Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH3:12].N[CH2:14][CH2:15][CH2:16]O.C(O)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.O.[Sn](Cl)Cl>O1CCOCC1.O.O.[Ru](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[CH3:12])[N:9]=[CH:16][CH:15]=[CH:14]2
Reactant: COc1ccc([N+](=O)[O-])cc1C
Reactant: NCCCO
Agent: Cl[Ru](Cl)Cl
Agent: Cl[Sn]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COc1cc2cccnc2cc1C
Temperature: 180 °C
Reaction time: 20 h
Yield: 15.4 %

Procedure:
1-methoxy-2-methyl-4-nitrobenzene (3A) (5 g, 30.0 mmol), 3-amino-1-propanol (0.57 mL, 7.5 mmol), isopropanol (3.43 mL, 4.5 mmol), ruthenium(III) chloride hydrate (156 mg, 0.75 mmol), triphenylphosphine (588 mg, 2.24 mmol), and tin(II) chloride dihydrate (1.69 g, 7.5 mmol) in dioxane/H2O (67 mL/7 mL) were placed in a stainless steel pressure vessel. After the system was flushed with argon, the mixture was stirred at 180° C. for 20 hours. The reaction mixture was filtered through a short silica gel column (ethyl acetate/chloroform mixture) to eliminate inorganic compounds and concentrated under reduced pressure. The organic layer was poured into saturated brine, extracted with chloroform, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residual oily material was separated by column chromatography to give the product 3B (200 mg, 15%). LCMS-ESI+ (m/z): 174.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:14](Cl)([Cl:17])(=[O:16])=[O:15]>C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([Cl:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CC#N
Product: O=S(=O)(Cl)N1CCN(Cc2ccccc2)CC1
Yield: 88.8 %

Procedure:
A solution of 1-benzylpiperazine (20.0 g, 0.114 mol) in acetonitrile (45 ml) was added to a solution of sulphuryl chloride (28 ml, 0.346 mol) in acetonitrile (50 ml) and the mixture heated under reflux for 17 hours, then cooled. The solvent was removed by evaporation under vacuum, then the residue triturated with ether (20×50 ml) to yield the title compound (27.8 g, 89%), which was used without further purification.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:15][CH2:14]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].I([O-])(=O)(=O)=[O:28].[Na+].Cl.[OH-].[Na+]>CO>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:18]2)=[O:28])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CS(=O)(=O)Nc1ccc(SC2CCN(CCc3cccnc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(S(=O)C2CCN(CCc3cccnc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
A mixture of 0.50 g (1.28 mmol) of 4-(4-methylsulfonylaminophenylthio)-1-[2-(3-pyridyl)ethyl]piperidine, 0.33 g (1.53 mmol) of sodium periodate, 5 ml of 1N hydrochloric acid and 5 ml of methanol was stirred at room temperature for 1 h. About 5 ml of a 1N sodium hydroxide solution was added thereto to adjust the pH to about 7. After extraction with chloroform, the organic layer was concentrated and the residue was purified by silica gel column chromatography (CHCl3 :CH3OH:NH4OH=95:5:0.5). The fraction containing the intended compound was concentrated to give a solid residue, which was recrystallized from ethyl acetate to give a 0.34 g (yield: 64%) of the compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:14][N:15]1[C:20](=[O:21])[N:19]([CH3:22])[C:18](=[O:23])[C:17]([N:24]2[CH2:29][CH2:28][NH:27][C:26](=[O:30])[CH2:25]2)=[N:16]1>>[CH3:14][N:15]1[C:20](=[O:21])[N:19]([CH3:22])[C:18](=[O:23])[C:17]([N:24]2[CH2:29][CH2:28][N:27]([C:5](=[O:6])[C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[C:2]([F:13])([F:12])[F:1])[C:26](=[O:30])[CH2:25]2)=[N:16]1.[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:9]([C:2]([F:13])([F:12])[F:1])=[CH:8][C:4]=1[C:5]([N:27]1[CH2:28][CH2:29][N:24]([C:17]2[C:18](=[O:23])[N:19]([CH3:22])[C:20](=[O:21])[N:15]([CH3:14])[N:16]=2)[CH2:25][CH2:26]1)=[O:6]
Reactant: Cn1nc(N2CCNC(=O)C2)c(=O)n(C)c1=O
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: Cn1nc(N2CCN(C(=O)c3cc(C(F)(F)F)ccc3C(F)(F)F)CC2)c(=O)n(C)c1=O
Product: Cn1nc(N2CCN(C(=O)c3ccccc3C(F)(F)F)C(=O)C2)c(=O)n(C)c1=O
Yield: 77 %

