.27 (sept, J=6.3 Hz, 1 H), 6.14 (d, J=2.5 Hz, 1 H), 6.24 (t, J=5.1 Hz, 1 H), 6.62 (dd, J=8.6, 2.5 Hz, 1 H), 7.08 (d, J=8.6 Hz, 1 H), 7.31 (s, 1 H), 7.73 (d, J=1.3 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.C([O:14][CH2:15][CH:16]1[CH2:24][CH:23]2[CH:19]([CH2:20][N:21]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22]2)[C:18](=[O:32])[CH2:17]1)(=O)C.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[CH2:25]([N:21]1[CH2:20][CH:19]2[CH:23]([CH2:24][CH:16]([CH2:15][OH:14])[CH2:17][C:18]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:32])[CH2:22]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)OCC1CC(=O)C2CN(Cc3ccccc3)CC2C1
Reactant: COc1ccccc1[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)CC(CO)CC2CN(Cc3ccccc3)CC21
Temperature: 20 °C
Reaction time: 20 h
Yield: 37.9 %

Procedure:
To a suspension of 2-methoxyphenylmagnesium bromide (prepared from 24.9 cm3 of 2-bromoanisole and 4.86 g of magnesium) in 200 cm3 of anhydrous tetrahydrofuran is added a solution of 8.0 g of (3aRS,6SR,7aSR)-6-acetoxymethyl-2-benzyl-4-perhydroisoindolone in 60 cm3 of anhydrous tetrahydrofuran. The reaction mixture is stirred for 20 hours at 20° C. and then cooled to +5° C. and treated with 120 cm3 of saturated aqueous ammonium chloride solution and 100 cm3 of ethyl acetate. After filtration of the mixture, the organic phase is washed with brine and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, height 40 cm) in a mixture of 1,2-dichloroethane and methanol (95/5 by volume). After recrystallization in ethyl ether, 3.2 g of (3aRS,4RS,6SR, 7aSR)-2-benzyl-6-hydroxymethyl-4-(2-methoxyphenyl)-4-perhydroisoindolol are obtained, in the form of a white solid melting at 110° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:34][C:8]=1[O:9][CH2:10][CH:11]([OH:33])[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[CH2:54](Br)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C)C=O>[CH2:1]([C:7]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:34][C:8]=1[O:9][CH2:10][CH:11]([O:33][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:12][O:13][C:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCCCc1ccc(CCCCCC)c(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccc(CCCCCC)c(OCC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OCc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
A 13.8 g portion of 1-(2-hexyl-5-tetradecylphenoxy)-3-(triphenylmethoxy)-2-propanol in 40 ml of dimethylformamide was added dropwise to a suspension of 14.5 g of prewashed 50% sodium hydride in 40 ml of dimethylformamide and the mixture was stirred 15 minutes. A 4.45 g portion of benzyl bromide was added and the mixture was stirred an additional 3 hours. This mixture was quenched slowly with water and then extracted several times with ether. The ether extracts were combined, washed with water, brine, dried and evaporated giving 15 g of the desired compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:14]1([N:20]2[CH2:25][CH2:24][N:23]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(CN2CCN(c3ccccc3)CC2)cc1

