Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:37])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:15][C@@H:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[CH2:17][NH:18]C(=O)OC(C)(C)C)=[O:14])[S:10][C:11]=1[Cl:12].C(O)(C(F)(F)F)=O.C(Cl)[Cl:46]>>[NH2:18][CH2:17][C@@H:16]([NH:15][C:13]([C:9]1[S:10][C:11]([Cl:12])=[C:7]([C:6]2[N:5]([CH3:37])[N:4]=[CH:3][C:2]=2[Cl:46])[CH:8]=1)=[O:14])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34]
Reactant: Cn1ncc(Br)c1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,1-dimethylethyl {(2S)-2-({[4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (crude from part a) was dissolved in TFA-DCM (3 mL, 1:2) and stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (5% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5](C(OC(C)(C)C)=O)[N:4]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[N+:20]=[N-:21]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1n[nH]c2ncccc12

Procedure:
A solution of 250 mg (0.80 mmol) of tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (1-1) and sodium azide (55 mg; 0.85 mmol) in 1 mL anhydrous DMF was heated at 90° C. for 5 hours. The reaction was cooled, diluted with water, and extracted twice with 25 mL portions of EtOAc. The combined EtOAc extracts were washed with brine, dried (anhydrous MgSO4) and concentrated to give a dark oil. The oil was purified by reverse phase preparative HPLC on a Gilson apparatus to give the title compound as a tan solid. MS M+1=152.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([N:29]([CH2:34][C:35]([OH:37])=[O:36])[CH2:30][C:31]([OH:33])=[O:32])[CH2:12][N:13]([CH2:18][CH2:19][N:20]([CH2:25][C:26]([OH:28])=[O:27])[CH2:21][C:22]([OH:24])=[O:23])[CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.[C:38](Cl)(Cl)=[S:39].C(Cl)(Cl)Cl>O>[C:31]([CH2:30][N:29]([CH2:34][C:35]([OH:37])=[O:36])[CH:11]([CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[C:38]=[S:39])=[CH:3][CH:4]=1)[CH2:12][N:13]([CH2:18][CH2:19][N:20]([CH2:21][C:22]([OH:24])=[O:23])[CH2:25][C:26]([OH:28])=[O:27])[CH2:14][C:15]([OH:17])=[O:16])([OH:33])=[O:32]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(CCCC(CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)CN(CCN(CC(=O)O)CC(CCCc1ccc(N=C=S)cc1)N(CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 6b (10.2 mg, 0.0152 mmol) in water (100 μL) was added dropwise 1M thiophosgene in CHCl3 (18.2 μL, 0.0182 mmol). The resulting mixture was stirred at room temperature for 3 h. The aqueous layer was concentrated in vacuo to provide pure 7b (10 mg, 97%) as a light yellowish solid. 1H NMR (MeOD, 300 MHz) δ 2.40-4.51 (m, 28H), 7.05-7.70 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([Br:1])=[CH:3][C:4]3[CH2:8][CH2:7][O:6][C:5]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1ccc(-c2cc3c(cc2Br)CCO3)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2cc3c(cc2Br)CCO3)cn1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of 5-(5-bromo-2,3-dihydrobenzo[3,4-b]furan-6-yl)-2-pyridylamine (139) (13 mg, 0.044 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (11 μl, 0.088 mmol) followed by addition of DIEA (38 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (100 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(5-bromo(2,3-dihydrobenzo[3,4-b]furan-6-yl))(2-pyridyl)]carboxamide (140) (15.5 mg, yield: 81.6%, purity>90%) as white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.CCN(CC)CC.[Cl:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1>C(O)C>[Cl:19][C:20]1[N:25]=[C:24]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)[CH:23]=[CH:22][N:21]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1CCN(c2ccnc(Cl)n2)CC1
Temperature: 80 °C
Reaction time: 0.13 h
Yield: 87.2 %

