Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([NH2:8])=[CH:4][C:5]([NH2:7])=[O:6].N.[CH3:12]NN.Cl>O.C(O)C>[CH3:12][N:8]1[C:3]([C:2]([F:10])([F:9])[F:1])=[CH:4][C:5]([OH:6])=[N:7]1
Reactant: CNN
Reactant: NC(=O)C=C(N)C(F)(F)F
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: Cn1nc(O)cc1C(F)(F)F
Temperature: 30 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
30.82 g (0.2 mol) of 4,4,4-trifluoro-3-amino-2-butenamide (prepared by addition of 2 equivalents of ammonia to the corresponding alkenoic ester) was added to 10.1 g (0.22 mol) of methylhydrazine at room temperature. A slight exotherm raised the temperature to 30° C. The mixture was stirred for 1 hr. at which time the mixture became semi-solid; 10 ml. of ethanol was added to improve stirring. After another 1.5 hr., 7 ml. of ethanol was added, again to aid in stirring the mixture. After a total of 24 hr., the mixture was taken up in 25 ml. of water, the pH was adjusted to 6.5-7.0 with conc. hydrochloric acid (17 ml.), and the precipitated product was collected by filtration and dried to obtain 21.37 g (65.3%) of product m.p. 129°-131° C.
Reaction SMILES: S(Cl)(C)(=O)=O.[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(=[O:9])[CH:7]=[CH2:8].C(N(CC)CC)C.[C:34]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:46](=[O:55])[C:47]1[CH:52]=[C:51](O)[CH:50]=[CH:49][C:48]=1[OH:54])(=[O:37])[CH:35]=[CH2:36]>C1COCC1>[C:34]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:46](=[O:55])[C:47]1[CH:52]=[C:51]([O:23][C:22](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6](=[O:9])[CH:7]=[CH2:8])=[CH:26][CH:25]=2)[CH:50]=[CH:49][C:48]=1[OH:54])(=[O:37])[CH:35]=[CH2:36]
Reactant: C=CC(=O)OCCCCCCOC(=O)c1cc(O)ccc1O
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OCCCCCCOC(=O)c1cc(OC(=O)c2ccc(OCCCCCCOC(=O)C=C)cc2)ccc1O
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
A solution of mesyl chloride (3.44 g) in 50 ml of dry THF was added dropwise under argon to a cooled (−25° C.) solution of 4-(6-acryloyloxyhexyloxy)benzoic acid (8.35 g) and triethylamine (6.07 g) in 100 ml of dry THF. After complete addition (15 min), the reaction mixture was stirred for a further 30 min at −25° C., treated with a solution of 2,5-dihydroxybenzoic-6-acryloyloxyhexyl ester in 50 ml of dry THF and further stirred at −25° C. for 4 h. The reaction mixture was then filtered through celite and the solvent was removed by evaporation. The filtrate was purified by flash chromatography using a short silica-gel column and dichloromethane/diethylether (39/1) as eluent to give 10.8 g of 5-[4-(6-acryloyloxyhexyloxy)benzoyloxy]-2-hydroxybenzoic acid 6-acryloyloxyhexyl ester as a slightly beige oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=1)[CH:23]=[C:24]1[C:29](=[O:30])[O:28][C:27]([CH3:32])([CH3:31])[O:26][C:25]1=[O:33])([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH:37]1([Mg]Br)[CH2:39][CH2:38]1.Cl.O>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:23]([CH:37]2[CH2:39][CH2:38]2)[CH:24]2[C:25](=[O:33])[O:26][C:27]([CH3:31])([CH3:32])[O:28][C:29]2=[O:30])[CH:34]=[CH:35][CH:36]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Br[Mg]C1CC1
Reactant: CC1(C)OC(=O)C(=Cc2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C(=O)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC(=O)C(C(c2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C2CC2)C(=O)O1
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
Under an argon atmosphere, to a solution of 5-(3-(((tert-butyldiphenylsilyl)oxy)methyl)benzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6.39 g) in THF (85 mL) was added dropwise a 0.70 M solution of cyclopropylmagnesium bromide in THF (54.7 mL) at 0° C. over 15 min, and the mixture was stirred at 0° C. for 5.5 hr. 0.50N Hydrochloric acid (300 mL) was added dropwise at 0° C., and water was further added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.05 g) as a colorless oil.
