Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][CH2:21][CH:20]([NH2:24])[CH2:19]3)[C:15]2=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=4)[CH2:19]3)[C:15]2=[O:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC3(CCCC(N)C3)C2=O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N2CCC3(CCCC(NC(=O)c4cccc(F)c4)C3)C2=O)CC1

Procedure:
4-(7-Amino-1-oxo-2-aza-spiro[4.5]dec-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.57 mmol), 3-fluorobenzoic acid (0.080 g, 0.56 mmol), BOP (0.252 g, 0.57 mmol), and triethylamine (0.115 g, 1.14 mmol) in methylene chloride (5.0 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified with chromatography (ethyl acetate) to afford the title compound which is a mixture of two diastereomers (cis/trans: 3/2; under LC-MS method C, the first peak with RT of 1.47 min was assigned as cis, and the second peak with RT of 1.50 min was assigned as trans.). 1H NMR (400 MHz, CDCl3) δ 8.5 (s, 0.6 H), 7.60-7.68 (m, 1H), 7.36-7.50 (m, 2H), 7.14-7.20 (m, 1H), 5.92 (d, J=6.8 Hz, 0.4 H), 4.55-4.65 (m, 0.4 H), 4.04-4.38 (m, 3.6H), 3.20-3.30 (m, 2H), 2.71-2.86 (m, 2H), 1.28-2.25 (m, 23H). ESI-MS m/z: 474 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH2:15])[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[N:29][CH:30]=2)O1.C(N(CC)CC)C.CO>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[N:29][CH:30]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:15])[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cn1
Yield: 87 %

Procedure:
In a separate vial, (2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation, see Intermediate 1) (50 mg, 0.156 mmol), methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (49.4 mg, 0.188 mmol), PdCl2(dppf) (17.17 mg, 0.023 mmol) and triethylamine (0.065 mL, 0.469 mmol) were combined in DME (0.5 mL) and MeOH (1 mL) and the mixture heated under microwave irradiation to 110° C. for 45 mins. The two crude reaction mixtures were combined and concentrated in vacuo. The residue was purified by chromatography (100 g column, EtOAc/cyclohexane followed by 2M methanolic ammonia/DCM gradient). The appropriate fractions were combined, concentrated in vacuo and dried in a vacuum oven to give a residue. This residue was partitioned between sat. aq. sodium bicarbonate (100 mL) and DCM (3×100 mL). The organic layers were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give methyl 5-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinate (555 mg, 1.64 mmol, 87% yield).
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14]([NH:16][CH3:17])[N:13]=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:18][I:19]>>[I-:19].[CH3:17][NH:16][C:14]1[N:13]=[CH:12][N+:11]([CH3:18])=[C:10]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[N:15]=1
Reactant: CNc1ncnc(-n2ccc3ccccc32)n1
Reactant: CI
Product: CNc1nc[n+](C)c(-n2ccc3ccccc32)n1
Product: [I-]
Yield: 29 %

Procedure:
Using a similar process to that described in Example 1, 2-(indol-1-yl)-4-methylamino-1,3,5-triazine was reacted with methyl iodide to afford 4-methylamino-2-(indol-1-yl)-1-methyl-1,3,5-triazinium iodide in 29% yield as a solid, mp 284°-285° C. (after recrystallisation from methanol).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:39])[O:11][C:12]1[CH:13]=[C:14]([CH:27]=[C:28]([C:30]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH3:38])[N:34]=2)=[O:31])[CH:29]=1)[O:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.O.[OH-].[Li+].Cl>C1COCC1.O>[OH:8][CH2:9][C@H:10]([CH3:39])[O:11][C:12]1[CH:13]=[C:14]([CH:27]=[C:28]([C:30]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH3:38])[N:34]=2)=[O:31])[CH:29]=1)[O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(C(=O)Nc3ccn(C)n3)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 108.7 %