Procedure:
The compound 53 (solid) is prepared from 2-trifluoromethyl-benzoyl chloride and from the intermediate 12b according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 77%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH3:37].[CH3:38][CH2:39]OC(C)=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:36][CH3:37])[CH2:38][CH3:39])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: COC(=O)c1ccc(CCCc2cc(N)ccc2OCc2ccccc2)cc1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)OC)cc2)c1
Reaction time: 18 h

Procedure:
To a mixture of methyl 4-[3-(2-benzyloxy-5-aminophenyl) propyl]benzoate (250 mg) in DMF (5 ml) was added potassium carbonate (0.2 g) and iodoethane (0.16 ml). The reaction was stirred for 18 hours, diluted with EtOAc, washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography to give the methyl 4-[3-(2-benzyloxy-5-(diethylamino) phenyl)propyl]benzoate as an oil (150 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:35][C:36]1[CH:37]=[C:38]([OH:50])[CH:39]=[C:40]([C:42]2([O:48][CH3:49])[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:41]=1>O>[F:35][C:36]1[CH:37]=[C:38]([CH:39]=[C:40]([C:42]2([O:48][CH3:49])[CH2:43][CH2:44][O:45][CH2:46][CH2:47]2)[CH:41]=1)[O:50][CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: NS(=O)(=O)c1ccc(-c2oc(CCl)nc2-c2ccccc2)cc1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(c2cc(F)cc(OCc3nc(-c4ccccc4)c(-c4ccc(S(N)(=O)=O)cc4)o3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
A mixture of 4-[2-chloromethyl-4-phenyloxazol-5-yl]benzenesulfonamide (Step 3) (0.5 g, 1.4 mmol), potassium carbonate (0.4 g, 2.8 mmol), dimethylformamide (20 mL), and 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol [prepared as described in J. Med Chem., 35, 2600–2609 (1992)] (0.3 g, 1.4 mmol) was stirred at room temperature, for 16 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (4×30 mL) The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The resulting crude product was purified by flash column chromatography on silica gel eluting with 50% ethyl acetate in hexanes to give 0.3 g (40%) of 4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-pyran-4-yl)phenoxy]methyl]-4-phenyl-oxazol-5-yl]benzenesulfonamide as a sticky white solid: m.p. 70–80° C. 1H NMR (CDCl3/300 MHz) δ 7.92 (d, 2H, J=8.9 Hz), 7.77 (d, 2H, J=8.9 Hz), 7.62 (m, 2H), 7.43 (m, 3H), 6.94 (s, 1H), 6.78 (m, 2H) 5.24 (s, 2H), 4.82 (bs, 2H), 3.82 (m, 4H), 3.00 (s, 3H), 1.95 (m, 4H). Anal. calcd for C28H27FN2O6S: C, 62.44; H, 5.05; N, 5.20. Found: C, 62.50; H, 5.11; N, 5.24.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:15]([CH3:14])(=[O:17])=[O:16])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1

Procedure:
N—BOC-piperazine and methanesulfonyl chloride were reacted together in dichloromethane and triethylamine to yield 4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester. Cleavage of the BOC protecting group using HCl (2M) in dichloromethane yielded 1-methanesulfonyl-piperazine. HCl salt.
Reaction SMILES: [Br:1][C:2]1[C:3](OC)=[C:4]([C:14]#[N:15])[C:5](=O)[N:6]([CH:8]([CH:10]2[CH2:12][CH2:11]2)[CH3:9])[CH:7]=1.[OH2:18].[NH2:19][NH2:20]>C(O)C>[NH2:15][C:14]1[C:4]2[C:5](=[O:18])[N:6]([CH:8]([CH:10]3[CH2:12][CH2:11]3)[CH3:9])[CH:7]=[C:2]([Br:1])[C:3]=2[NH:20][N:19]=1
Reactant: NN
Reactant: COc1c(Br)cn(C(C)C2CC2)c(=O)c1C#N
Reactant: O
Solvent: CCO
Product: CC(C1CC1)n1cc(Br)c2[nH]nc(N)c2c1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of 5-bromo-1-(1-cyclopropylethyl)-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step B of Example 163 (1.2 g), hydrazine monohydrate (1.01 g) and ethanol (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate). The residue was dissolved in ethyl acetate, and the solution was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.20 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.[Na].CCCCCCC.[C:17]([C:19]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([OH:24])[C:20](OC)=[O:21])#[CH:18]>CO>[C:17]([C:19]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([OH:24])[C:20]([O:8][CH:4]1[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)=[O:21])#[CH:18]
Reactant: C#CC(O)(C(=O)OC)c1ccccc1
Reactant: CN1CCCC(O)C1
Agent: [Na]
Solvent: CO
Solvent: CCCCCCC
Product: C#CC(O)(C(=O)OC1CCCN(C)C1)c1ccccc1

