Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][CH2:11][C:12](=[O:22])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[N:14]=1.B(Br)(Br)Br.C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][CH2:11][C:12](=[O:22])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[N:14]=1
Reactant: COc1ccccc1C1=NN(c2ccccc2Br)C(=O)CO1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1COC(c2ccccc2O)=NN1c1ccccc1Br
Reaction time: 1 h
Yield: 71.8 %

Procedure:
In methylene chloride (1000 ml) was dissolved 2-(2-methoxyphenyl)-4-(2-bromophenyl)-4H-1,3,4-oxadiazine-5(6H)-one (91.0 g) obtained in Example 17. Under ice-cooling, 1.0M boron tribromide/methylene chloride solution (900 ml) was added dropwise thereinto over 1 hour, followed by stirring for 1 hour. By adding an aqueous saturated sodium bicarbonate to the reaction solution, the organic layer was separated, and then purified by Cromatorex NH silica gel chromatography (methylene chloride). The resulting crude crystals were recrystallized from methylene chloride/hexane, to give the title compound (62.8 g, 74%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH:3]([CH2:20][CH3:21])[CH:4]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15]([NH2:17])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[C:23](N1C=CN=C1)([N:25]1C=CN=C1)=[O:24].N>C(Cl)Cl.O>[CH3:1][N:2]([CH3:22])[CH:3]([CH2:20][CH3:21])[CH:4]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15]([NH:17][C:23]([NH2:25])=[O:24])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCC(C(c1ccc2nc(N)sc2c1)n1ccnc1)N(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: ClCCl
Product: CCC(C(c1ccc2nc(NC(N)=O)sc2c1)n1ccnc1)N(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (50 mg, 0.151 mmol) and carbonyldiimidazole (50 mg, 30 mmol) in DCM was stirred at RT for 5 h. Aqueous ammonia was added and the reaction was stirred over night. The reaction was diluted with water and extracted with DCM. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC to afford 1-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)urea. MS ESL m/z 359.27 [M+1+].
Reaction SMILES: [C:1]([CH:9]([CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[C:2]1([C:1]2[S:33][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccccc2)sc1-c1ccccc1
Yield: 54.5 %