Procedure:
A solution of ethyl 4-(3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)benzoate (3.78 g, 6.84 mmol) in THF (100 mL) was added to a solution of lithium hydroxide monohydrate (1.44 g, 33 mmol) in water (50 mL). The mixture was stirred at ambient temperature for 72 hours. 1M Hydrochloric acid was added until pH=2 and the mixture stirred for a further 1 hour. The THF was removed in vacuo and the solid precipitate filtered off, washed with water and dried in vacuo to give the desired compound (3.06 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH:9]1[CH:13]=[C:12]([CH:14]=[O:15])[N:11]=[CH:10]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[N:11]=[CH:10]2)=[N:6][CH:7]=1
Reactant: O=Cc1c[nH]cn1
Reactant: Fc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cn(-c2ccc(Br)cn2)cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A mixture of 5-bromo-2-fluoropyridine (630 mg, 3.58 mmol), 4-imidazolecarboxaldehyde (355 mg, 3.70 mmol) and K2CO3 (1.00 g, 7.25 mmol) in DMF (10 mL) was stirred at 70° C. overnight. After being cooled down, H2O was added to induce precipitation. The precipitate was collected and dried on vacuum to give 1-(5-bromopyridin-2-yl)-1H-imidazole-4-carbaldehyde (738 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)=[CH:3][CH:2]=1.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:23]=1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH:19][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:24]5[N:23]=[C:22]([C:21]([F:37])([F:36])[F:20])[O:26][N:25]=5)[CH:28]=4)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[S:10][CH:11]=2)=[CH:3][CH:2]=1
Reactant: NCC1(c2nc(-c3ccncc3)cs2)CCOCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(c2nc(-c3ccncc3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 38 %

Procedure:
This compound was synthesized from (4-(4-(pyridin-4-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (60 mg, yield 38%): 1H NMR (400 MHz, DMSO-d6) δ 8.82 (t, J=6.3 Hz, 1H), 8.57 (d, J=5.8 Hz, 2H), 8.45 (s, 1H), 8.40 (s, 1H), 8.19 (d, J=7.9 Hz, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.87 (d, J=5.8 Hz, 2H), 7.70 (t, J=7.8 Hz, 1H), 3.87-3.84 (dt, J=12.1 Hz, 3.4 Hz, 2H), 3.59-3.58 (d, J=6.1 Hz, 2H), 3.42 (m, 2H), 2.28-2.24 (d, J=13.4 Hz, 2H), 2.04-1.96 (m, 2H). MS (ESI) m/z: Calculated for C24H20F3N6O3S: 515.12. found: 516.0 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[OH-].[K+].[CH2:11]([OH:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:11]([O:19][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCO
Reactant: O=C(O)CCCCBr
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCOCCCCC(=O)O
Temperature: 97 °C
Reaction time: 27 h
Yield: 9 %

Procedure:
5-bromopentanoic acid (2g, 11.0 mmol) was added to a solution of potassium hydroxide (2.48 g, 44.2 mmol) in 1-octanol (20 mL) and stirred at 97° C. for 27 hrs. After cooling, the product was extracted at pH=1 with ethyl acetate and water. The organic phase was dried over sodium sulfate and solvent was removed. 1-octanol was removed by short path (Kugelrohr) distillation (50-70° C., 0.5 mm Hg). To ensure complete cleavage of the octyl ester, the residue was stirred 3 hrs with methanol/water/KOH (50%/50%/2.5 g, 40 mL) at 25° C. 1-octanol was extracted into ethyl acetate at pH=12. 5-(octyloxy)pentanoic acid was extracted from the aqueous phase into ethyl acetate after adjusting the pH to 1.5 with HCl. After drying over sodium sulfate, the solvent was removed at reduced pressure. Silica column chromatography in 10% ethyl acetate/ hexane/0.3% formic acid, yielded 5-(octyloxy)pentanoic acid (235 mg, 9%): mp <30° C.; 1H NMR (300 MHz, CDC13) δ 0.88 (t, 3H, J=6.6), 1.18-1.39 (bm, 10H, methylene envelope), 1.48-1.77 (bm, 6H, CH2CH2OCH2CH2, CH2CH2COOH), 2.39 (t, 2H, J=7.1, CH2COOH), 3.34-3.49 (bm, 4H, CH2OCH2), 10.66 (br, 1H, COOH); 13 C NMR (75.4 MHz, CDC13) 14.18, 21.59, 22.73, 26.22, 29.03, 29.32, 29.51, 29.72, 31.89, 33.85, 70.22, 71.07, 179.55; m/z 231 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([O:11][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH:5]=1
Reactant: Cc1cccc(CCBr)c1
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(I)c(OCCc2cccc(C)c2)c1
Reaction time: 10 h
Yield: 80.7 %

