Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.O.[C:11]1([C:17]23[CH2:25][CH:21]4[CH2:22][CH:23]([CH2:24]2)[C:19]([C:26](=[O:28])[CH3:27])([CH2:20]4)[CH2:18]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[N+](C)([O-])=O>[N+:1]([C:14]1[CH:15]=[CH:16][C:11]([C:17]23[CH2:25][CH:21]4[CH2:22][CH:23]([CH2:24]2)[C:19]([C:26](=[O:28])[CH3:27])([CH2:20]4)[CH2:18]3)=[CH:12][CH:13]=1)([O-:4])=[O:2]
Reactant: CC(=O)C12CC3CC1CC(c1ccccc1)(C3)C2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CC(=O)C12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Nitration mixture (1 mL) [the nitration mixture was prepared by mixing of 10.5 g of nitric acid (d 1.375 at 22° C.), 180.0 g of conc. sulphuric acid (d 1.84 at 22° C.), and 16 g of H2O) was added drop wise to a stirred solution of 1-(1-phenyltricyclo[3.3.1.03,7]non-3-yl)ethanone (240 mg, 1.0 mmol) obtained in preparation 1, in nitromethane (4 mL) at 0° C. After stirring for 2 h, the reaction mixture was poured into ice cold water and extracted with EtOAc, the combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography to obtain 1-[1-(4-nitrophenyl)tricyclo[3.3.1.03,7]non-3-yl]ethanone as an off-white solid (250 mg) in 88% yield. M.R: 61.3-66.6° C. m/z (M+1) 286; IR cm−1 2953, 1697, 1598, 1519, 1217, 1110, 852, 768. 1H NMR (CDCl3) 300 MHz δ 8.17 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 2.87-2.80 (m, 1H), 2.61-2.55 (m, 1H), 2.34-2.26 (m, 1H), 2.23 (s, 3H), 2.13-1.98 (m, 4H), 1.90-1.71 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Cl-].[NH4+]>ClCCl>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:48][CH:47]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:37]=[CH:36][C:33]([CH2:34][N:53]6[CH2:54][CH2:55][N:50]([CH3:49])[CH2:51][CH2:52]6)=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:44][CH:43]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C=O)cc3)cn2)cc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CN4CCN(C)CC4)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzaldehyde (76 mg, 0.118 mmol) in dichloromethane (2 ml), 1-methylpiperazine (40 μl, 0.354 mmol), sodium triacetoxy borohydride (100 mg, 472 mmol) and acetic acid (12.6 μl, 0.236 mmol) were added, followed by stirring at room temperature for 40 hours. To the reaction mixture, saturated aqueous ammonium chloride solution was added, followed by extraction twice with ethyl acetate (10 ml). The organic layer was washed with brine (10 ml), and dried over sodium sulfate, followed by distilling off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/2M-ammonia methanol=100/1 to 30/1), whereby bis-(4-methoxy-benzyl)-(5-{7-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-amine was obtained as a brown powder (44 mg, 51%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[S:14](Cl)(=[O:16])=[O:15])([O-:3])=[O:2].[CH3:18][N:19]([CH3:25])[CH2:20][CH2:21][CH2:22][NH:23][CH3:24]>C(Cl)Cl>[CH3:18][N:19]([CH3:25])[CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[S:14]([C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:16])=[O:15]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: CNCCCN(C)C
Solvent: ClCCl
Product: CN(C)CCCN(C)S(=O)(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-nitro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (500 mg, 1.73 mmol) in CH2Cl2 (5 ml) was added N1,N1,N3-trimethylpropane-1,3-diamine (0.26 ml, 1.8 mmol). The resulting mixture was allowed to stir at room temperature for 20 min. Diluted with CH2Cl2 (30 ml) and washed the organic layer with 9% aq. Na2CO3 (10 ml) and brine (10 ml). Dried over anhydrous sodium sulfate, filtered and concentrated to a white solid, which was used without further purification. MS m/z=370.1 [M+H]+. Calc'd for C13H18F3N3O4S: 369.4.
Reaction SMILES: [O:1]=[S:2]1(=[O:9])[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl.Cl>[O:1]=[S:2]1(=[O:9])[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=S1(=O)CCC(CO)C1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCS(=O)(=O)C2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
A mixture of (1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-yl)-methanol (3.59 g), 4-toluenesulfonyl chloride (9.11 g) and pyridine 5.8 mL) in chloroform (50 mL) was heated to 60° C. and stirred overnight. The reaction mixture was cooled and diluted with 100 mL 1N HCl and extracted with methylene chloride. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (60% EtOAc in hexanes) to give 4.012 g of toluene-4-sulfonic acid 1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-ylmethyl ester.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21].C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[CH2:22]([CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][O:15][CH2:14][CH2:13][CH2:12][NH:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH3:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCCC(CC)COCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCCCC(CC)COCCCNc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 62.4 %

