Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([Cl:15])[N:12]=[N:11][C:10]=2[C:16]([OH:18])=[O:17])=[C:4]([F:19])[CH:3]=1.[C:20](OC(=NC(C)C)NC(C)C)([CH3:23])([CH3:22])[CH3:21]>C1COCC1.C(OCC)(=O)C>[C:20]([O:17][C:16]([C:10]1[N:11]=[N:12][C:13]([Cl:15])=[CH:14][C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:19])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)c1nnc(Cl)cc1Nc1ccc(Br)cc1F
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1nnc(Cl)cc1Nc1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
To the stirred solution of 4-(4-bromo-2-fluoro-phenylamino)-6-chloro-pyridazine-3-carboxylic acid (516 gm, 1.49 mmol) in THF (10 ml) under argon at room temperature is added a solution of 2-tert-butyl-1,3-diisopropylisourea (1.49 g, 7.45 mmol) in THF (1.0 ml). The resulted mixture is refluxed for 6 hours. The reaction mixture is then cooled to room temperature and diluted with ethyl acetate. The organic layer is washed with 10% K2CO3 (20 ml×2) and saturated NaCl (30 ml×3), dried over Na2SO4 and concentrated in vacuum. The residue is dissolved in 30 ml of dichloromethane and the resulting white solid (urea byproduct) is filtered out. The filtrate is concentrated under reduced pressure. The residue is purified by flash column chromatography to provide the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:15]1[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(C=O)cc2F)cn1
Temperature: 90 °C
Reaction time: 6 h
Yield: 14.6 %

Procedure:
3,4-Difluorobenzaldehyde (30.0 g) was dissolved in DMF (400 mL), and 4-methyl-1H-imidazole (34.8 g) and potassium carbonate (58.5 g) were added to the solution at room temperature. The reaction solution was stirred at 90° C. for six hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system), solidified with tert-butyl methyl ether, and separated by filtration to obtain 6.28 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:21])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@@H:18]2[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=[O:15].Cl.[H-].[Na+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH2:25]([O:21][C:10]1[C:11]2[O:12][C@H:13]3[C:14](=[O:15])[CH2:16][CH2:17][C@@H:18]4[C@@:5]53[CH2:4][CH2:3][N:2]([CH3:1])[C@@H:19]4[CH2:20][C:7]([C:6]=25)=[CH:8][CH:9]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1ccccc1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC[C@]23c4c5ccc(OCc6ccccc6)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 82.1 %

Procedure:
To Hydromorphone HCl (50.0 g, 155.3 mmol) in dimethylformamide (500 mL) was added sodium hydride (14.30 g, 357.4 mmol) portionwise with cooling. The addition was conducted over 25 minutes. The reaction was stirred at room temperature for 1.5 hours before the addition of benzyl chloride (17.88 mL, 357.4 mmol) over 10 minutes with cooling. The reaction was allowed to warm to room temperature and stirred for 40 hours. The reaction was incomplete so additional benzyl chloride (1.79 mL, 15.5 mmol) was added. After 4 hours, the reaction was quenched with water (60 mL), acidified with aqueous HCl (2M, 800 mL) and washed with ethyl acetate/diethyl ether (3:1) (2×800 mL). The aqueous phase was basified with aqueous NaOH (2M, 800 mL) and extracted with ethyl acetate (2×1 L). The organic phases were combined, washed with water/brine (1:1) (2×800 mL) and dried over MgSO4 before concentration under reduced pressure. The residue was taken up in ethyl acetate and washed with water/brine (2×500 mL), dried over MgSO4 before concentration under reduced pressure to give (4R,4aR,7aR,12bS)-9-(benzyloxy)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (47.9 g, 95% pure by NMR, 82% yield); [M+H]+376.2. This was taken onto the next step without purification.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:31]=[C:30](F)[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].C[N:34]([CH3:37])C=O>>[N:1]1[C:6]2[NH:7][C:8]3[C:15]([C:25]([C:24]4[CH:28]=[CH:29][C:30]([N:34]5[CH:37]=[CH:9][C:8]([CH3:15])=[N:7]5)=[CH:31][C:23]=4[F:22])=[O:26])=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccn(-c2ccc(C(=O)c3cccc4c3Nc3ncccc3CN4)c(F)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (3.0 g, 15.2 mmol) in dimethylformamide (35 mL) under nitrogen was added potassium carbonate (6.3 g, 45.6 mmol) followed by a solution of the crude 2,4difluorobenzoylchloride of Step A (22.8 mmol) in dimethylformamide (15 mL). After stirring at room temperature for 20 minutes, the reaction mixture was washed with water and stirred to give a solid which was collected by filtration. The solid was dissolved in chloroform and washed with 1 N sodium hydroxide and brine. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 20% ethyl acetate in hexane provided the title compound (2.6 g, 51%) as a white foam which crystallized by sonication from hexane-ethanol, m.p. 161-163° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[N:16]=[CH:15][C:14]([CH2:17]O)=[C:13]([I:19])[CH:12]=1.C(O)C.C(=O)(O)[O-].[Na+]>ClCCl>[F:10][C:11]1[CH:12]=[C:13]([I:19])[C:14]([CH2:17][F:7])=[CH:15][N:16]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCc1cnc(F)cc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: FCc1cnc(F)cc1I
Reaction time: 3 h
Yield: 53 %

