Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13](=[N:20][OH:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]>C1(C)C(C)=CC=CC=1>[C:7]([O:6][C:5]([N:4]1[CH2:1][CH:2]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([NH:20][O:21][CH2:3]2)[CH2:12]1)=[O:11])([CH3:10])([CH3:9])[CH3:8]
Reactant: C=CCN(CC(=NO)c1ccccc1)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CC2CONC2(c2ccccc2)C1
Temperature: 130 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A solution of tert-butyl N-allyl-N-[-2-hydroxyimino-2-phenyl-ethyl]carbamate as a mixture of E and Z isomers (3.2 g, 10.9 mmol) in xylene (100 mL) is stirred at 100° C. for 2 hours, 130° C. for 6 hours, 100° C. for 12 hours and 130° C. for 2 hours. The cooled reaction is concentrated under reduced pressure to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:0) to hexane/ethyl acetate (0:1) to give the title compound (1.5 g, 48%). ES/MS (m/e): 291 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2([CH:14]=[CH:13][CH:12]=[CH:11][CH2:10]2)[CH2:7][CH2:8][OH:9])=[CH:2]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:9][CH2:8][CH2:7][C:6]1([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH2:14]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: OCCC1(c2ccsc2)C=CC=CC1
Solvent: c1ccncc1
Product: CC(=O)OCCC1(c2ccsc2)C=CC=CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
1-(3-Thienyl)phenethyl alcohol (10 g, 49 mmol) was dissolved in a 2:1 pyridine and acetic anhydride mixture (50 ml). This was stirred at 80° C. for 4 h. Excess of pyridine and acetic anhydride mixture was removed under reduced pressure and the residue was dissolved in water (100 ml). This was extracted with methylene chloride (3×75 ml) and the combined organic layer was dried over MgSO4 and filtered. Removal of the solvent gave 1-(3-thienyl)phenethyl acetate (10.2 g, 84% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:12])[C:10]#[N:11].O.Cl.[O:15]1CCOCC1>C(OCC)(=O)C>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:12])[C:10]([NH2:11])=[O:15]
Reactant: C1COCCO1
Reactant: N#CC(=O)c1ccccc1CCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)C(=O)c1ccccc1CCl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Crude 2-(2-chloromethylphenyl)-2-oxoacetonitrile (purity: about 72%)(17.6 g), water (1.76 g) and 5N hydrogen chloride/dioxane solution (200 ml) were added into a round-bottom flask. The flask was stoppered, and then the mixture was stirred at room temperature for 3 days. After the reaction mixture was ice-cooled, water (150 ml) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was diluted with ethyl acetate, and washed successively with a saturated aqueous solution of sodium bicarbonate, water and saturated brine. The ethyl acetate layer obtained was dried over anhydrous sodium sulfate and at the same time decolorized with Norit SX-3. Evaporation of the solvent under reduced pressure gave the crude product (16.6 g). The crude product was crystallized from ethyl acetate-hexane, and the crystallization mother liquor was purified by column chromatography on silica gel to obtain the title compound (11.3 g, total yield in the two steps: 57.3%, pale yellow crystals).
Reaction SMILES: [ClH:1].C([N:6]([CH:10]1[CH2:14][CH:13]([CH3:15])[O:12][CH:11]1[CH3:16])C(=O)O)(C)(C)C.Cl>CCOCC>[ClH:1].[CH3:16][CH:11]1[CH:10]([NH2:6])[CH2:14][CH:13]([CH3:15])[O:12]1
Reactant: CC1CC(N(C(=O)O)C(C)(C)C)C(C)O1
Agent: Cl
Solvent: CCOCC
Product: CC1CC(N)C(C)O1