Procedure:
To a stirring solution of ethyl 2-benzoyl-4-oxo-4-phenylbutanoate 69 (0.812 g, 2.62 mmol) in toluene (20 mLs) was added Lawesson's reagent (1.270 g, 3.14 mmol) and the reaction mixture was refluxed for 4 h then concentrated. The crude residue was purified by ISCO (40 g column, 0 to 30% ethyl acetate in hexane) to afford ethyl 2,5-diphenylthiophene-3-carboxylate 70 (0.44 g 55% yield) as a yellow oil. LRMS (ESI): (calc.) 308.09 (found) 309.27 (MH)+
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]([CH2:10]/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N+]=[N-]>C(OCC)C>[CH2:10]([NH2:7])/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCC/C=C/C=C/CN=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCC/C=C/C=C/CN
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, 1 M LiAlH4 in diethyl ether (2.89 ml) was diluted with dry diethyl ether (30 ml) and cooled in an ice bath. A solution of (2E,4E)-1-azidododeca-2,4-diene (1 g) in dry diethyl ether (10 ml) was added slowly. The mixture was stirred at 0° C. for 1 h, the ice bath was removed and stirring was continued for 1 h while warming to room temperature. Water was added carefully until gas evolution ceased and the reaction mixture was dried over sodium sulfate, filtered and concentrated to give a yellow liquid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:16]CC2C=CC=CC=2)=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)=[O:4].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH:46]CC1C=CC=CC=1.[BH4-].[Na+].C(OCC)C>ClCCl.CO.O>[OH:16][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH2:2][NH:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][CH2:36][CH2:35][O:34][C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)=[CH:10][C:9]=1[NH:11][S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: c1ccc(CNCCCCCCOCCCCOc2ccc3ccccc3c2)cc1
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)Nc1cc(C(O)CNCCCCCCOCCCCOc2ccc3ccccc3c2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
A solution of N-[5-(bromoacetyl)-2-(phenylmethoxy)phenyl]methanesulphonamide (1.96 g), N-[6-[4-[(2-naphthalenyl)oxy]butoxy]hexyl]benzenemethanamine (2.0 g) and DEA (0.96 g) in dichloromethane (45 ml) was stirred under nitrogen at room temperature for 22 h. The mixture was treated with water (100 ml) and extracted with dichloromethane (2×150 ml). The combined organic extracts were dried and evaporated in vacuo to give an oil which was dissolved in methanol (30 ml) and dichloromethane (20 ml) and cooled to 0°-5° C. under nitrogen. Sodium borohydride (0.50 g) was added portionwise and the solution stirred at room temperature for 30 min, then carefully diluted with water (20 ml). The solvent was evaporated in vacuo, the residue partitioned between water (100 ml) and dichloromethane (150 ml) and the aqueous phase re-extracted with dichloromethane (150 ml), the combined organic extracts being dried and evaporated in vacuo to give an oil which was purified by FCC eluting with System C (95:5:1). A solution of the oil (3.41 g) in absolute ethanol (60 ml) was hydrogenated over pre-reduced 10% palladium on charcoal catalyst (50% aqueous paste, 1.5 g) in absolute ethanol (10 ml) for 4.5 h. The mixture was filtered through hyflo and evaporated in vacuo to give an oil which was purified by FCC eluting with System B (40:10:1) to give a cream solid. Trituration with diethyl ether gave the title compound as a white solid (1.23 g), m.p. 99.5°-100.5° .
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[N:14]=[C:15]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[S:16][C:17]=3[C:18](O)=[O:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=1>>[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:18]([C:17]2[S:16][C:15]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:14][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:2][CH:3]4[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]4)[CH2:8]2)[CH2:10]3)=[O:19])[CH:31]=1
Reactant: O=C(O)c1sc(C2CCCCC2)nc1CCC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1cccc(N)c1
Product: COC(=O)c1cccc(NC(=O)c2sc(C3CCCCC3)nc2CCC23CC4CC(CC(C4)C2)C3)c1
Yield: 59 %

Procedure:
The product from step c was reacted with 3-amino-benzoic acid methyl ester using essentially the same method as in Example 52, step a. The product was obtained as a white solid in 59% yield. 1H NMR (300 MHz, CDCl3) 8.00 (2H, m), 7.82 (1H, d), 7.47 (2H, m), 3.93 (3H, s), 3.06 (3H, m), 2.18-1.27 (27H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[F:16][C:13]([F:14])([F:15])[C:8]1([C:9]([F:10])([F:11])[F:12])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:19](=[O:21])[O:17]1
Reactant: Nc1ccccc1C(O)(C(F)(F)F)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C(C(F)(F)F)(C(F)(F)F)O1
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a stirred solution of 2-(2-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.20 g, 16.20 mmol) in THF (160 mL) was added triphosgene (4.80 g, 16.20 mmol). The reaction was stirred overnight, quenched with ammonium chloride solution (sat.) and extracted several times with ethyl acetate. The organic layer was dried over magnesium sulfate and triturated with ether/hexane to give 2.78 g of 4,4-bis(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as a tan solid (60%). 1H NMR (DMSO-d6): δ 11.37 (s, 1H), 7.62 (m, 2H), 7.29 (t, J=7.5 Hz, 1H), 7.11 (dd, J=8.0, 0.8 Hz, 1H). MS (ESI) m/z 284 ([M−H]−); HRMS: calcd for C10H5F6NO2, 285.0224; found (ESI_FT), 286.0299; Anal. Calcd for C10H5F6NO2: C, 42.12; H, 1.77; N, 4.91. Found: C, 42.63; H, 1.79; N, 4.72.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(N)CN.[OH-].[Na+]>C(Cl)Cl.CS(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:27])([F:29])[F:28])=[O:23])[CH:19]([CH3:20])[CH3:21])[CH:14]=[N:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(N)cc23)c1)C(=O)NCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(C)[C@H](Nc1cncc(-c2c[nH]c3ncc(N)cc23)c1)C(=O)NCC(F)(F)F
Reaction time: 18 h