Procedure:
2 g of para-fluoronitrobenzene was added to a solution of 20 ml of N-methylpyrrolidinone, 3.19 g of 2-ethylhexyl 3-aminopropyl ether and 2.35 g of K2CO3. The reaction medium was heated at 60° C. for 10 hours and, after it was cooled to room temperature, poured into a water+ice mixture. The resulting medium was extracted with ethyl acetate, and the organic phase was then concentrated by evaporating under vacuum. 2.73 g of N-[2-(3-ethylheptyloxy)ethyl]-4-nitro-1-aminobenzene (9) were obtained.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1.CCOCC>C(O)C>[Cl:24][C:25]1[CH:26]=[C:27]2[C:28](=[CH:29][CH:30]=1)[NH:31][C:15]([C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=1)=[C:16]2[CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C(O)CCCC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
Triethylamine (5 mL, 3.6 g, 36 mmol) was added dropwise to a stirred suspension of 4-chloro-δ-oxobenzenepentanoic acid (7.91 g, 35 mmol) and (4-chlorophenyl)hydrazine hydrochloride (6.29 g, 35 mmol) in ethanol (54 mL) and the mixture was stirred at room temperature for 3 h. Ether (500 mL) was added, the mixture was filtered and the solvent was evaporated under reduced pressure. The residue was added slowly to trifluoroacetic acid (120 mL) and the mixture was heated under reflux for 2 h. The mixture was cooled, water (250 mL) was added and the mixture was extracted with ethyl acetate (300 mL). The organic fraction was washed with brine (30 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was recrystallized from EtOAc/isohexane to give the title compound (7.6 g, 65%). 1H NMR (250 MHz, DMSO-d6) δ 12.01 (1H, br s), 11.36 (1H, s), 7.56-7.47 (5H, m), 7.26 (1H, d, J 8.5 Hz), 7.01 (1H, dd, J 8.5, 2.0 Hz), 2.96 (2H, t, 8.0 Hz), and 2.43 (2H, t, 8.0 Hz).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]3[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=3[Cl:37])=[CH:25][CH:24]=2)(=O)=O)=CC=1>C1COCC1>[Br:36][C:34]1[CH:33]=[CH:32][C:31]([Cl:37])=[C:30]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:24][CH:25]=2)[CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(Cc3cc(Br)ccc3Cl)cc2)cc1
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CCCC2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of cyclopentanol (0.86 g) in anhydrous THF (8.6 mL), NaH (2.0 eq) was added in portions at 0° C., and then the mixture was stirred at 0° C. for 3 h. Then 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl 4-methylbenzenesulfonate (intermediate AB) (2.43 g, 0.5 eq) was added in portions. The mixture was stirred at room temperature overnight, whereupon TLC showed the reaction was complete. Then the reaction mixture was quenched with saturated NH4Cl, extracted with EtOAc, washed with water and brine, dried with anhydrous Na2SO4, and concentrated to a crude oil. The crude oil was purified by column chromatography (PE:EA=100:1) to obtain oil AC (1.0 g, yield ˜50%).
Reaction SMILES: COC1C=CC([CH2:9][CH2:10][N:11]([C@H:26]2[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]2)[C:12](=[O:25])[NH:13][C:14]2[S:15][C:16]([S:19]([CH2:21][C:22]([OH:24])=[O:23])=[O:20])=[CH:17][N:18]=2)=CC=1.[CH2:33]([O:40]CCN(C1CCC(C)CC1)C(=O)NC1SC(SCC(O)=O)=CN=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([O:40][CH2:9][CH2:10][N:11]([C@H:26]1[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]1)[C:12](=[O:25])[NH:13][C:14]1[S:15][C:16]([S:19]([CH2:21][C:22]([OH:24])=[O:23])=[O:20])=[CH:17][N:18]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC1CCC(N(CCOCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: COc1ccc(CCN(C(=O)Nc2ncc(S(=O)CC(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1
Product: C[C@H]1CC[C@H](N(CCOCc2ccccc2)C(=O)Nc2ncc(S(=O)CC(=O)O)s2)CC1

Procedure:
The compound was prepared as previously described for {2-[3-[2-(4-methoxy -phenyl)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfinyl}-acetic acid using {2-[3-(2-benzyloxy-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid.
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:19][CH2:18]1)[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][N:9]2[CH:14]=[O:15].[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1.C[O-].[Na+]>CO>[OH:1][CH:2]([CH2:16][N:17]1[CH2:18][CH2:19][CH:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)[CH2:21][CH2:22]1)[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][N:9]2[CH:14]=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(OCC2CCN(CC(O)COc3cccc4c3CCN4C=O)CC2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)Nc1ccc(OCC2CCN(CC(O)COc3cccc4c3CCN4C=O)CC2)cc1