Procedure:
1-Methyl-3-piperidinol (3.5 g., 0.03 mole) and a small piece of sodium (~0.05 g.) were refluxed in 150 ml. of n-heptane for about 1 hour in a flask equipped with a small distilling head. Methyl α-ethynyl-α-phenylglycolate (4.0 g., 0.02 mole) was then added intermittently over a one hour period with the temperature of the reaction mixture maintained at 90°. The reaction mixture was heated at 90°-95° for three hours during which time very little methanol was collected. The reaction mixture was subsequently refluxed for 11 hours and the azeotrope collected periodically. During this time sodium methoxide (0.075 g.) was added and 50 ml. of fresh n-heptane was added as an equal volume of distillate was collected simultaneously. These operations were carried out twice. Heating was stopped and a total of 0.3 ml. (38% of theory) of methanol was obtained. As the reaction mixture cooled, an oil settled out. The n-heptane was decanted and the residue was washed with ice water (3×10 ml.). Ether and ice were added to the oil and the mixture worked up as described in Example 12, to yield 1.9 g. (35%) of the product as a yellow oil. Crystallization was effected by dissolving the material in ether, adding 30°-60° petroleum ether to produce turbidity and refrigerating the solution for several days. The product melted at 92°-95° after recrystallization from hexane.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C>COC(C)(C)C>[CH3:9][S:10]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:12])=[O:11]
Reactant: C#CC(O)(CF)CF
Reactant: CS(=O)(=O)Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: C#CC(CF)(CF)OS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
An amount (1.2 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol and methanesulfonyl chloride (0.85 ml) were dissolved in tert-butyl methyl ether (15 ml); to the solution under cooling with ice, triethylamine (1.5 ml) was added dropwise in a nitrogen atmosphere. After the end of the dropwise addition, the solution was stirred for 1.5 hours under cooling with ice. To the reaction mixture, tert-butyl methyl ether was added, followed by washing with water and a saturated aqueous solution of sodium chloride. The mixture was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (1.9 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][C:11](Cl)=[O:12].Cl.[CH3:15][NH:16][O:17][CH3:18]>ClCCl>[CH3:18][O:17][N:16]([CH3:15])[C:11](=[O:12])[CH2:10][O:9][CH3:8]
Reactant: COCC(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)N(C)OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
35.96 ml of triethylamine (258 mmol), followed by a solution of 14 g of methoxyacetyl chloride (Aldrich, 129 mmol) in 250 ml of dichloromethane, are added to a solution of N-methyl-O-methylhydroxylamine hydrochloride in 250 ml of dichloromethane cooled to 0° C. The mixture is stirred for 3 hours while allowing it to return to ambient temperature. A 1N solution of HClaq is added and then the organic phase is washed with water, dried over sodium sulphate, filtered, and concentrated under vacuum. 13.14 g of expected product are obtained in the form of an oil which is used without subsequent purification (crude yield=76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14](S(C)=O)=[N:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>COCCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1ccc2cnc(S(C)=O)nn12
Reactant: COc1ccc(N)cc1
Solvent: COCCO
Product: COc1ccc(Nc2ncc3ccc(-c4cc(Cl)ccc4OC)n3n2)cc1
Temperature: 180 °C
Yield: 14 %