Procedure:
To a mixture of 2,5-dimethyldihydrofuran-3(2H)-one oxime (23 g, 0.175 mol) and Raney Ni (4 g) in THF/NH3.H2O (1:1, 200 mL) was stirred at 60° C. under 4 MPa for overnight. The mixture was cooled and filtered, the filtrate was concentrated to give 2,5-dimethyltetrahydrofuran-3-amine To a mixture of 2,5-dimethyltetrahydrofuran-3-amine and Et3N (53.2 g, 0.526 mol) in DCM (300 mL), (Boc)2O (42 g, 0.193 mol) was dissolved in DCM (100 mL) and dropwise added in the mixture at 0° C. After addition, the reaction mixture was stirred at rt. for 4 hours before water was added in the reaction. The aqueous phase was extracted with DCM, the organic layer was washed with H2O, dried over Na2SO4, concentrated. The residue was purified by column to give tert-butyl(2,5-dimethyltetrahydrofuran-3-yl)carbamate hydrochloride. To a solution of tert-butyl(2,5-dimethyltetrahydrofuran-3-yl)carbamate hydrochloride in ether, ether.HCl was added dropwise at 0° C. After addition, the mixture was filtered to give 2,5-dimethyltetrahydrofuran-3-amine hydrochloride. 1H NMR (ppm, 300 MHz, D2O) δ 3.5-4.4 (m, 3H), 1.5-2.7 (m, 2H), 1.2-1.3 (m, 6H).
Reaction SMILES: OS([O-])=O.[Na+].[CH3:6][O:7][N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1.[C-:16]#[N:17].[K+]>O>[OH:15][CH:14]([CH:11]1[CH2:12][CH2:13][N:8]([O:7][CH3:6])[CH2:9][CH2:10]1)[C:16]#[N:17]
Reactant: CON1CCC(C=O)CC1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CON1CCC(C(O)C#N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaHSO3 (11.4 g, 110 mmol) was added to a solution of 1-methoxy-piperidine-4-carbaldehyde (7.5 g, 52.4 mmol) in water (200 mL). After the mixture was stirred at room temperature for 3 h, a solution of KCN (7.2 g, 110 mmol) in water (100 mL) was added to the mixture. The reaction mixture was stirred for 2 h. Then the mixture was extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, concentrated under vacuum to dryness and the residue was purified by column chromatography on silica gel. Yield: 6.2 g of hydroxy-(1-methoxy-piperidin-4-yl)-acetonitrile as an oil.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[CH3:7][S:8][C:9]1[N:14]=[C:13](SC)[C:12]2=[N:17][CH:18]=[C:19]([C:20]#[N:21])[N:11]2[N:10]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:7][S:8][C:9]1[N:14]=[C:13]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C:12]2=[N:17][CH:18]=[C:19]([C:20]#[N:21])[N:11]2[N:10]=1
Reactant: NCC(F)(F)F
Reactant: CSc1nc(SC)c2ncc(C#N)n2n1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CSc1nc(NCC(F)(F)F)c2ncc(C#N)n2n1
Temperature: 120 °C

Procedure:
(I3A): 2,2,2-trifluoroethanamine (1252 mg, 12.64 mmol) was added to a solution of 2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (I2A), 300 mg, 1.264 mmol) in NMP (3 mL) and the resulting mixture was heated at 120° C. for 5 h. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 0-40% ethyl acetate/dichloromethane). 2-(methylthio)-4-((2,2,2-trifluoroethyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (363 mg) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.Cl[C:28]1[N:29]=[C:30]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][C@@H:39]2[CH3:44])[C:31]2[CH2:36][N:35]([CH3:37])[CH2:34][C:32]=2[N:33]=1>>[OH:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:28]3[N:29]=[C:30]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][C@@H:39]4[CH3:44])[C:31]4[CH2:36][N:35]([CH3:37])[CH2:34][C:32]=4[N:33]=3)=[CH:16][CH:17]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(O)n3)cc2)OC1(C)C
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Nc3cccc(O)n3)cc2)nc2c1CN(C)C2
Yield: 9.2 %

Procedure:
Method as described for example 47 using 1-(6-hydroxypyridin-2-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea and (S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 12) as starting materials. The reaction mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and reduced in vacuo. The residue was purified by prep LCMS (high pH), to yield the title compound (7.9 mg, 0.017 mmol, 9.2%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23][C@@H:24]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([NH:23][C@@H:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:21])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)COC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 76.1 %