Reaction SMILES: [NH:1]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20]CC1C=CC=CC=1)=[O:19])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])=[O:4].N(C(OC(C)(C)C)=O)CC(NCC(O)=O)=O>C(O)(=O)C>[NH:1]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])=[O:4]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Solvent: CC(=O)O
Product: CC(C)[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
IV (6.2 g, 0.012 mole) in acetic acid was hydrogenated and worked up as for II to obtain V quantitatively, no sharp m.p. 74°-83° C. Rf3, 0.25; Rf4, 0.15. Anal. Calcd. for C19H32N4O7 : C, 51.10; H, 7.67; N, 12.54%. Found: C, 51.28: H, 7.50 N, 12.38%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:20])[C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([CH3:18])[CH:11]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[NH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:20])=[O:19])=[CH:11][C:12]=1[CH3:18]
Reactant: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1C#N
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CN
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A solution of N-(4-chloro-phenyl)-4-cyano-3,N-dimethyl-benzamide from Example E115.1 (5.1 g, 17.9 mmol) in methanol (250 ml) was treated with cobalt(II) chloride hexahydrate (8.4 g, 35.8 mmol). The mixture was stirred for 15 min at room temperature then cooled down to 0° C. and sodium borohydride (6.7 g, 179 mmol) was added portionwise. The mixture was stirred for 1 h at room temperature, filtered through Celite® filter agent, washed with methanol and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:10% methanol:89% dichloromethane) to yield the title compound (3.6 g, 70%).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1.[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][C:31]=1[Br:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[OH:35])=[CH:32][C:31]=1[Br:38])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOc1ccc(Br)cc1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(C(O)c2ccc(OCc3ccccc3)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
Then, 1.6 M n-butyllithium hexane solution (22.9 mL) was added to a mixture of 4-bromophenetole (7.3 g, 0.037 mol) and tetrahydrofuran (70 mL) at −78° C. After stirred for 0.5 hours, 4-benzyloxy-3-bromobenzaldehyde (7.0 g, 0.024 mol) in a tetrahydrofuran (70 mL) solution was added and further stirred for 15 minutes, and the reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain colorless oily [4-(benzyloxy)-3-bromophenyl](4-ethoxyphenyl)methanol (8.7 g, 86%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH3:18])[CH:11]=1)(C)(C)C.[ClH:20].C(OCC)(=O)C>C(OCC)(=O)C.C(OCC)C>[ClH:20].[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH2:7])=[CH:11][C:12]=1[O:17][CH3:18]
Reactant: COc1cc(CCNC(=O)OC(C)(C)C)ccc1F
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1cc(CCN)ccc1F
Reaction time: 2.5 h

Procedure:
To a solution of [2-(4-fluoro-3-methoxyphenyl)ethyl]carbamic acid t-butyl ester (90 mg) in ethyl acetate (3 mL) was added a solution of 4N hydrochloric acid-ethyl acetate (3 mL) at room temperature and allowed to stand for 2.5 hours. The resulting solid was diluted with diethyl ether, then filtered, and washed with diethyl ether. After drying by aeration, and the title compound (416 mg) was obtained as a colorless solid.