Procedure:
To a solution N2-{5-[5-(amino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl]pyridin-3-yl}-N-(2,2,2-trifluoroethyl)valinamide 5-1b (50 mg, 0.093 mmol) in DCM (2 mL) was added TFA (1.4 mL, 18.6 mmol) and the resultant mixture was stirred for 2 h. The mixture was concentrated in vacuo, resuspended in MeOH (1 mL) and to this was added ethylenediamine (13 μl, 0.186 mmol) and sodium hydroxide (10 M aq) (0.065 mL, 0.652 mmol). After 18 h, the reaction was transferred to vial with an additional 1 mL of dimethylsulfoxide and this solution was purified by mass triggered reverse phase HLPC. The fractions containing product 5-1 were basified with NaHCO3, dried over MgSO4, filtered and concentrated. MS APCI: [M+H]+ m/z=407.1.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[N:25][C:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:23]2)[C:6]1=[O:34])[CH2:2][CH2:3][CH3:4].N1CCOCC1.CO>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[N:25][C:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:23]2)[C:6]1=[O:34])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCn1cnc(Cc3ccccc3)n1)c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCn1c(=O)n(CCCn2cnc(Cc3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 18 h
Yield: 61.9 %

Procedure:
A solution of 3-butyl-8-chloro-1-{3-[3-(phenylmethyl)-1H-1,2,4-triazol-1-yl]propyl}-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (669 mg, 1.39 mmol) in THF (7 ml) was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh3)4 (160 mg, 0.14 mmol) was added and the mixture degassed once more. Morpholine (1.2 ml, 13.9 mmol) was added and the mixture was stirred under nitrogen for 18 h, then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted again with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated, giving a yellow residue. MeOH was added and then passed down an aminopropyl SPE with the product eluting with 2-3% AcOH/MeOH. The product fractions were combined and concentrated giving a pale yellow solid (380 mg). Approximately a quarter of the material was purified by autoprep HPLC and rest was crystallised from MeOH:DMSO (1:1) giving the title compound as a white solid (125 mg, 31%).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])[CH:7]=[CH:6][C:5]=1[NH:18][C:19](=[O:22])[CH2:20][CH3:21].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:24]1([NH:30][C:31](=[O:32])[NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:8]2[CH:7]=[CH:6][C:5]([NH:18][C:19](=[O:22])[CH2:20][CH3:21])=[C:4]([CH:9]=2)[C:3]([OH:2])=[O:23])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCC(=O)Nc1ccc(Oc2ccccc2N)cc1C(=O)OC
Solvent: ClCCl
Product: CCC(=O)Nc1ccc(Oc2ccccc2NC(=O)Nc2ccccc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of 2-propionylamino-5-(2-amino-phenoxy)-benzoic acid methyl ester (50.0 mg, 0.153 mmol, prepared as described in EXAMPLE 2) and phenyl isocyanate (21.0 mg, 0.175 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 2 hours. The solvent was removed by evaporation and the crude ester product was hydrolysed in methanol (1 mL) and 1M NaOH (1 mL) over night. The reaction mixture was acidified with 1M HCl and the product was collected by filtration (54 mg, total yield 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH:10]2[C:16](OCC)=O)[CH:6]=[CH:7][CH:8]=1.[OH-:21].[Na+].CO>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11](=[O:21])[C:10]2=[CH2:16])[CH:6]=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: CCOC(=O)C1CN(C)CCC1c1cccc(OC)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C1C(=O)N(C)CCC1c1cccc(OC)c1
Yield: 93.1 %