Procedure:
In the same manner as in Example 67 (1), [N-benzyloxycarbonyl-4-piperidinyloxy]acetic acid (530 mg, 1.81 mmol) and ethyl (S)-2-amino-3-(4-nitrophenyl)propionate hydrochloride (500 mg, 1.82 mmol) were condensed to give 707 mg of ethyl (S)-2-[(N-benzyloxycarbonyl-4-piperidinyloxy)acetylamino]-3-(4-nitrophenyl)propionate as a yellow oil (76%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].F[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[N:1]1([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Fc1cccnc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cncc(-n2ccnc2)c1
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a solution of imidazole (420 mg, 6.3 mmol) in DMF (6 mL) was added NaH (60% dispersion in mineral oil, 250 mg, 6.3 mmol) and the resultant solution was stirred at room temperature for 30 min under argon. To the solution was added a solution of 3-fluoropyridine (183 μL, 2.1 mmol) in DMF (2 mL) and the resultant solution was heated to 100° C. and stirred overnight. The solution was cooled to it, poured into aqueous saturated sodium bicarbonate (50 mL), extracted with ethyl acetate (3×50 mL), washed with brine, dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CH2Cl2, 5/95, Rf=0.12) to afford the title compound 63 (176 mg, 59% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.75 (m, 1H), 8.63 (m, 1H), 7.87 (s, 1H), 7.73 (m, 1H), 7.44 (m, 1H), 7.30 (s, 1H), 7.26 (s, 1H); LRMS (ESI) m/z calcd for C8H8N3 [M+H]+ 146. found 146; HRMS (ESI) m/z calcd for C8H8N3 [M+H]+ 146.0718. found 146.0730; HPLC>99% (tR=7.18 min, 55 (A):45 (B): 0.032 (C); 5.06 min, 55 (A):45 (B): 0.1 (C).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23](I)[N:22]=[CH: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.CC[Mg+].[Br-].[CH3:30][C:31]1[C:32]([CH:36]=[O:37])=[CH:33][S:34][CH:35]=1>C(Cl)Cl>[CH3:30][C:31]1[C:32]([CH:36]([C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:24]=2)[OH:37])=[CH:33][S:34][CH:35]=1
Reactant: Cc1cscc1C=O
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: ClCCl
Product: Cc1cscc1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 3 h

Procedure:
To a solution of N-trityl-4-iodo-imidazole (11.8 g, 27 mmol) in dry CH2Cl2 (75 mL) was added EtMgBr (10.0 mL, 3.0M in Et2O), and the solution was stirred for 3 hrs. Then a solution of 4-methylthiophene-3-carboxaldehyde (3.3 g, 27 mmol) in CH2Cl2 (25 mL) was added. The reaction mixture was stirred at room temperature overnight and then was quenched with aqueous NH4Cl. The mixture was transferred to a separatory funnel, and the aqueous layer was extracted with a second portion of CH2Cl2. The combined extracts were washed with a small portion of water, dried (Na2SO4), and filtered. The solvent was evaporated in vacuo to give a thick syrup which was triturated with Et2O to give a solid which was recrystallized with charcoal treatment from EtOAc to give (4-methylthien-3-yl)-1-trityl-imidazol-4-yl-methanol, B2. 1H NMR (CDCl3) supported the assigned structure. ##STR39##
Reaction SMILES: CC(F)(F)F.C([Cl:11])C(F)(F)F.[CH2:12]([Cl:17])[C:13]([Cl:16])([F:15])[F:14].[CH:18]([C:21]([F:24])(F)[F:22])([Cl:20])[Cl:19].C(C(Cl)(Cl)Cl)(F)(F)F.CC(F)(F)Cl>>[CH2:12]([Cl:17])[C:13]([Cl:16])([F:15])[F:14].[CH:18]([Cl:20])([Cl:19])[C:21]([Cl:11])([F:24])[F:22]
Reactant: FC(F)(F)CCl
Reactant: FC(F)(F)C(Cl)Cl
Agent: CC(F)(F)Cl
Agent: CC(F)(F)F
Agent: FC(F)(Cl)CCl
Solvent: FC(F)(F)C(Cl)(Cl)Cl
Product: FC(F)(Cl)C(Cl)Cl