Procedure:
Add diethylaminosulfur trifluoride (892 mg, 4 mmol) drop-wise to a solution of (6-fluoro-4-iodo-pyridin-3-yl)-methanol in dichloromethane (25 mL) in a round bottom flask under nitrogen, and then add ethanol (0.3 mL) at 0-5° C. Stir the mixture for 3 hours. Pour the reaction mixture into saturated sodium bicarbonate solution. Abstract the product into chloroform, and wash with water and saturated aqueous sodium chloride. Separate the organic layer from the aqueous layer and dry over MgSO4. After filtration, evaporate the organic solvent in vacuo to give a crude product. Purify the crude with flash column chromatography (10% methanol in dichloromethane) to give the title compound (0.32 g, 53%). MS (ES) m/z 256 [M+1]+.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[NH:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl.N1C=CC=CC=1>N1C=CC=CC=1>[CH2:21]([C:20]1[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCC(=O)Nc1cnc2ccccc2c1NCCCCCSC
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCc1nc2cnc3ccccc3c2n1CCCCCSC
Yield: 94.4 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, N-(4-{[-(methylthio)pentyl]amino}quinolin-3-yl)heptanamide (4.44 g, 11.46 mmol), pyridine hydrochloride (0.13 g, 1.15 mmol), and anhydrous pyridine (50 mL) under a nitrogen atmosphere. The reaction was judged to be complete after stirring at reflux for 1.5 hours. The solution was cooled and partitioned between ethyl acetate and water. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford 2-hexyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinoline (4.0 g, 10.82 mmol) as a brown oil which was used without further purification.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[CH3:13][CH:14]([NH2:23])[CH:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:23][CH:14]([CH3:13])[CH:15]([OH:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)#[N:2]
Reactant: COC(=NC#N)c1ccccn1
Reactant: CC(N)C(O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(N=C(NC#N)c1ccccn1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.3 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.24 g, 1.5 mmol) was dissolved in methanol (5 ml), DL-phenylpropanolamine hydrochloride (0.31 g, 1.7 mmol, supplied by Tokyo Chemical Industry Co., Ltd.) and triethylamine (0.17 g, 1.7 mmol) were added, and the resulting mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was extracted with ethyl acetate (30 ml×3). The ethyl acetate layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue thus obtained was crystallized from diethyl ether to give the title compound (0.23 g, 0.8 mmol, yield: 54%) as colorless crystals.
Reaction SMILES: [NH2:1][OH:2].[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][C:14](=O)[CH2:15]3)[CH2:5][CH2:4]1>C(O)C>[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][C:14](=[N:1][OH:2])[CH2:15]3)[CH2:5][CH2:4]1
Reactant: O=C1CC2CCC(C1)N2CCN1CCOCC1
Reactant: NO
Solvent: CCO
Product: ON=C1CC2CCC(C1)N2CCN1CCOCC1
Temperature: 25 °C

Procedure:
After 22.2 ml of 50% hydroxylamine aqueous solution was added to a solution of 40.0 g of 8-(2-morpholinoethyl)-8-azabicyclo[3.2.1]octan-3-one in 200 ml of ethanol, the mixture was stirred at room temperature for an hour. The solvent was distilled off and toluene was added followed by azeotropic distillation. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform:NH3 -saturated methanol=20:1) to give 32.8 g of 8-(2-morpholinoethyl)-8-azabicyclo[3.2.1]octan-3-one oxime.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-])=O)[CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C>[C:11]([O:10][C:9](=[O:15])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)=[CH:3][C:4]=1[NH2:16])([CH3:14])([CH3:13])[CH3:12]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N