Procedure:
To a solution of ethyl piperidine-4-carboxylate (13.0 g, 82.69 mmol,) in ethanol (130 ml) were added Et3N (17.29 ml, 124 mmol) and 2,4-dichloropyrimidine (13.55 g, 90.96 mmol). After stirring for 8 minutes at 80° C., the solvent was removed under reduced pressure and purified by normal phase chromatography, eluting with Heptane with 50% ethyl acetate to give compound ethyl 1-(2-chloropyrimidin-4-yl)piperidine-4-carboxylate (19.45 g, 76%) as a colourless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[NH:9][N:8]=1.[H-].[Na+].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>O1CCCC1>[CH3:20][N:21]([CH3:25])[C:22]([N:8]1[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[N:11][C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[N:9]1)=[O:23]
Reactant: c1cnc(-c2n[nH]c(-c3cnccn3)n2)cn1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)n1nc(-c2cnccn2)nc1-c1cnccn1

Procedure:
To 2.25 g. (0.01 mole) of 3,5-dipyrazinyl-1,2,4-triazole in 200 ml. of tetrahydrofuran is added 57% sodium hydride (.42 g., 0.01 mole). The reaction mixture is heated at reflux for one hour, cooled, and a solution of dimethylcarbamoyl chloride (1 gram, 0.01 mole) in 10 ml. of tetrahydrofuran is added dropwise. The reaction mixture is then refluxed four hours, cooled, filtered and concentrated to a solid. After recrystallization from benzene 1-dimethylcarbamoyl-3,5-dipyrazinyl-1,2,4-triazole is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:8].Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH2:31])=[O:30]>>[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:8])(=[O:30])[NH2:31]
Reactant: NC(=O)CCCCBr
Reactant: O=C(NCc1ccccn1)c1cc(O)ccc1OCC(F)(F)F
Product: NC(=O)CCCCOc1ccc(OCC(F)(F)F)c(C(=O)NCc2ccccn2)c1
Yield: 45.7 %

Procedure:
Using the general method of Example I Part A, 6.5 g (0.02 mole) of 5-hydroxy-N-(2-pyridylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide was reacted with 3.3 g (0.018 mole) of 5-bromovaleramide to give 3.5 g of white powdery 5-(4-carbamoylbutoxy)-N-(2-pyridylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide, m.p.138°-139° C.
Reaction SMILES: [Cl-].[Cl-].C([Al+2])C.[C:6]([O:10][CH3:11])(=[O:9])[CH:7]=[CH2:8].[C:12]([O:15][C@@H:16]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:18]([CH2:19][CH2:20][C@@H:21]3[C:31]2=[CH:30][CH2:29][C@@:28]2([CH3:36])[C@H:22]3[CH2:23][CH2:24]/[C:25]/2=[CH:26]/[CH3:27])[CH2:17]1)(=[O:14])[CH3:13].O>C(Cl)Cl>[C:12]([O:15][C@@H:16]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:18]([CH2:19][CH2:20][C@@H:21]3[C:31]2=[CH:30][CH2:29][C@@:28]2([CH3:36])[C@H:22]3[CH2:23][CH:24]=[C:25]2[C@H:26]([CH3:27])[CH2:8][CH2:7][C:6]([O:10][CH3:11])=[O:9])[CH2:17]1)(=[O:14])[CH3:13]
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Reactant: C=CC(=O)OC
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC[C@@H](C)C1=CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
Ethyl aluminum dichloride (14.2 mL, 25 mmol, 1.8M in toluene) was added to a solution of methyl acrylate (1.89 mL, 20 mmol) in DCM (60 mL) at 0° C. under inert atmosphere. The resulting solution was stirred for 15 min and then compound 1.6a (3 g, 8.7 mmol) was added. After stirring for an additional 20 min at 0° C., the temperature was raised to 25° C. and held there for a further 18 h. At this point the reaction was determined to be complete by TLC, then the mixture was poured into cold (0° C.) water (60 mL). The phases were separated and the aqueous layer was extracted with DCM (60 mL). The organic layers were combined and washed sequentially with water (50 mL) and saturated brine solution (100 mL). It was then dried over anhydrous Na2SO4 (5 g) and filtered. The filtrate was concentrated under vacuum, providing compound 1.7b (2.6 g, 70%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[CH:12]([O-])([O-])OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:12][O:11][C:2]1[CH2:3][CH2:4][C:5]2[C:10]([CH:1]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC([O-])[O-]
Reactant: O=C1CCc2ccccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC1=Cc2ccccc2CC1
Yield: 75 %