Procedure:
An alternative approach to HCFC's is the chlorination of fluorocarbons such as CH3CF3 (HFC-143a). For example, McBee (Industrial and Engineering Chemistry, Vol. 39, pp. 409-412 (1947)) reported that vapor phase chlorination of HFC-143a afforded a mixture of HCFC-133a, HCFC-132b, CHCl2CF3 (HCFC-123), and the fully chlorinated CF3CCl3 (CFC-113a). McBee also reported the chlorination of CH3CClF2 (HCFC-142b) to give HCFC-132b, HCFC-122, and the fully chlorinated CClF2CCl3 (CFC-112a). Again, using this technique --CH2Cl and --CHCl2 groups dominate the attainable substitution pattern.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15]Br.C([O-])([O-])=O.[K+].[K+]>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15][N:10]([CH2:15][C:14]1[CH:13]=[C:12]([F:11])[CH:19]=[C:18]([F:20])[CH:17]=1)[C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: Fc1cc(F)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc(F)cc(CN(Cc2cc(F)cc(F)c2)c2ccc3[nH]cnc3c2)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 3,5-difluorobenzylbromide (455 mg; 0.285 ml; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.065 g (16.7%); MS m/z: 386.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.75 (s, 4H); 6.67-6.70 (m, 2H); 6.97-6.99 (m, 4H); 7.07 (tt, 2H, 4J=2.3 Hz, 3JH,F=9.3 Hz); 7.36-7.37 (m, 1H); 7.94 (s, 1H); 11.96 (br s, 1H); HPLC (METHOD [A]): rt 16.26 min (100%)
Reaction SMILES: C(O)CCCO.C(OCC=C)(=O)C.[CH2:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22]CC=C)[CH:15]=[CH2:16]>>[CH2:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH:15]=[CH2:16]
Reactant: C=CCOCCCCOCC=C
Agent: C=CCOC(C)=O
Solvent: OCCCCO
Product: C=CCOCCCCO

Procedure:
A reaction was performed by the procedure of Example 1, except for using 1,4-butanediol instead of 1-octanol and using allyl acetate in an amount of 10 mmol. The reaction mixture was analyzed by gas chromatography to find that 3-(4-allyloxy-butoxy)-propene and 4-allyloxy-1-butanol were formed in yields of 78% and 6%, respectively.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](Cl)=[O:22].N12CCN(CC1)CC2.O>CN(C)C=O.CCCCCCC>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:7][CH:6]=2)=[O:18])=[CH:11][CH:12]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: COc1ccc(C(=O)Nc2ccc(O)nc2)cc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(OC(=O)N(C)c3ccccc3)nc2)cc1
Yield: 57.2 %

Procedure:
A solution of N-(6-hydroxy-pyridin-3-yl)-4-methoxy-benzamide (1.22 g, 5.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.85 g, 5.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.56 g, 5.00 mmol) in dimethylformamide (20 mL) was stirred at room temperature for 2 hours. Water (100 mL) was added. The solids were isolated by suction and washed with water. Crystallisation from ethyl acetate:heptane yielded the title compound (1.08 g, 57% yield).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([N+:9]([O-])=O)[C:7]=1[NH2:8].[CH3:22][O:23][CH2:24][C:25]#[CH:26]>>[CH3:22][O:23][CH2:24][CH2:25][CH2:26][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[CH:3]=1
Reactant: C#CCOC
Reactant: Nc1c(I)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Product: COCCCc1cc(-c2ccccc2C(F)(F)F)cc(N)c1N

Procedure:
The title compound was prepared from 3-iodo-5-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (as prepared in Example 9, step A) and 3-methoxy-propyne according to the procedures described in Example 10, steps A and B.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O>CN(C)C=O>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC(F)(F)F)CC1
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a colorless oil (50%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+].Br[CH:22]([CH3:29])/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)Cl>[CH3:28][O:27][C:25](=[O:26])[CH2:24][C:23]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[N:7]([C:8]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:14])[C:22]=1[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1sccc1Br
Reactant: COC(=O)/C=C/C(C)Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(C(=O)OC(C)(C)C)c2sccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.3 %