Procedure:
A mixture of tert-butyl (4-bromo-2-nitrophenyl)carbamate (19.4 g, 61.2 mmol), thiophene-2-boronic acid (9.94 g, 77.7 mmol) and K2CO3 (22.2 g, 160 mmol) in 60 mL of dioxane and 60 mL of water was degassed by bubbling nitrogen through the mixture for 30 min. Next, Pd[PPh3]4 (5.25 g, 4.53 mmol) was added and the heterogeneous mixture was warmed to reflux for 20 h. The mixture was cooled and diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and concentrated. The resulting solid was dissolved in diethylether (500 mL) and filtered through a pad of silica. The solvents were removed under reduced pressure to yield the yellow-brown solid: 1H NMR (600 MHz, CDCl3): δ 9.65 (s, 9H), 8.58 (d, J=8.8 Hz, 1H), 8.39 (d, J=2.1 Hz, 1H), 7.81 (dd, J=8.8, 1.8 Hz, 1 H), 7.32 (m, 2H), 7.09 (dd, J=5.3, 3.8 Hz, 1H), 1.54 (s, 9H); MS (ESI+): cal'd [M+Na]+ 343.1, obs'd 343.1.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>O>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:3][CH:4]=3)[S:9][C:10]=2[CH:16]=1
Reactant: C1CCNC1
Reactant: COc1ccc2nc(-c3ccc(F)nc3)sc2c1
Solvent: O
Product: COc1ccc2nc(-c3ccc(N4CCCC4)nc3)sc2c1
Temperature: 100 °C

Procedure:
In a microwave vial were added 2-(6-fluoropyridin-3-yl)-6-methoxy-1,3-benzothiazole (75 mg, 0.29 mmol), water (2.5 mL) and pyrrolidine (0.50 mL) and the reaction was heated in a microwave oven at 100° C. for 5 min. The precipitated product was filtered off, washed with water and methanol and dried in a desicator over P2O5 to give the title compound (76 mg) as a white solid. 1H NMR (CHLOROFORM-d) δ 8.77 (d, 1 H) 8.13 (dd, 1 H) 7.87 (d, 1 H) 7.33 (d, 1 H) 7.05 (dd, 1 H) 6.44 (d, 1 H) 3.89 (s, 3 H) 3.63-3.46 (m, 4 H) 2.11-1.98 is (m, 4 H); MS m/z (M+H) 312.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:13]=O.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[ClH:21]>C(O)C.CC(C)=O>[ClH:21].[CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:12])[CH2:11][CH2:13][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: C=O
Reactant: CC(=O)C=Cc1ccc(C)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1ccc(/C=C/C(=O)CCN2CCOCC2)cc1
Temperature: 25 °C

Procedure:
8 g (0.05 mole) of 4-(4-methylphenyl)-3-buten-2-one (prepared analogously to the intermediates for the foregoing examples), 2 g (a 30% excess) of paraformaldehyde and 4.35 g (0.05 mole) of morpholine are dissolved in a mixture of ethanol (60 ml) and concentrated HCl (6 ml). The mixture is heated at reflux temperature for 18 hours. The mixture is then cooled to room temperature and diluted with acetone to a volume of 250 ml. The solution is chilled overnight. It is then concentrated to a volume of about 25 ml. The residue is triturated with ethyl alcohol. The insoluble material is filtered and recrystallized from ethyl alcohol/methyl alcohol. The resultant crystals are filtered and vacuum dried overnight, yielding 3.3 g of (E)-1-(4-methylphenyl)-5-(4-morpholinyl)-1-penten-3-one hydrochloride; m.p. 188°-190° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[S:13]([CH2:23][N+:24]#[C-:25])([C:16]1[CH:22]=[CH:21][C:19](C)=[CH:18][CH:17]=1)(=[O:15])=[O:14].[C-:26]#N.[Na+]>>[C:22]1([CH3:26])[C:16]([S:13]([C@@H:23]2[C@@H:7]([C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=3)[O:8][CH:25]=[N:24]2)(=[O:14])=[O:15])=[CH:17][CH:18]=[CH:19][CH:21]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: [C-]#N
Agent: [Na+]
Product: Cc1ccccc1S(=O)(=O)[C@H]1N=CO[C@@H]1c1ccc(C(F)(F)F)cc1