Procedure:
The ester ethyl 4-(3'-methoxyphenyl)-1-methylpiperidine-3-carboxylate (23)(5.0 g, 17.5 mmol), NaOH (1.49 g, 35 mmol), CH3OH (50 mL), and H2O (25 mL) were refluxed for 5 h. After the thorough removal of solvents, the residue was mixed with acetic anhydride (50 mL) and refluxed for 1 h, then cooled and evaporated and the crude reaction product partitioned between CHCl3 (50 mL) and saturated NaHCO3 (50 mL, pH 8). The aqueous layer was extracted with CHCl3 (2×50 mL) and the combined organic phases dried and evaporated. Distillation gave 3.77 g (92%) of 4-(3'-methoxyphenyl)-1-methyl-3-methylene-2-piperidone (24). Recrystallization (CH3Cl2 /hexane) gave the analytical sample: mp 67°-70° C: NMR δ 7.29 (m, 1H), 6.82 (m, 3H), 6.40 (t,J=2 Hz, 1H), 5.07 (t,J=2 Hz, 1H), 3.75 (s, 3H), 3.34 (m, 2H), 3.04 (s, 3H), 2.17 (m, 2H); IR (KBr) 1645, 1600 cm-1 ; mass spectrum m/e (real intensity) 231 (100), 216 (13). Anal. Calcd for C14H17NO2 : C, 72.7; H, 7.4; N, 6.1. Found: C, 72.6; H, 7.3; N, 6.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]=[O:19].[OH-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:18][OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: OCn1ccc2c(OCc3ccccc3)cccc21

Procedure:
Compounds of Formula I also can be prepared as illustrated by exemplary reaction in Scheme 2. Reaction of 4-benzyloxy-indole with formaldehyde in the presence of a base such as NaOH produced 4-benzyloxy-1-hydroxymethyl-indole. The benzyl protecting group was removed by hydrogenation to give the 4-hydroxy-1-hydroxymethyl-indole. Reaction of 4-hydroxy-1-hydroxymethyl-indole with an aryl-aldehyde, such as 5-bromoveratraldehyde and malononitrile in the presence of a base, such as piperidine produced the substituted 7-hydroxymethyl-pyrrolo[2,3-h]chromene.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:9][C:10]1[CH:11]=[C:12]([C:14](I)=[CH:15][C:16]=1[CH3:17])[NH2:13]>>[CH3:17][C:16]1[CH:15]=[C:14]2[C:12](=[CH:11][C:10]=1[CH3:9])[NH:13][C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[CH:2]2
Reactant: C#Cc1cccnc1
Reactant: Cc1cc(N)c(I)cc1C
Product: Cc1cc2cc(-c3cccnc3)[nH]c2cc1C

Procedure:
3-Ethynylpyridine and 3,4-dimethyl-6-iodoaniline are processed according to the method described in Example 86 to give 5,6-dimethyl-2-pyridin-3-yl-1H-indole. MS (ESI) m/z 223.13 (M+H)+.
Reaction SMILES: Br[C:2]1[C:6]([CH2:7][CH3:8])=[CH:5][S:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:22]=[CH:21][N:14]2[C:15](=[O:20])[CH:16]=[C:17]([OH:19])[N:18]=[C:13]2[CH:12]=1.C([SnH](CCCC)CCCC)CCC.[F-].[K+]>C1(C)C=CC=CC=1>[CH2:7]([C:6]1[CH:2]=[C:3]([CH2:9][CH2:10][C:11]2[CH:22]=[CH:21][N:14]3[C:15](=[O:20])[CH:16]=[C:17]([OH:19])[N:18]=[C:13]3[CH:12]=2)[S:4][CH:5]=1)[CH3:8]
Reactant: CCc1csc(CCc2ccn3c(=O)cc(O)nc3c2)c1Br
Agent: CCCC[SnH](CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCc1csc(CCc2ccn3c(=O)cc(O)nc3c2)c1
Temperature: 140 °C
Yield: 158.5 %