Procedure:
10.0 g of 3-Hydroxy-4-iodo-benzoic acid methyl ester, 14.3 g of 1-(2-bromo-ethyl)-3-methyl-benzene, and 10.0 g of K2CO3 were stirred in anhydrous DMF at 80° C. for 10 h. Then, 14.3 g of 1-(2-bromo-ethyl)-3-methyl-benzene, and 10.0 g of K2CO3 were added and stirring was continued at 80° C. for 10 h. 400 ml of EA were then added and the mixture was washed twice using 200 ml of water each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EAIHEP (gradient) yielded 11.5 g of the title compound, colorless oil.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[O:17]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18]1.C(=O)([O-])[O-].[K+].[K+].O>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.CN(C)C=O>[O:17]1[CH:21]=[CH:20][C:19]([C:2]2[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=2)=[CH:18]1
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccoc2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a mixture of tert-butyl N-(4-bromobenzyl)carbamate (0.14 g), 2-(furan-3-yl)-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (0.12 g), potassium carbonate (0.1 g), water (0.2 mL) and N,N-dimethylformamide (1 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.03 g), and the resulting mixture was stirred at 80° C. for 12 hours. The reaction mixture was cooled to room temperature and then the insoluble material was filtered out. The filtrate was partitioned between ethyl acetate (110 mL) and water (50 mL). The organic layer was washed successively with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on aminopropylated silica gel (eluent: hexane/ethyl acetate=1/1) to give tert-butyl N-[4-(furan-3-yl)benzyl]-carbamate. The compound obtained was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.57 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate (15 mL) was added dropwise and the whole was extracted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate/brine (1/1, 10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.06 g).
Reaction SMILES: [Br:1][C:2]1[C:15](=[O:16])[NH:14][C:5]2[N:6]=[C:7]([NH:11][CH2:12][CH3:13])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][OH:23]>CN(C=O)C>[Br:1][C:2]1[C:15](=[O:16])[N:14]([CH2:20][CH2:21][CH2:22][OH:23])[C:5]2[N:6]=[C:7]([NH:11][CH2:12][CH3:13])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: OCCCBr
Reactant: CCNc1nc(C)c2cc(Br)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNc1nc(C)c2cc(Br)c(=O)n(CCCO)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a solution of 6-bromo-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.35 mmol) in DMF (2 mL), prepared using procedures analogous to those described in Example 14, was added NaH (30 mg, 60%, 0.7 mmol). The mixture was stirred for 30 min at room temperature and was warmed to 70° C. 3-Bromopropanol (48 mg, 0.35 mmol) was then added. The stirring was continued for 12 h. Standard workup and purification by column chromatography gave 33 mg (27% yield) of 6-bromo-2-(ethylamino)-8-(3-hydroxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 5.42 (br s, 1H), 4.59 (br s, 2H), 3.50-3.47 (m, 5H), 2.55 (s, 3H), 2.02 (br s, 2H), 1.28 (t, 3H); MS (EI) for C13H17BrN4O2: 341 (MH+).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[N:23][C:22](I)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([OH:29])[C:27]#[CH:28].C(N(CC)CC)C.O>CN(C)C=O.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>[OH:29][CH2:26][C:27]#[C:28][C:22]1[N:23]=[CH:24][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:21]=1
Reactant: C#CCO
Reactant: Ic1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: OCC#Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirred solution of 1-trityl-3-iodo-1,2,4-triazole (26.24 g, prepared as described in Example 5), propargyl alcohol (3.56 ml) and triethylamine (40 ml) in dry N,N-dimethylformamide (750 ml) was treated successively with tetrakis(triphenylphosphine)palladium (2.77 g) and cuprous iodide (1.0 g). It was stirred for four hours at room temperature under nitrogen and allowed to stand overnight but the reaction had not proceeded to completion. Stirring was continued for a further four periods of seven hours, then the mixture was poured into water (1 l) and extracted with chloroform (5×250 ml). The extracts were dried over magnesium sulphate, evaporated under reduced pressure and chromatographed on silica, using ethyl acetate-hexane (4:1) as eluant. Trituration with ether gave 1-hydroxy-3(1-trityl-1,2,4-triazol-3-yl)prop-2-yne (12.20 g). Recrystallisation from chloroform gave material m.p. 211° C. NMR (CDCl3): δ 4.45(2H,s), 7.1-7.3(15H,m), 7.95(1H,s). 13C NMR provided confirmation. M/S: M+ 365.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])=[C:6]([C:19]([F:22])([F:21])[F:20])[N:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:25]([C:30]2[S:34][CH:33]=[N:32][C:31]=2[CH:35]=O)[C:26]([CH3:29])=[CH:27][CH:28]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:23][C:24]1[N:25]([C:30]2[S:34][CH:33]=[N:32][C:31]=2[C:35]2[N:10]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:9])[C:7]3[C:6]([C:19]([F:22])([F:20])[F:21])=[N:5][CH:4]=[CH:3][C:2]=3[N:1]=2)[C:26]([CH3:29])=[CH:27][CH:28]=1
Reactant: Cc1ccc(C)n1-c1scnc1C=O
Reactant: Nc1ccnc(C(F)(F)F)c1C(=O)NCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1scnc1-c1nc2ccnc(C(F)(F)F)c2c(=O)n1CCc1ccccc1
Temperature: 110 °C
Yield: 17.2 %