Reaction SMILES: [NH2:1]N.[CH3:3][O:4][C:5](=[O:21])[C:6]1[CH:19]=[CH:18][C:9]([C:10]([N:12]=[C:13]([N:15](C)C)[CH3:14])=O)=[CH:8][C:7]=1[Cl:20]>C(O)(=O)C>[CH3:3][O:4][C:5](=[O:21])[C:6]1[CH:19]=[CH:18][C:9]([C:10]2[N:12]=[C:13]([CH3:14])[NH:15][N:1]=2)=[CH:8][C:7]=1[Cl:20]
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)N=C(C)N(C)C)cc1Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2n[nH]c(C)n2)cc1Cl
Temperature: 90 °C
Yield: 67.1 %

Procedure:
Anhydrous hydrazine (0.30 mL, 9.6 mmol) was added via syringe to a solution of the intermediate of Step B (4.8 mmol) in glacial acetic acid (6 mL) under a nitrogen atmosphere. The reaction was heated at 90° C. for 30 minutes, then cooled and concentrated in vacuo to a light brown solid. The solid was redissolved in aqueous methanol and the solution neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane and ethyl actate, the extracts were combined and dried over sodium sulfate. Evaporation of the solvents yielded a solid which was triturated with ether to provide the title product (0.81 g) as an off-white solid, m.p. 196-198° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:7].CO[CH2:10][N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:17]([N:11]1[CH2:12][CH:4]2[CH2:5][CH2:6][O:1][C:2](=[O:7])[CH:3]2[CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1C=CCCO1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OCCC2CN(Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 6 h
Yield: 82.87 %

Procedure:
To a solution of 5,6-dihydro-2H-pyran-2-one (1.00 g, 1 eq) in CH2Cl2 (150 mL) was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.2 eq). After the mixture was cooled to 0° C., a solution of TFA in CH2Cl2 (0.1 eq, 1M) was added slowly. The reaction mixture was slowly heated to room temperature and stirred for 6 h. The reaction mixture was washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 2:1 (v/v) PE/EA) to give the title compound as colorless oil (1.95 g, 82.87%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 232.3 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>CO>[NH:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[NH2:13]
Reactant: NN
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CO
Solvent: O
Product: NNc1ncccc1[N+](=O)[O-]

Procedure:
2-Chloro-3-nitropyridine (100 g, 0.63 mol), hydrazine monohydrate (70.4 mL, 72.6 g, 1.45 mol) and methanol (1.3 L) were mixed and heated to reflux with stirring. After 30 min the reaction mixture was cooled and filtered collecting the insoluble materials. The filtrate was concentrated by evaporation under reduced pressure and the residue obtained as well as the insoluble materials from the filtration were diluted with water. The insoluble solids present were collected by filtration, washed with water, and dried to obtain 95.2 g (98 percent of theory) of the title compound as a bright yellow powder melting at 168°-169° C.
Reaction SMILES: [Li]CCCC.[CH3:6][Si:7]([CH3:12])([CH3:11])[C:8]#[C:9][CH3:10].Cl[CH2:14][C:15]1[N:19]([CH3:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]=1>C1COCC1>[CH3:20][N:19]1[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]=[C:15]1[CH2:14][CH2:10][C:9]#[C:8][Si:7]([CH3:12])([CH3:11])[CH3:6]
Reactant: Cn1c(CCl)nc2ccccc21
Reactant: CC#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(CCC#C[Si](C)(C)C)nc2ccccc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
n-BuLi (1.35 mL, 3.39 mmol, 2.5 M) was added to a solution of trimethyl-prop-1-ynyl-silane (0.55 mL, 3.69 mmol) in THF (1 mL) at −78° C. After 2 hours, a solution of 2-chloromethyl-1-methyl-1H-benzoimidazole (556 mg, 3.08 mmol) in THF (5 mL) was added to the reaction mixture at −78° C. then the reaction mixture was stirred for 30 min at −78° C. and 1 hour at room temperature and was quenched with water. The aqueous phase was extracted with DCM. The organic phase was washed with water, dried over MgSO4, filtered and evaporated to yield 1-methyl-2-(4-trimethylsilanyl-but-3-ynyl)-1H-benzoimidazole (178 mg, 0.69 mmol, 23%).