Procedure:
3.3 g. 4-{2-Hydroxy-3-[4-(4-aminophenoxymethyl)-piperidino]-propoxy}-1-formylindoline (preparation see Example 15b) are stirred with a mixture of 25 ml. acetic anhydride and 25 ml. pyridine for 10 hours at ambient temperature, then evaporated in a vacuum and the residue dissolved in water and dichloromethane. After neutralization with sodium bicarbonate, the organic phase is distilled and the residue obtained is converted in methanol with sodium methylate solution into the desired compound. By shaking out between dichloromethane and water and evaporating the organic phase, there is obtained 1.0 g. (27% of theory) 4-{2-hydroxy-3-[4-(4-acetamidophenoxymethyl)-piperidino]-propoxy}-1-formylindoline; m.p. 177°-179° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13]([O:19][CH3:20])[CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:15]([C:14]3[CH:17]=[CH:18][C:11]([OH:10])=[CH:12][C:13]=3[O:19][CH3:20])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: Nc1cc(Br)cnc1N
Product: COc1cc(O)ccc1-c1nc2cc(Br)cnc2[nH]1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 4-hydroxy-2-methoxybenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[F:17])=[CH:4][CH:3]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28](C(OC(C)(C)C)=O)[C:27]([CH3:37])([CH3:36])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:19]3[CH:20]=[C:21]4[NH:28][C:27]([CH3:37])([CH3:36])[CH2:26][N:22]4[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:17])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Oc2ccc(Cl)nc2)c(F)c1
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4ccc(Cl)nc4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((6-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and tert-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]([C:22]([F:25])([F:24])[F:23])[CH2:10][CH:11]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:13]=3[O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])O.[Na+]>O>[C:1]1([CH2:7][O:8][CH:9]([C:22]([F:25])([F:23])[F:24])[CH2:10][CH:11]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([NH:21][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:19]=[CH:20][C:13]=3[O:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc2c(c1)CCC(CC(OCc1ccccc1)C(F)(F)F)O2
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Nc1ccc2c(c1)CCC(CC(OCc1ccccc1)C(F)(F)F)O2

Procedure:
A solution of 3.6 g (10 mmol) of 2-(2-phenylmethoxy-3,3,3-trifluoropropyl)-6-amino-3,4-dihydro-2H-1-benzopyran in 34 ml of a 9/1 mixture of tetrahydrofuran and water is reacted for 20 min with 1.1 ml (11 mmol) of ethyl chloroformate and 1.3 g (15 mmol) of sodium hydrogencarbonate. The mixture is then diluted with water and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. By chromatography of the residue on a silica column using a 20/80 mixture of cyclohexane and dichloromethane, 4.2 g of product are obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([CH3:15])[CH:4]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]1)[C:5]([OH:7])=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:22]=[CH:23][C:24]=1[Cl:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>N1C=CC=CC=1.CN(C=O)C.O>[Cl:25][C:24]1[CH:23]=[CH:22][C:21]([CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])=[CH:20][C:19]=1[NH:18][C:5](=[O:7])[CH:4]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]1)[CH:3]([CH3:15])[C:2]([F:1])([F:17])[F:16]
Reactant: CC1CCN(C(C(=O)O)C(C)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)CCc1ccc(Cl)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(C(C(=O)Nc2cc(CCC(=O)OC(C)(C)C)ccc2Cl)C(C)C(F)(F)F)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
270 mg of 4,4,4-trifluoro-3-methyl-2-(4-methylpiperidin-1-yl)butanoic acid (crude product, racemic diastereomer mixture) were dissolved in 2.5 ml of pyridine and 4.9 ml of DMF, and 286 mg (1.12 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)propanoate and 527 mg (1.37 mmol) of HATU were added at RT. The mixture was stirred at 40° C. overnight. A further 0.5 eq. of HATU and 2 ml of N,N-diisopropylethylamine were added, and the reaction mixture was once more stirred at 50° C. for 5 h and then added to water. The mixture was extracted three times with ethyl acetate and the combined organic phases were washed with a little 1 N hydrochloric acid, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 50 mg of the target product (9.6% of theory) as a diastereomer mixture (about 3:2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([CH2:27][CH2:26][NH:25][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NCCN1CCOCC1)c1n[nH]c2ccccc12
Yield: 24.3 %