Procedure:
To a solution of tert-butyl 3-bromothiophen-2-ylcarbamate (1 g, 3.59 mmol) in DMF (15 mL) was added K2CO3 (1.987 g, 14.38 mmol) and (E)-methyl 4-bromopent-2-enoate (prepared according to C. Girard et al, TL, vol 30, No. 52, pp 7399-7402, 1989) (1.388 g, 7.19 mmol). The reaction mixture was stirred at ambient temperature for 16 h. Palladium(II) acetate (0.040 g, 0.180 mmol) and PPh3 (0.094 g, 0.359 mmol) were added and the reaction mixture was heated to 85° C. for 18 h. DCM was added and the resulting solution was washed with water. The layers were separated and the organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (heptane/EtOAc: 95/5 to 55/45) to give the title compound (0.404 g, 36.3%): LC/MS (Table 1, Method d) Rt=2.40 min; MS m/z 310 (M+H)+; 1H NMR (CDCl3) δ 6.97 (m, 2H), 3.72 (s, 3H), 3.62 (s, 2H), 2.56 (s, 3H), 1.70 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([C:12]([O:14]CC)=[O:13])=[C:7]([C:17]3[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20]([OH:27])=[C:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:18]=3)[C:6]=2[CH:32]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([C:12]([OH:14])=[O:13])=[C:7]([C:17]3[CH:22]=[C:21]([C:23]([CH3:25])([CH3:26])[CH3:24])[C:20]([OH:27])=[C:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:18]=3)[C:6]=2[CH:32]=1
Reactant: CCOC(=O)c1c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cc(Cl)ccc2oc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1cc(-c2c(C(=O)O)c(=O)oc3ccc(Cl)cc23)cc(C(C)(C)C)c1O
Temperature: 70 °C
Yield: 69.3 %

Procedure:
A mixture of ethyl 6-chloro-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-2H-1-benzopyran-3-carboxylate (2.0 g), 2N NaOH (11 ml) and ethanol (20 ml) was heated at 70° C. for 10 minutes. Then, the mixture was made acid with 2N HCl and extracted with ethyl acetate. The extract was washed with water and dried (MgSO4), and then, the solvent was removed to obtain 6-chloro-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid as powders (1.3 g, 69.1%).
Reaction SMILES: [CH:1]1[N:9]2[C:4]([NH:5][NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][N:2]=1.[C:14](Cl)(=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[C:14]([N:5]1[C:4]2=[N:3][N:2]=[CH:1][N:9]2[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]1[C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: c1ccc2c(c1)NNc1nncn1-2
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)N1c2ccccc2-n2cnnc2N1C(=O)CCCCCCCCCCCCCCCCC
Temperature: 60 °C
Yield: 39.1 %

Procedure:
A mixture of 5 g (0.029 mole) of 4,5-dihydro-s-triazolo[3,4-c]benzo-as-triazine, 2 g (0.066 mole) of stearoyl chloride and 50 ml of dry dimethyl formamide is heated at 60° C. for one hour under argon atmosphere. The reaction mixture is poured onto ice and the product is filtered off. 8 g (45%) of the title compound are obtained; m.p.: 77°-78° C.
Reaction SMILES: C([N:8]1[C:12]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:11]([CH3:20])[CH:10]=[N:9]1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)=O>[CH3:20][C:11]1[CH:10]=[N:9][NH:8][C:12]=1[NH:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Cc1cnn(Cc2ccccc2)c1NC1CCOCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Product: Cc1cn[nH]c1NC1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.5 %

Procedure:
A mixture of 1-benzyl-4-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (1.9 g), activated carbon-supported 20 mass % palladium hydroxide (0.6 g) and formic acid (20 mL) was stirred at room temperature for 16 hr. The insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.73 g, 40%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[C:16]3[N:15]=[C:14]([N:17]([CH2:25][C:26]#[CH:27])C(=O)OC(C)(C)C)[N:13]=[CH:12][C:11]=3[CH2:10][CH2:9][C:8]=2[N:28]=1)(=[O:3])[CH3:2]>Cl>[CH2:25]([NH:17][C:14]1[N:13]=[CH:12][C:11]2[CH2:10][CH2:9][C:8]3[N:28]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=3[C:16]=2[N:15]=1)[C:26]#[CH:27]
Reactant: C#CCN(C(=O)OC(C)(C)C)c1ncc2c(n1)-c1sc(NC(C)=O)nc1CC2
Agent: Cl
Product: C#CCNc1ncc2c(n1)-c1sc(NC(C)=O)nc1CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.05 g (0.13 mmol) of the compound obtained in Example 82 are dissolved in 5 ml ethereal hydrochloric acid and stirred for 16 hours at ambient temperature. The resulting solid is suction filtered, triturated with diethyl ether/acetone 9:1 and suction filtered again. Yield: 0.03 g