Procedure:
A mixture of 1.4 g of 2-tetralone, 1.5 mL of methyl orthoformate, and a few crystals of para-toluenesulfonic acid monohydrate in 75 mL of benzene was stirred for 22 hours and then evaporated in vacuo. The residue was chromatographed on Florisil® eluting with hexane/ethyl ether to provide 1.15 g (75%) of the desired title intermediate. NMR.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CC(N(C)C)=O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[N:25]=[C:21]([NH:20][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[C:4]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[N:3]=3)[S:22][CH:23]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc2nc(-c3cccnc3)nc(Nc3nc(-c4ccc(Cl)cc4)cs3)c2c1
Temperature: 80 °C
Reaction time: 9.5 h
Yield: 36.2 %

Procedure:
(The method G13 is representative of method G12 also. This method can be implemented in a similar way except for substitution of the appropriate base, solvent and temperature) To a suspension of 4-chloro-6-methoxy-2-(pyridine-3-yl)quinazoline (645.2 mg, 2.375 mmol) and 2-amino-4-(4-chlorophenyl)thiazole (1050 mg, 4.98 mmol) in DMA (40 mL) was added Cs2CO3 (2430 mg, 7.46 mmol) at room temperature. The mixture was stirred at 80° C. for 9.5 h. Water was added and a precipitate formed which was collected by filtration and washed with H2O. Recrystallization from acetone/DMF/methanol gave 383.6 mg of the product in a 36% yield as yellow solid, >98% purity by 1H NMR). 1H NMR (400 MHz DMSO-d6) δ 12.52 (s, 1H), 9.78 (d, J=1.56 Hz, 1H), 8.91-8.88 (m, 1H), 8.74 (dd, J=4.74, 1.60 Hz, 1H), 8.33 (brs, 1H), 8.06 (d, J=8.56 Hz, 2H), 7.93 (d, J=9.08 hz, 1H), 7.89 (s, 1H), 7.66-7.59 (m, 2H), 7.55 (d, J=8.56 Hz, 2H), 4.01 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1)[CH2:2][CH2:3][CH3:4].C(OO)(=[O:18])C.O>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]2[CH:12]([O:18]2)[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OO
Reactant: CCCCOCCOCC1C=CCCC1
Solvent: ClCCl
Solvent: O
Product: CCCCOCCOCC1CCC2OC2C1

Procedure:
A 500 mL round bottom flask equipped with a stirrer bar was charged with 13.78 g (0.065 mol) 3-butoxyethoxymethylcyclohexene, and 100 niL of methylene chloride. Peracetic acid (15.5 g, 35 wt. % in acetic acid; 0.065 mol) in methylene chloride (80 mL) was added dropwise to above mixture over 30 min. in an ice bath. After the above mixture was reacted at room temperature overnight, 250 mL of water was added to above reaction mixture, the water layer was extracted with methylene chloride (2×150 mL), the organic layer was combined, and washed with saturated sodium carbonate solution (2×150 mL), then with water (2×150 mL) and dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:15][CH2:16][NH:17][CH:18]=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14].C(N(CC)CC)C.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[Cl:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH:43]=[O:44].Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:39][C:40]1[CH:41]=[C:42]([CH:43]([OH:44])[C:18]([NH:17][CH2:16][CH2:15][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:19])[CH:45]=[CH:46][C:47]=1[Cl:48]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CCC#CCOc1ccc(CCNC=O)cc1OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC#CCOc1ccc(CCNC(=O)C(O)c2ccc(Cl)c(Cl)c2)cc1OC
Temperature: -78 °C
Reaction time: 4 h