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][N:18]=[CH:19]2>C(O)C>[CH:19]1[C:20]2[C:15](=[C:14]([NH:13][C:4]3[C:5](=[O:12])[C:6](=[O:11])[C:7]=3[O:8][CH2:9][CH3:10])[CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: Nc1cccc2cnccc12
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2cccc3cnccc23)c(=O)c1=O
Yield: 29.2 %

Procedure:
To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4 mmol) in absolute ethanol (100 mL) was added a suspension of 5-aminoisoquinoline (4.24 g, 29.4 mmol) in ethanol (50 mL). The mixture was heated to reflux overnight and then filtered to yield 2.30 g (29%) of solid: mp 182(dec) ° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[F:28][C:29]([F:45])([F:44])[CH:30]1[CH:35]([NH2:36])[CH2:34][CH2:33][N:32]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:31]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:36][C@H:35]4[CH2:34][CH2:33][N:32]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:31][C@H:30]4[C:29]([F:28])([F:44])[F:45])=[O:22])=[CH:19][N:18]=3)=[O:16])[CH2:13][CH2:14]2)=[O:8])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(C(F)(F)F)C1
Reactant: COc1ccc(C(=O)C2CCN(C(=O)c3ccc(C(=O)O)cn3)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C2CCN(C(=O)c3ccc(C(=O)N[C@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4C(F)(F)F)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.4 %

Procedure:
To a mixture of 6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinic acid (0.094 g, 0.257 mmol, 1.0 eq), and 3-trifluoromethyl-4-amino-1-Boc-piperidine (0.257 mmol, 1.0 eq) was added dimethylformamide (2.5 mL) and triethylamine (0.054 mL, 0.386 mmol, 1.5 eq). HATU (0.107 g, 0.283 mmol, 1.1 eq) was added and the reaction was stirred at room temperature for 14 hours and partitioned between EtOAc (120 mL) and NaHCO3-water (1:1, 120 mL). The organics were further washed with brine (100 mL), water (100 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→10% MeOH—CH2Cl2) yielded the coupled product (0.104 g, 68%) as a colourless oil; 1H nmr (CDCl3) δ 8.90 (1H, br s, pyH-6), 8.08 (1H, br d, J 7.0 Hz, pyH-4), 7.92 (2H, d, J 9.0 Hz, 2H of C6H4OMe), 7.50 (2H, m, pyH-3, NH), 6.94 (2H, d, J 9.0 Hz, 2H of C6H4OMe), 4.61 (2H, m, 1H of pipH-2, H-4, H-6, 1H of BzpipH-2, H-6), 3.86 (3H, s, OCH3), 3.86-3.74 (2H, m, 1H of pipH-2, H-4, H-6, 1H of BzpipH-2, H-6), 3.52 (1H, m, BzpipH-4), 3.52-3.38 (2H, m, 2H of pipH-2, H-4, H-6), 3.26-3.04 (1H, m, 1H of pipH-2, H-3, H-4, H-6), 3.22 (1H, m, 1H of BzpipH-2, H-6), 3.12 (1H, t, J 11.5 Hz, 1H of BzpipH-2, H-6), 2.76 (1H, m, 1H of pipH-2, H-3, H-4, H-6), 2.00 (1H, m, 1H of BzpipH-3, H-5), 1.90-1.65 (5H, m, pipH-5, 3H of BzpipH-3, H-5), 1.45 (9H, s, C(CH3)3); 19F nmr (CDCl3) δ −62.7; m/z 619 [M+H]+.
Reaction SMILES: [N:1]1[NH:2][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]3[CH2:13][CH2:12][C:11]4=[C:14]([CH:18]=[O:19])[CH:15]=[CH:16][CH:17]=[C:10]4[C:9]=1[C:8]=23.P([O-])(O)(O)=[O:21].[Na+].Cl[O-].[Na+].Cl>CS(C)=O.O>[N:1]1[NH:2][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]3[CH2:13][CH2:12][C:11]4=[C:14]([C:18]([OH:21])=[O:19])[CH:15]=[CH:16][CH:17]=[C:10]4[C:9]=1[C:8]=23
Reactant: O=P([O-])(O)O
Reactant: O=Cc1cccc2c1CCc1cccc3[nH]nc-2c13
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cccc2c1CCc1cccc3[nH]nc-2c13
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
85 mg of 6,7-dihydro-2H-benzo[6,7]cyclohepta[cd]indazole-8-carboxaldehyde prepared in Example 2 was dissolved in 8 ml of dimethyl sulfoxide. To the reaction mixture was added a solution of 0.75 g of sodium dihydrogenphosphate in 4 ml water. Further, a solution of 0.25 g of sodium hypochlorite in 1 ml water was added dropwise at room temperature, followed by stirring for 0.5 hour. To the reaction mixture was added 0.01 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:1), to give 85 mg of the title compound as a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C(C)=CC=CC=1>O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 90.3 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate were heated to 120° C. in 40 ml of glycol and 10 ml of water. At 80° C., 0.1 mol % of a catalyst solution prepared as described in C.3.1 was added. After the reaction was complete, 50 ml of xylene were added and the organic phase was separated off. Distillation gave 19 g of 2-cyano-4'-methylbiphenyl (mp. 140° C./mbar).