Procedure:
8-[2-(3-Bromo-4-ethyl-2-thienyl)ethyl]-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (96 mg, 0.25 mmol) dissolved in toluene (6 ml) was added with tributyltin hydride (75 μl) and 2,2-azobisisobutyronitrile (4 mg, 0.025 mmol) and refluxed by heating at 140° C. Then 2,2-azobisisobutyronitrile and tributyltin hydride were further added until the reaction was completed while the progress of the reaction was monitored by LC-MS. 34 mg (0.22 mmol) of 2,2-azobisisobutyronitrile and 350 μl (1.30 mmol) of tributyltin hydride were used. The reaction solution was returned to room temperature and the reaction was stopped with an aqueous solution of potassium fluoride. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine. Then, the aqueous layer was extracted with ethyl acetate. The organic layer collected was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (chloroform:methanol=20:1) to obtain 119 mg of the title compound with contained impurities.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([O:14]C(OCC(Cl)(Cl)Cl)=O)[CH2:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH2:10][CH:9]2[CH2:31][CH2:32][CH3:33])=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:9]([CH2:31][CH2:32][CH3:33])[CH2:10][NH:11][CH2:12][CH:13]2[OH:14])=[CH:4][CH:3]=1
Reactant: CCCC1CN(C(=O)OCC(Cl)(Cl)Cl)CC(OC(=O)OCC(Cl)(Cl)Cl)C1c1ccc(Cl)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCC1CNCC(O)C1c1ccc(Cl)cc1
Reaction time: 5 h
Yield: 54.7 %

Procedure:
A mixture of 13.05 g (21.6 mmol) of 2,2,2-trichloro-ethyl (3RS,4SR,5SR)-4-(4-chloro-phenyl)-3-propyl-5-(2,2,2-trichloroethoxycarbonyloxy)-piperidine-1-carboxylate and 14.5 g of zinc in 200 ml of glacial acetic acid was treated in an ultrasound bath for 15 hours. In order to complete the reaction, a further 5 g of zinc were subsequently added and the mixture was left in the ultrasound bath for a further 5 hours. For the working-up, the zinc was filtered off under suction, the residue was rinsed with glacial acetic acid and the solution was evaporated to dryness under reduced pressure. The residue was partitioned between 1 N NaOH and ethyl acetate, the separated aqueous phase was then again extracted with ethyl acetate and finally the combined organic phases were evaporated under reduced pressure. The crude product obtained was crystallized from diethyl ether and gave 3.0 g (55% of theory) of (3RS,4RS, 5SR)-4-(4-chloro-phenyl)-5-propyl-piperidin-3-ol as colourless crystals; MS: 253 (M)+. For purification, the mother liquor was chromatographed on silica gel using a 90:10:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There were obtained a further 1.1 g (20% of theory) of (3RS,4RS,5SR)-4-(4-chloro-phenyl)-5-propyl-piperidin-3-ol.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:19][OH:20])[O:4][C@H:5]2[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:18].C[Si](Cl)(C)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N>N1C=CC=CC=1>[OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:19][OH:20])[O:4][C@H:5]2[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH:18][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of nucleoside 61A (0.32 g, 1.15 mmol) in anhydrous pyridine (1 cm3) was added trimethylsilyl chloride (0.73 cm3, 5.73 mmol) and the mixture was stirred at room temperature for 20 min. Benzoyl chloride (0.67 cm3, 5.73 mmol) was added at 0° C., and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and ice-cold water (15.0 cm3) was added. After stirring for 5 min, a 32% (w/w) aqueous solution of ammonia (1.5 cm3) was added and the mixture was stirred for 30 min. The mixture was evaporated to dryness and the residue was dissolved in water (25 cm3). After evaporation of the mixture under reduced pressure, the residue was purified by silica gel chromatography using dichloromethane/methanol (97:3, v/v) as eluent to give nucleoside 61B as a white solid material (0.55 g). FAB-MS m/z 384 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:3]1.C(N(C(C)C)CC)(C)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(=O)([O-])O.[Na+]>ClCCl>[CH3:29][S:30]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)=[CH:11][CH:10]=2)[CH2:3]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O[C@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Reaction time: 4 h

Procedure:
(S)-3-Hydroxy-1-(4-pyrrolidinophenethyl)pyrrolidine (6.30 g, 23.4 mmol) was dissolved in 100 ml of dichloromethane. Diisopropylethylamine (5.28 ml, 30.0 mmol) and methanesulfonyl chloride (2.34 ml, 30.0 mmol) were added to the obtained solution at 0° C. and they were stirred for 4 hours. The reaction mixture was distributed into 5% aqueous sodium hydrogencarbonate solution and dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with dichloromethane and methanol (10:1), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (S)-3-methanesulfonyloxy-1-(4-pyrrolidinophenethyl)pyrrolidine in the form of a light yellow oily substance (7.50 g, 49%).