Procedure:
34 g (13.0 mmol) N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-formamide and 4.3 ml (32 mmol) triethylamine are dissolved in 13 ml CH2Cl2. 1.4 g (4.7 mmol) bis(trichloromethyl) carbonate (triphosgene) in 9 ml CH2Cl2 is added at +5° C. The mixture is stirred for 4 hours at +5° C. and then cooled to −78° C. A solution of 1.43 ml (13.0 mmol) TiCl4 in 20 ml CH2Cl2 is added and the mixture is stirred for 2 hours at −40° C. 2.5 g (12.9 mmol) 3,4-dichlorobenzal-dehyde in 7 ml CH2Cl2 is added dropwise and the mixture is stirred for 17 h at room temperature. The mixture is hydrolysed with 7 ml HCl 5N, stirred 30 minutes at room temperature and washed with water. After evaporation the residue is submitted to flash-chromatography (ethyl acetate 6,hexanes 4) to give the 2-(3,4-dichloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-acetamide.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH3:6][S:7]([C:10]([C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([C:23]3[CH:24]=[C:25]([CH2:29][CH:30]([C:37]4[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=4)[C:31](N(OC)C)=[O:32])[CH:26]=[CH:27][CH:28]=3)[CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2)([CH3:12])[CH3:11])(=[O:9])=[O:8]>C1COCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[CH:1]1([C:31](=[O:32])[CH:30]([C:37]2[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][CH:42]=2)[CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:21]3[CH:22]=[C:13]([C:10]([S:7]([CH3:6])(=[O:9])=[O:8])([CH3:12])[CH3:11])[CH:14]=[C:15]4[C:20]=3[N:19]=[CH:18][CH:17]=[CH:16]4)[CH:24]=2)[CH2:3][CH2:2]1
Reactant: CON(C)C(=O)C(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(c1cc(-c2cccc(CC(C(=O)C3CC3)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Anhydrous CeCl3 (266 mg, 1.26 mmol) was heated 2 h at 130° C. under high vacuum, refluxed in THF (10 mL) for 1 h then cooled to 0° C. To the resulting white suspension at 0° C. was added freshly prepared cyclopropylmagnesium bromide (0.6M, THF, 2.11 mL, 1.25 mmol) and the resulting mixture stirred at 0° C. for 1 h then cooled to −78° C. The 3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-N-methoxy-N-methyl-propionamide from Step 1 (in THF, 150 mg, 0.25 mmol) was added and the mixture warmed to 0° C. for 1 h, diluted with ethyl acetate and saturated ammonium chloride solution. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 1:4) provided the 1-cyclopropyl-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propan-1-one compound as a white foam.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-:12].[NH2:13][N:14]1[CH:18]=[CH:17][N+:16]([N:19]=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)=[C:15]1[CH2:30][CH3:31]>C(O)(=O)C>[Cl-:12].[CH3:29][N:27]([CH3:28])[C:24]1[CH:23]=[CH:22][C:21]([CH:20]=[N:19][N+:16]2[CH:17]=[CH:18][N:14]([N:13]=[CH:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:15]=2[CH2:30][CH3:31])=[CH:26][CH:25]=1
Reactant: CCc1n(N)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCc1n(N=Cc2ccc([N+](=O)[O-])cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.61 g (4 mmol) of p-nitrobenzaldehyde is added to a solution of 1.19 g (4 mmol) of 3-amino-1-[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazolium chloride in 10 ml of glacial acetic acid, the mixture is stirred at room temperature for 16 hours and the product is precipitated by the addition of ether. The product is then filtered off and recrystallized from ethanol. There is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-ethyl-3-[(p-nitrobenzylidene)amino]imidazolium chloride of melting point 250°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CCN(C(C)C)C(C)C.[N:24]([C:27]([CH3:33])([CH3:32])[CH2:28][C:29](Cl)=[O:30])=[N+:25]=[N-:26]>C(Cl)Cl>[N:24]([C:27]([CH3:33])([CH3:32])[CH2:28][C:29]([N:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:1])=[O:30])=[N+:25]=[N-:26]
Reactant: CCCCCCCCCCCCNC
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a stirred ice cold solution of N-methyldodecanamine (5.0 g, 25.1 mmol) and DIEA (5.70 mL, 1.3 equiv, 32.6 mmol) in anhydrous DCM (150 mL) was added 3-azido-3-methylbutanoyl chloride (4.05 g, 1 equiv, 25.1 mmol) in small portions. The ice bath was removed and the reaction was stirred and left at room temperature for 3 h. The content of the reaction was poured into a separatory funnel. The organic layer was washed with 1 M HCl (3×100 mL) and saturated NaHCO3 (2×100 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (8.08 g, quant). This material was purified on an ISCO flash chromatography system with a gradient from 10-40% ethyl acetate and hexanes as eluent. The desired fractions were collected and concentrated to give a pale yellow oil (7.28 g, 89.3%). 1H NMR (CDCl3, 400 MHz): δ 0.88-0.94 (m, 3H), 1.26-1.35 (m, 6H), 1.47-1.48 (d, J=4, 6H), 1.50-1.59 (m, 2H), 2.51 (s, 2H), 2.94-3.04 (d, J=40, 3H), 3.30-3.40 (m, 2H). LRMS (ESI+) for C18H36N4O (324.3); Found: 325 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.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>[CH2:15]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:14]=[CH2:13]
Reactant: COC(=O)Cc1ccccc1I
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1ccccc1CC(=O)OC
Temperature: 110 °C
Yield: 65 %