Reaction SMILES: [CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][O:6][C:7]1[CH:11]=[C:10]([N:12]2[C:20]3[CH:19]=[C:18]([CH2:21]O)[N:17]=[CH:16][C:15]=3[N:14]=[CH:13]2)[S:9][C:8]=1[C:23]([NH2:25])=[O:24])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][O:6][C:7]1[CH:11]=[C:10]([N:12]2[C:20]3[CH:19]=[C:18]([CH2:21][S:31]([CH3:30])(=[O:33])=[O:32])[N:17]=[CH:16][C:15]=3[N:14]=[CH:13]2)[S:9][C:8]=1[C:23]([NH2:25])=[O:24])[CH3:2]
Reactant: CCc1ccccc1COc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1ccccc1COc1cc(-n2cnc3cnc(CS(C)(=O)=O)cc32)sc1C(N)=O

Procedure:
In a similar manner as described for example 49 (step 1), 210 mg of 3-[(2-ethylbenzyl)oxy]-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 112 mg of methanesulfonyl chloride, and 104 mg of triethylamine in 5 ml DMF give 3-[(2-ethylbenzyl)oxy]-5-{6-[(methylsulfonyl)methyl]-1H-imidazo[4,5-c]pyridin-1-yl}thiophene-2-carboxamid as crude material that is used for step 2 without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:18][N:6]2[C:7](=[O:17])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][N:12]=3)[N:10]=[C:5]2[NH:4][CH2:3]1.[H-].[Na+].[N:22]1[C:27]2[CH2:28][CH:29]([CH2:31]OS(C)(=O)=O)[CH2:30][C:26]=2[N:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[N:22]1[C:27]2[CH2:28][CH:29]([CH2:31][N:4]3[C:5]4=[N:10][C:9]([C:11]5[CH:16]=[CH:15][N:14]=[CH:13][N:12]=5)=[CH:8][C:7](=[O:17])[N:6]4[CH2:18][C:2]([CH3:19])([CH3:1])[CH2:3]3)[CH2:30][C:26]=2[N:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCC1Cc2nccnc2C1
Reactant: CC1(C)CNc2nc(-c3ccncn3)cc(=O)n2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CN(CC2Cc3nccnc3C2)c2nc(-c3ccncn3)cc(=O)n2C1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 10.6 %

Procedure:
A suspension of 0.5 g (1.94 mmol) of 7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 10 ml of anhydrous dimethylformamide was treated with 155 mg (3.89 mmol) of sodium hydride (50% suspension in mineral oil) and the resulting mixture was stirred for 40 min at 50° C. 0.888 g (3.89 mmol) of methanesulfonic acid 6,7-dihydro-5H-cyclopentapyrazin-6-ylmethyl ester in 2 ml of anhydrous dimethylformamide was added and the reaction mixture stirred at room temperature for 18 h. The solution was treated with water and extracted with ethyl acetate. The organic phase was dried and evaporated to give crude product, which was purified by silica gel chromatography, eluting with dichloromethane/methanol in the proportions 100/1 to 95/5 to give 80 mg of pure product obtained in the form of free base which was transformed into the hydrochloride salt. Mp: 193-195° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.[N+:16]([O-])([OH:18])=[O:17].C(O)(=O)C.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1[N+](=O)[O-])C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
50 g (250 mmoles) of 2-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene are dissolved in 200 ml of acetic anhydride. The solution is cooled to 0° C. and there is slowly added a solution of 10.5 ml (250 mmoles) of nitric acid, 20 ml of acetic acid and 20 ml of acetic andydride, while maintaining the temperature between 0 and 5° C. The reaction mixture is then stirred for 1 hour at ambient temperature, poured into ice water and filtered. The resulting solid is washed with water. The solid is dissolved in methylene chloride, washed with water and then with a saturated solution of sodium bicarbonate, dried on MgSO4 and evaporated. 45.8 g (74%) of 2-methyl-3-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene which melts at 143-144° C. are obtained.