Procedure:
In a manner analogous to Preparation 1, 4-(trifluoromethyl)-benzaldehyde (0.54 mL, 3.95 mmol), tosylmethylisocyanide (0.75 g, 3.84 mmol) and NaCN (0.02 g, 0.40 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 411.2 (M+CH3CN+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.N1CCCC1>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 193.5 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to at a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. And the above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (7.9 ml) is added to the bottle, and then pyrrolidine (7.8 ml) is added thereto within 15 min at the temperature, the above mixture is further reacted at the temperature for 0.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (12.3 g). The yield is about 75.6%.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([N:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)(=[O:18])=[O:17])COC)=[CH:10][C:9]([Cl:30])=[CH:8][N:7]=1)=[O:5].I[C:33]1[C:34]2[CH:41]=[CH:40][N:39](COCC[Si](C)(C)C)[C:35]=2[N:36]=[CH:37][N:38]=1.CO.Cl>C1COCC1.C([Mg]Cl)(C)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:12][C:11]2[C:6]([C:4]([C:33]3[C:34]4[CH:41]=[CH:40][NH:39][C:35]=4[N:36]=[CH:37][N:38]=3)=[O:5])=[N:7][CH:8]=[C:9]([Cl:30])[CH:10]=2)(=[O:18])=[O:17])=[CH:20][C:21]=1[C:26]([F:27])([F:29])[F:28]
Reactant: C[Si](C)(C)CCOCn1ccc2c(I)ncnc21
Reactant: COCN(c1cc(Cl)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ncnc2[nH]ccc12

Procedure:
Prepared from 259 mg (0.52 mmol) of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid methoxy-methyl-amide, 213 mg (0.52 mmol) of 90% 4-iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 2 mL THF with 0.26 mL of 2 M isopropylmagnesium chloride solution in THF added. All of the resulting intermediate ketone was used in the second step with 2 mL methanol and 2 mL 6N hydrochloric acid mixture to give after purification 40 mg of the final product as a yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)#[N:4].[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl.O>CN(C)C=O>[C:3]([C:5]1([CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)#[N:4]
Reactant: N#CC1c2ccccc2COc2ccccc21
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCC1(C#N)c2ccccc2COc2ccccc21
Yield: 42 %

Procedure:
Sodium hydride (5.0 g; 0.10 mole) is added portionwise with cooling (5°-10° C.) under a nitrogen atmosphere to a solution of 11-cyano-6,11-dihydrodibenz[b,e]oxepin of Example 1A, (20.0 g; 0.09 mole) in dry DMF (200 ml). After thirty minutes, effervescence ceases and 2-dimethylaminoethyl chloride (10.0 g; 0.09 mole) in dimethyl formamide [DMF] (200 ml) is added dropwise. Stirring is continued at 80° C. for sixteen hours. The reaction is cooled and poured into three liters of water. After extraction with ether, the ether is re-extracted with 1 N HCl, and the combined aqueous extracts are made basic with 50% NaOH. After extracting with ether and drying (K2CO3), the solvent is removed in vacuo to provide an oil which is chromatographed on an alumina column. The resulting oil crystallizes upon standing and trituration with hexane yields 11.0 g (42%) of a solid of 11-cyano-11-[2-(dimethylamino)ethyl]-6,11-dihydrodibenz[ b,e]oxepin (m.p. 63°-65° C.),
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4](=[O:20])[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[N:6][N:7]([S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])[CH:8]=1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cn(S(=O)(=O)c2ccccc2)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 78.8 %

Procedure:
A solution of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (100 mg) and benzenesulfonylchloride (79 mg) in pyridine (4.00 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting solid was washed with ethyl acetate and diethyl ether, and dried to give the title compound (120 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:16][N:17]([CH2:25][CH:26]=O)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C(B)#N.[Na]>CO.C(O)(=O)C.CO.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:15])[C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:5][N:6]([CH2:26][CH2:25][N:17]([CH3:16])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:7][CH2:8]1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: CN(C)C1(c2ccccc2)CCNCC1
Agent: BC#N
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCN1CCC(c2ccccc2)(N(C)C)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
7 g (1 eq) N,N-dimethyl-4-phenylpiperidin-4-amine were added in portions to a solution of 6.5 g (1.5 eq) tert-butyl methyl(2-oxoethyl)carbamate in 60 ml methanol. This reaction mixture was cooled to 0° C., 3.97 g (2.5 eq) sodium cyanoboron hydride were added in portions and then the mixture was stirred for 10 min at room temperature. The reaction mixture obtained was adjusted to a pH of ˜5 with acetic acid and stirred for 12 h at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). As the conversion was still not complete, 1.5 g sodium cyanoboron hydride and acetic acid were added and the reaction mixture was stirred for a further 30 to 45 min. Once the conversion was complete, the methanol was distilled off, 100 ml saturated NaHCO3 solution were added and the mixture obtained was extracted with chloroform (2×200 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 5% MeOH/CHCl3). 8 g (64%) of product were obtained in the form of an oil.