Procedure:
A solution of 4-amino-N-phenethyl-2-(trifluoromethyl)nicotinamide (25.5 mg, 0.082 mmol), 5-(2,5-dimethyl-1H-pyrrol-1-yl)thiazole-4-carbaldehyde (17 mg, 0.082 mmol) and TsOH (1.4 mg, 0.008 mmol) in toluene was heated at reflux overnight. The reaction was then filtered and to the crude mixture was added manganese oxide. The reaction was heated at 110° C. for 4 h. The reaction mixture was filtered, concentrated and purified with silica gel chromatography providing a solid, 2-(5-(2,5-dimethyl-1H-pyrrol-1-yl)thiazol-4-yl)-3-phenethyl-5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one (7 mg). 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.76 (d, 1H), 7.69 (m, 1H), 7.51 (m, 1H), 7.48 (d, 1H), 7.32 (m, 5H), 4.20 (m, 2H), 3.32 (m, 2H), 2.07 (s, 6H). MS m/z 496.5 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[O:8][CH2:7][CH2:6][CH:5]2[CH:3]1[CH:4]2[C:9]([O:11][CH2:12][CH3:13])=[O:10].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[OH:1][CH:2]1[O:8][CH2:7][CH2:6][CH:5]2[CH:3]1[CH:4]2[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1C2CCOC(=O)C21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1C2CCOC(O)C21
Reaction time: 6 h
Yield: 85 %