Procedure:
7-(5-Chloro-2-methoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (75.0 mg, 0.000233 mol) and 4-Methoxybenzenamine (57.4 mg, 0.000466 mol) were dissolved in 2-Methoxyethanol (1.64 mL) and the reaction was heated at 180° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 12.41 mg of [7-(5-Chloro-2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-methoxy-phenyl)-amine as a lyophilized powder. (M+H)=381.11. 1H NMR (400 MHz, DMSO, d6) δ 9.29 (s, 1H), 8.95 (s, 1H), 8.05 (m, 1H), 7.63 (d, 2H, J=9.09 Hz), 7.46 (m, 1H), 7.23 (d, 1H, J=8.84 Hz), 7.03 (d, 1H, J=4.55 Hz), 6.90 (d, 1H, J=4.55 Hz), 6.85 (m, 2H), 3.82 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.C(N(CC)CC)C.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N>ClCCl>[Si:22]([O:8][CH2:7][C:3]1[CH:2]=[C:1]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24]
Reactant: OCc1cccc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.4 %

Procedure:
To 1,3-benzenedimethanol (5.10 g, 36.91 mmol) in dichloromethane (70 ml) was added at 0° C. triethylamine (7.47 g, 73.82 mmol), 4-dimethyl-aminopyridine (451 mg, 3.61 mmol) and t-butyldimethylchlorosilane (5.56 g, 36.91 mmol) successively, and the mixture was stirred for 20 hours at room temperature. Thereto was added a saturated ammonia solution and the mixture was extracted with ethyl acetate and separated by a separating funnel. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to give the subject compound (4.23 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](N)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.N([O-])=O.[Na+].C1C=CN=CC=1.[FH:25]>>[Cl:1][C:2]1[CH:11]=[C:10]([F:25])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)cc(N)c2c1
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc2nc(Cl)cc(F)c2c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A solution of 2-chloro-6-methoxyquinolin-4-amine (4.50 g, 21.6 mmol) in HF-pyridine (45 mL) was cooled to −10-0° C. Then NaNO2 (1.80 g, 26.1 mmol) was added portionwise and the mixture was stirred at 0° C. for 1 hour and at 30° C. for 1 hour. Then the mixture was heated to 65° C. for 1.5 hours. The mixture was quenched with ice-water (100 mL); the aqueous layer was neutralized with 2 M NaOH to pH 7. The mixture was filtered off and the filtrate was extracted with EtOAc (50 mL×3), the organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography on silica gel (PE/EtOAc=15/1) gave Intermediate 7 (3.60 g, yield: 40%). 1H NMR (CDCl3 400 MHz): (δ 7.92 (dd, J=9.2, 1.6 Hz, 1H), 7.40 (dd, J=9.2, 2.8 Hz, 1H), 7.25 (s, 1H), 7.10 (d, J=9.2 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][CH2:14][OH:15].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]2[O:15][CH2:14][CH2:13][CH2:12][O:8]2)[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: OCCCO
Reactant: COc1ccc(Br)cc1C=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(Br)cc1C1OCCCO1
Yield: 84.3 %

Procedure:
A mixture of 5-bromo-o-anisaldehyde (10.0 g, 46,5 mmol), propane-1,3diol (3.90 g, 51.2 mmol) and BF3-Et2O(0.15 ml) in toluene (50 ml) was refluxed in a Dean-Stark apparatus for 3 h. The reaction mixture was cooled, diluted with ether. The organic layer was washed successively with sat. NaHCO3 aq., water and brine, dried (MgSO4), and concentrated in vacuo to give crude product. The residue was distilled to give Compound 38 (10.7 g, 84%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1.Cl[C:13]1[C:18]([CH3:19])=[N:17][CH:16]=[CH:15][N:14]=1>>[CH3:19][C:18]1[C:13]([NH:1][CH2:2][CH2:3][N:4]2[CH2:5][CH2:6][CH:7]([CH2:10][OH:11])[CH2:8][CH2:9]2)=[N:14][CH:15]=[CH:16][N:17]=1
Reactant: Cc1nccnc1Cl
Reactant: NCCN1CCC(CO)CC1
Product: Cc1nccnc1NCCN1CCC(CO)CC1
Temperature: 120 °C
Yield: 28 %

Procedure:
A mixture of 1-(2-amino-ethyl)-4-piperidinemethanol (5.2 g), 2-chloro-3-methylpyrazine (5.0 g) and CaO (4.5 g) was stirred for hours at 120° C. The reaction mixture was cooled and purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3)92/8). The pure fractions were collected and the solvent was evaporated, yielding 2.3 g (29%)1-[2-[(3-methyl-2-pyrazinyl)amino]-ethyl]-4-piperidinemethanol (intermediate 1).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]([NH2:18])=[O:17])=[CH:10]3)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH:22](OC)OC)[CH3:21]>O1CCOCC1>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16](/[N:18]=[CH:19]/[N:20]([CH3:22])[CH3:21])=[O:17])=[CH:10]3)=[CH:4][CH:3]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CN(C)/C=N/C(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 100 °C
Yield: 93.2 %