Procedure:
Same procedure followed as described in Example 1. The following amounts were used: 1H-indazole-3-carboxylic acid (0.65 g, 4 mmol), 1,1'-carbonyldiimidazole (0.65 g, 4 mmol) and 4-(2-aminoethyl)morpholine (0.52 mL, 4 mmol). The ethyl acetate extracts were evaporated to 0.468 g solid. Crystallization from ethyl acetate provided 0.267 g colorless crystals. Mass spectrum, m+ =274.
Reaction SMILES: [C:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][NH:7][CH2:6][C@H:5]1[CH3:11])(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][NH:7][CH2:6][C@H:5]1[CH3:11])[CH3:2]
Reactant: CC(=O)N1[C@H](C)CNC[C@@H]1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCN1[C@H](C)CNC[C@@H]1C

Procedure:
(2R,6S)-1-Acetyl-2,6-dimethylpiperazine was reduced with lithium aluminum hydride to obtain (2R,6S)-1-ethyl-2,6-dimethylpiperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[S:42](Cl)(=[O:44])=[O:43]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:42]([C:34]4[CH:35]=[C:36]([N+:39]([O-:41])=[O:40])[CH:37]=[CH:38][C:33]=4[CH3:32])(=[O:43])=[O:44])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc([N+](=O)[O-])ccc4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-methyl-5-nitro-benzenesulfonyl chloride. Purity (ELSD, based on MW=620.7)=88%.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-])=O)=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].O.NN>CO>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH2:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc([N+](=O)[O-])cc2C1
Agent: NN
Solvent: CO
Solvent: O
Product: CC(=O)N1CCc2ccc(N)cc2C1
Yield: 86.8 %

Procedure:
A mixture of 13 (5.1 g, 23 mmol), activated carbon (4.2 g), ferric chloride hexahydrate (2.1 g, 7.6 mmol) and methanol (140 ml) is stirred under refluxing for 20 minutes. To the boiling mixture is added hydrazine hydrate (8.5 g, 265 mmol) dropwise, and the mixture is refluxed for an additional 4 h, cooled and filtered and the residue washed with methanol. The filtrate is concentrated in vacuo and the residue recrystallized from EtOAc to give compound 14 (3.8 g, 85% yield). 1H NMR [300 MHz, (CD3)2SO], a 3:2 mixture of amide conformers doubling most signals, δ 6.80 (1H, d, H-5), 6.40 (1H, d, H-6), 6.33 (1H, s, H-7), 4.89 (2H, br s, NH2), 4.46 (0.8H, s, ArCH2N), 4.41 (1.2H, s, ArCH2N), 3.57 (2H, t, ArCH2CH2N), 2.66 (1.2H, t, ArCH2CH2N), 2.55 (0.8H, t, ArCH2CH2N), 2.06 (1.2H, s, COCH3), 2.05 (1.8H, s COCH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20]OS(C)(=O)=O)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:26][C:27]([F:42])([F:41])[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:38]4[CH2:39][CH2:40][N:35]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[O:28][C:27]([F:26])([F:41])[F:42])[CH2:36][CH2:37]4)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Reactant: FC(F)(F)Oc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(N1CCCC(CN2CCN(c3ccccc3OC(F)(F)F)CC2)C1)C1(c2ccc(Cl)cc2)CCC1
Yield: 32.3 %

Procedure:
Compound 9 was prepared using the method described in Example 3, starting with compound 2 (1.0 g, 2.60 mmol), 1-(2-trifluoromethoxyphenyl)piperazine (0.70 g, 2.86 mmol), and cesium carbonate (1.27 g, 3.90 mmol) to give 9 (0.45 g, 32%); C28H33ClF3N3O2, LRMS (m/z)=537 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[C:20](=S)=[S:21]>O1CCCC1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([CH2:8][CH2:9][CH2:10][N:11]=[C:20]=[S:21])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: S=C=S
Reactant: NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Solvent: C1CCOC1
Product: S=C=NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Temperature: -10 °C
Reaction time: 48 h
Yield: 88.3 %

Procedure:
To a solution of N,N-dicyclohexylcarbodiimide (2.08 g, 10 mmol) in dry tetrahydrofuran (20 ml) was slowly added at -10° C. a solution of N-(4-bromobenzyl)-N-(pyridin-2-yl)-propane-1,3-diamine (3.20 g, 10 mmol) and carbondisulfide (4.3 ml, 70 mmol) in dry tetrahydrofuran (20 ml) under an atmosphere of nitrogen. The mixture was stirred at -10° C. for 3 h and for 48 h at room temperature. The reaction mixture was filtered and the solvent evaporated in vacuo. The residue (5.29 g) was extracted with diethyl ether (3×20 ml) and the combined organic extracts were evaporated in vacuo affording 3.2 g (88%) of N-(4-bromobenzyl)-N-(3-isothiocyanatopropyl)-N-(pyridin-2-yl)amine as an oil.