Procedure:
To a solution of ethyl (1SR,6SR,7SR)-2-oxo-3-oxa-bicyclo[4.1.0]heptane-7-carboxylate (15.2 g, 82.8 mmol) in anhydrous tetrahydrofuran (300 mL) at −78° C. and under argon, a 1.5 M solution of diisobutylaluminium hydride in toluene (82.8 mL, 124.2 mmol) in anhydrous tetrahydrofuran (150 mL) at −78° C. under an argon atmosphere was added dropwise via cannula. The solution was stirred for six hours at this temperature and then diluted with ethyl acetate (200 mL) and quenched with a saturated aqueous solution of sodium tartrate (200 mL). The resulting mixture was stirred at room temperature overnight. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated in vacuo. The residue was purified by column chromatography using ethyl acetate and hexane 1:2 as eluent to afford 12.3 g (85% yield) of (2RS) and (2SR) ethyl (1SR,6RS,7SR)-2hydroxy-3-oxa-bicyclo[4.1.0]heptane-7-carboxylate as a colorless oil, which exist with their corresponding open hydroxyaldehyde forms.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([OH:18])[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[CH3:19]N(C)P(N(C)C)(N(C)C)=O.[H-].[Na+].IC>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([O:18][CH3:19])[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: OC(Cn1ccnc1)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(Cn1ccnc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.38 g. of 1-[2-(2-naphthyl)-2-hydroxyethyl]imidazole in 40 ml. of hexamethylphosphoramide under nitrogen is added 480 mg. of a 56% dispersion of sodium hydride in mineral oil. After stirring for 1 hour at room temperature, the temperature is adjusted to 50° C. and stirring is continued for 1 to 2 hours. The reaction mixture is then cooled to about 5° C. and 0.74 ml. of iodomethane is added dropwise. Thereafter, the solution is stirred at 5° to 10° C. for 1 hour, then at room temperature for 4 hours and then heated at 50° C. for 2 hours. The reaction mixture is then poured into water and the resultant aqueous mixture extracted with ether and the ether extracts washed with water. The organic phase is dried over magnesium sulfate and evaporated. The resulting residue may be chromatographed on silica gel to effect purification of the free base. Elution of the gel with 5 to 10% methanol in dichloromethane yields 1-[2-(2-naphthyl)-2-(methoxy)ethyl]imidazole.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[CH:18]=[O:19]>CS(C)=O>[CH2:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH:10]1[CH:18]1[CH2:4][O:19]1
Reactant: O=CC1Cc2ccccc2C1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc2c(c1)CC(C1CO1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
To a mixture containing NaH (9.8 mg, 0.2 mmol) and trimethylsulfoxoniumiodide (57.8 mg, 0.26 mmol) was added slowly DMSO (0.44 ml). After 30 minutes stirring at room temperature, a solution of indan-2-carbaldehyde (32 mg, 0.22 mmol) in DMSO (0.1 ml) was added. The reaction mixture was stirred 18 hours at room temperature and then quenched with H2O. The aqueous phase was extracted with ethylacetate, combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 98:2) to provide (RS)-2-indan-2-yl-oxirane (9 mg, 26%) as a colorless oil, MS: m/e=160.0 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].[CH3:28][NH:29][CH3:30].[CH2:31]=O>C(O)(=O)C.O>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][C:24]([OH:26])=[C:25]([CH2:28][N:29]([CH3:31])[CH3:30])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: C=O
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4cc(O)ccc4c3nc12
Reactant: CNC
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4c(CN(C)C)c(O)ccc4c3nc12
Reaction time: 48 h

Procedure:
3-Hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (26 mg) was sonicated in acetic acid (2 mL) to give a fine suspension. To this was added a 40% solution of dimethylamine in water (3 mL) and a 37% solution of formaldehyde in water (3 mL). The reaction mixture was left stirring for 2 days. The volatiles were then removed in vacuo to yield the title compound (29 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=1.[C:21](=O)([O-])[OH:22].[Na+].C[CH:27]([C:31](Cl)=[O:32])[C:28](Cl)=[O:29].Cl>C(OCC)(=O)C>[CH3:21][O:22][C:31](=[O:32])[CH2:27][C:28]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[CH:3]=2)=[CH:8][C:9]=1[C:14]([F:15])([F:16])[F:17])=[O:29]
Reactant: O=C([O-])O
Reactant: CC(C(=O)Cl)C(=O)Cl
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
0.515 g (1.8 mmol) 4-(3-Fluoro-benzyloxy)-2-trifluoromethyl-phenylamine is dissolved in 20 ml ethyl acetate. 0.38 g (4.51 mmol) sodium hydrogencarbonate is added and the mixture cooled in the ice-bath. 0.27 g (2.0 mmol) methyl malonyl chloride, dissolved in 5 ml ethyl acetate is slowly added over a period of about 15 min. The resulting mixture is stirred at room temperature overnight. 10 ml 2M aqueous hydrochloric acid is added, the organic layer separated and dried over magnesium sulfate. Evaporation of the solvent gives a slightly yellow solid which is recrystallised from methanol. Colorless solid, Yield=58%. MS: m/e=386.1 (M++H).