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (1.65 g), 1-phenylpiperazine (1.3 ml) and potassium carbonate (1.2 g) in dimethylformamide (50 ml) was stirred at 60° C. for 1 hr. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (100 ml×3). The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown solid (4.4 g). The obtained solid was purified by silica gel column chromatography (developing solvent; chloroform:methanol=10:1) to give a pale-brown solid (3.45 g). The obtained solid was crystallized from ethyl acetate and the crystals were recrystallized from a mixture of ethyl acetate, ethanol and hexane to give the title compound (1.4 g) as white crystals, m.p.=135-136° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[H-].[Na+].O1CCCC1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>ClCCl.O>[CH2:28]([O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: CCCCCCCCCCCCBr
Reactant: OCCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCOCCc1cccs1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
13 g of 2-thiopheneethanol was cooled to 0° C., and to this, a suspension formed by adding 5.8 g of sodium hydride (60% in oil) to 100 ml of tetrahydrofuran was added dropwise. The solution was stirred at 0° C. for 20 minutes under a nitrogen atmosphere, and to this, 25 g of 1-bromododecane was added dropwise. The resulting solution was heated to 90° C. and stirred for 11.5 hours. 100 ml of water and 150 ml of dichloromethane were added to the reaction solution to separate the organic layer. The organic layer was washed with 300 ml of water and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated by a rotary evaporator and purified by a column chromatography (filler: silica gel, eluent: hexane/dichloromethane) to obtain 16 g of 2-(2-dodecyloxyethyl)thiophene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[C:13]1[C:17]([CH3:18])=[CH:16][S:15][CH:14]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[C:13]1[C:17]([CH3:18])=[CH:16][S:15][CH:14]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(-c2cscc2C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1-c1cscc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of methyl 3-methoxy-4-(4-methyl-3-thienyl)benzoate obtained in step 1 (2.30 g; 8.77 mmol) in EtOH (70 mL), was added at RT an aqueous solution of sodium hydroxide (5 M; 5.26 mL; 26.31 mmol). The reaction mixture was stirred at 60° C. for one hour. The reaction mixture was concentrated under vacuum to give a brown solid. It was taken up in water and the aqueous phase was washed twice with EtOAc. Aqueous phase was acidified with concentrated HCl (2 mL) to pH 2. Then it was concentrated under vacuum until a precipitate was formed (⅓ of volume). The suspension was filtered off and dried under vacuum, affording the title compound as a brown solid (1.81 g, 83% for 2 steps). 1H NMR: (DMSO-d5) δ 13.05 (s, 1H), 7.62-7.59 (m, 2H), 7.40-7.39 (d, J=3.23 Hz, 1H), 7.32-7.29 (d, J=7.48 Hz, 1H), 7.25-7.23 (m, 1H), 3.82 (s, 3H), 2.99 (s, 3H). LC/MS (Method A): 248.8 (M+H)+; 246.9 (M−H)−. HPLC (Method A) Rt 3.99 min (Purity: 97.4%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][CH2:7][C:8]1([OH:21])[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[CH3:2].[CH3:26][I:27]>CC(C)=O>[I-:27].[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][CH2:7][C:8]1([OH:21])[CH2:9][CH2:10][N+:11]([CH3:26])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)[CH3:2]
Reactant: CI
Reactant: CCOc1ccccc1OCC1(O)CCN(Cc2ccccc2)CC1
Solvent: CC(C)=O
Product: CCOc1ccccc1OCC1(O)CC[N+](C)(Cc2ccccc2)CC1
Product: [I-]
Temperature: 30 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A solution of 6.5 g (0.02 mole) of 4-[(2-ethoxyphenoxy)methyl]-1-phenylmethyl-4-piperidinol in 100 ml of dry acetone was stirred at 10° C. while 4.2 g (0.03 mole) of methyl iodide was added in one portion. The solution was warmed to 30° C. and allowed to cool while stirring overnight. The solid precipitate was collected by filtration to yield 7 g (72.5%) of pale yellow crystals, m.p. 187°-189° C.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH:18]2[CH2:20][CH2:19]2)[N:3]=1.[K].[CH:22]([C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[N:29][CH:30]=1)([CH3:24])[CH3:23]>>[CH:22]([C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH:34][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH:18]3[CH2:20][CH2:19]3)[N:3]=2)(=[O:33])=[O:32])=[N:29][CH:30]=1)([CH3:24])[CH3:23]
Reactant: COc1ccccc1Oc1c(Cl)nc(C2CC2)nc1Cl
Reactant: CC(C)c1ccc(S(N)(=O)=O)nc1
Agent: [K]
Product: COc1ccccc1Oc1c(Cl)nc(C2CC2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
According to the procedure described in Example 1g) 3.3 g 4,6-dichloro-2-cyclopropyl-5-(o-methoxyphenoxy)-pyrimidine (prepared according to procedures described in Example 1) was reacted with 5-i-propyl-2-pyridyl-sulfonamide potassium salt to give 4.04 g 5-i-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide. LC-MS: tR=5.64 min, [M−1]−=473.29.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6](NC)=[N:5][CH:4]=1.[CH2:11]([N:13](CC)CC)C.[I:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(#N)C>[I:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:13][CH2:11][C:6]2[CH:7]=[CH:8][N:3]=[CH:4][N:5]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CNc1ccncn1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CC#N
Product: O=S(=O)(NCc1ccncn1)c1ccc(I)cc1
Temperature: 0 °C

Procedure:
Pyrimidin-4-yl-methylamine dihydrochloride (1.0 eq) and triethylamine (3.0 eq) were dissolved in acetonitrile (5 mL/mmol) and the solution was cooled to 0° C. 4-Iodobenzenesulfonic acid chloride (1.0 eq) was added in portions and the reaction mixture was warmed to room temperature. The solvent was evaporated under reduced pressure and the residue was washed with cold water and cold diisopropyl ether to yield the title compound as beige solid.
Reaction SMILES: [CH:1]1([NH:8][C:9]([CH2:11][C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.Cl.[OH-].[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[CH:1]1([NH:8][CH2:9][CH2:11][C:12]2[C:13]3[CH2:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:21]=3[CH:22]=[CH:23][CH:24]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(Cc1ccc2c(c1)Cc1ccccc1-2)NC1CCCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2c(c1)Cc1c(CCNC3CCCCCC3)cccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
In dry tetrahydrofuran (30 ml) was dissolved 2-cycloheptylcarbamoylmethylfluorene (1.9 g) followed by dropwise addition of borane-methyl sulfide complex (1.8 ml) with ice-cooling. The mixture was then refluxed for 4 hrs, at the end of which time methanol (0.72 ml) was added with ice-cooling. The mixture was stirred at room temperature for 30 minutes, followed by addition of concentrated hydrochloric acid (1.8 ml) with ice-cooling. The mixture was refluxed again for 30 minutes. The reaction mixture was then cooled with ice and the resulting solid was recovered by filtration and washed with ether. The solid matter thus obtained was dissolved in chloroform and the solution was alkalinized with aqueous sodium hydroxide solution. The chloroform layer was taken and dried and the solvent was distilled off under reduced pressure to give 2-cycloheptylaminoethylfluorene (1.2 g).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-])=O>[Pd].CCO.CO>[C:16]1([NH:15][CH2:14][C:5]2[C:4]([NH2:1])=[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=[N:12]3)=[CH:7][CH:6]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1c(CNc2ccccc2)ccc2cccnc12
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Nc1c(CNc2ccccc2)ccc2cccnc12
Reaction time: 4 h
Yield: 101.6 %

Procedure:
Palladium on Carbon (10%, 36 mg) was added to a solution of (8-nitro-quinolin-7-ylmethyl)-phenyl-amine (Intermediate 205) (478 mg, 1.69 mmol) in EtOH (10 ml) and the mixture was stirred under an atmosphere of hydrogen for 4 h. The mixture was diluted with MeOH (40 ml), filtered through celite and the filtrate was concentrated in vacuo to give the title compound (428 mg, 89%).