Procedure:
To a solution of 13-bromo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-4-carboxamide (2.0 g, 6.5 mmol) in dioxane (30 mL) was added DMF-DMA (2.6 mL, 19 mmol). The reaction mixture was heated at 100° C. for 1 h. The solvent was removed under reduce pressure and the residue was triturated with hot diethyl ether. The solid was collected by filtration, washed with diethyl ether and dried in vacuo to afford 13-Bromo-N-[(1E)-(dimethylamino)methylidene]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-4-carboxamide (2.2 g, 93% yield) as a yellow solid. LCMS (ESI) m/z: 365.1 [M+H+]
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][C@H:12]2[CH2:15][C@@H:14]([C:16]3[N:20]4[CH:21]=[CH:22][N:23]=[C:24]([Cl:25])[C:19]4=[CH:18][N:17]=3)[CH2:13]2)(=O)=O)=CC=1.C1(C)C=CC(S(OC[C@H]2C[C@H](C3N4C=CN=C(Cl)C4=CN=3)C2)(=O)=O)=CC=1.[C:53]([Si:57](Cl)([CH3:59])[CH3:58])([CH3:56])([CH3:55])[CH3:54]>>[Si:57]([O:10][CH2:11][C@@H:12]1[CH2:13][C@H:14]([C:16]2[N:20]3[CH:21]=[CH:22][N:23]=[C:24]([Cl:25])[C:19]3=[CH:18][N:17]=2)[CH2:15]1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:59])[CH3:58]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3ncc4c(Cl)nccn43)C2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](c3ncc4c(Cl)nccn43)C2)cc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](c2ncc3c(Cl)nccn32)C1

Procedure:
cis-3-[3-(tert-Butyldimethylsilanyloxymethyl)cyclobutyl]-8-chloroimidazo[1,5-a]pyrazine and trans-3-[3-(tert-butyldimethylsilanyloxynethyl)cyclobutyl]-8-chloroimidazo[1,5-a]pyrazine were prepared according to the general procedure for the preparation for cis-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl toluene-4-sulfonate and trans-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl toluene-4-sulfonate, except tert-butylchlorodimethylsilane was used instead of p-toluenesulfonic anhydride.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][O:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:35][NH:36][CH3:37].C1C[O:41][CH2:40][CH2:39]1>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][O:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[C:40](=[O:41])[CH2:39][N:36]([CH3:37])[CH3:35])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CNC
Reactant: C1CCOC1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCNCc1ccc(CC(=O)OC)cc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1ccc(CC(=O)OC)cc1)C(=O)CN(C)C

Procedure:
The title compound was prepared by the method of example 29 step (vi) with the product of example 29 step (v) (180 mg) and a 2M THF solution of dimethylamine (0.2 ml). The title compound was obtained as a white solid (15 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(Cl)=[S:9].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.[CH:26]([C:29]1[C:30]([O:43][CH2:44][O:45][CH3:46])=[CH:31][C:32]([O:39][CH2:40][O:41][CH3:42])=[C:33]([CH:38]=1)[C:34]([NH:36][NH2:37])=[O:35])([CH3:28])[CH3:27]>O1CCCC1>[CH2:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:8](=[S:9])[NH:37][NH:36][C:34](=[O:35])[C:33]2[CH:38]=[C:29]([CH:26]([CH3:28])[CH3:27])[C:30]([O:43][CH2:44][O:45][CH3:46])=[CH:31][C:32]=2[O:39][CH2:40][O:41][CH3:42])[CH2:14][CH2:15]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: S=C(Cl)Cl
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)NN
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)NNC(=S)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrahydrofuran (5 mL), triethylamine (0.086 mL, 1.25 mmol), thiophosgene (0.042 mL, 0.55 mmol) and 4-amino-1-benzyl-piperidine (0.112 mL, 0.55 mmol) were placed in a 10 mL eggplant shaped flask and stirred at room temperature for 2 hours, and then 5-isopropyl-2,4-bis-methoxymethoxy-benzoic acid hydrazide (IM4-a, 149 mg, 0.5 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. After completing the reaction, the reaction mixture was concentrated under reduced pressure. The residue obtained was subjected to the next reaction without further purification.