Procedure:
To a solution of methyl 2-iodophenylacetate (1.00 g, 3.62 mmol, prepared from the corresponding acid according to litt. Tetrahedron 63, 2007, 9979) in toluene (45 mL) was added Tetrakis(triphenylphosphine)palladium (209 mg, 0.0.181 mmol) and allyl tributylstannane (1.35 mL, 4.34 mmol). The resulting solution was heated to 110° C. for 20 h and then cooled down. The solvents were removed in vacuo. The yellow oil was partitioned between acetonitrile (30 mL) and hexane (30 mL) and the acetonitrile layer was washed with hexane (2*30 mL). The acetonitrile was removed in vacuo and the residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (15/1) to give Methyl 2-allylphenylacetate (colourless oil, 446 mg, 65%). C12H14O2; MW: 190.24; LCMS (method A) RT 1.74 min; ES: 191 (100%, MH+); IR. 2951, 1734 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.14-7.41 (4H, m), 5.99 (1H, m), 5.12 (1H, m), 5.03 (1H, m), 3.73 (3H, s), 3.72 (2H, s), 3.47 (2H, dt) ppm.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC(OC)=CC=3)C=2N=1)(C)(C)C.N1CC[C@H](O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:28][CH2:27][C@H:25]([OH:26])[CH2:24]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(Cn2nnc3c(N4CCOCC4)nc(C(C)(C)C)nc32)cc1
Agent: COc1ccc(Cn2nnc3c(Cl)nc(C(C)(C)C)nc32)cc1
Agent: O[C@H]1CCNC1
Product: COc1ccc(Cn2nnc3c(N4CC[C@H](O)C4)nc(C(C)(C)C)nc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of 4-(5-tert-butyl-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)morpholine (example 58, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-pyrrolidin-3-ol and isolated as light-yellow solid. MS(m/e): 383.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH:9]([CH3:13])[C:10](Cl)=[O:11].Cl>>[Cl:8][CH:9]([CH3:13])[C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: Nc1ccccc1
Reactant: CC(Cl)C(=O)Cl
Agent: Cl
Product: CC(Cl)C(=O)Nc1ccccc1
Yield: 94.8 %

Procedure:
18 g of aniline are introduced dropwise into 22.6 g of 2-chloropropionyl chloride at a temperature of about 10° C., with stirring until the evolution of HCl has ended. After filtration, 31 g (yield: 84.5%) of α-chloro-α-methylacetanilide are obtained in the form of a pink powder. M.p. (inst.)=80° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C)[C:3]1=[O:21].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:13][CH2:12][CH2:11][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]([CH3:1])[C:3]1=[O:21]
Reactant: Cn1c(=O)n(CCNC(=O)OC(C)(C)C)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n(CCN)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)carbamate (100 mg, 0.345 mmol) in DCM (3 mL) was added TFA (1.5 mL) at 0° C. to 5° C. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the crude product, which was used in the next step without further purification (140 mg crude). MS (ESI) m/z 192.1 [M+H]+.