Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:60]1([CH2:66][CH2:67][NH2:68])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][CH2:67][CH2:66][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NCCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NCCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 2-phenylethanamine (58.0 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to give the yellow title compound (198 mg). LC-MS (ES) m/z=459 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH2:35][OH:36])([CH2:33][OH:34])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:13]([C:29]([F:32])([F:31])[F:30])[CH:12]=1)(C)(C)C.[ClH:38].O1CCOCC1>C(Cl)Cl>[ClH:38].[NH2:7][C:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:13]([C:29]([F:30])([F:31])[F:32])[CH:12]=1)([CH2:33][OH:34])[CH2:35][OH:36]
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(OCCCCCc2ccccc2)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(CO)(CO)CCc1ccc(OCCCCCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Compound 5-1 (560 mg) was dissolved in methylene chloride (5 ml), hydrogen chloride-containing dioxane (4 mol/l 5 ml) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (410 mg) as a white powder.
Reaction SMILES: [OH:1][C:2]1(/[CH:8]=[CH:9]/[CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].[CH3:20]I>C1COCC1>[CH3:20][O:1][C:2]1(/[CH:8]=[CH:9]/[CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: OC1(/C=C/COC2CCCCO2)CCOCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(/C=C/COC2CCCCO2)CCOCC1

Procedure:
The desired compound was prepared by addition of a solution in THF of 4-hydroxy-4-[3-(tetrahydropyran- 2-yloxy)-trans-prop-1-enyl]tetrahydro-pyran, prepared as in step 2, to a suspension of NaH in THF, followed by alkylation of the resulting anion with methyl iodide.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]2[C:14]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[C:13](=[O:19])[O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([SH:30])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].[OH-].[Na+]>C(O)(C)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30][CH:11]([C:14]2([C:13]([OH:12])=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: O=C1OC(CCCCc2ccccc2)C12CCCC2
Reactant: COc1ccc(S)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1ccc(SC(CCCCc2ccccc2)C2(C(=O)O)CCCC2)cc1OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 66.7 %

Procedure:
3-(4-Phenylbutyl)-2-oxaspiro[3,4]octan-1-one (2 g, 7.7 mmol) and 3,4-dimethoxybenzenethiol (2 g, 11.7 mmol) are dissolved in isopropanol (30 mL) and cooled to 0° C. A 1 M solution of NaOH (9.7 mL, 9.7 mmol) is added slowly, and after 5 minutes at 0° C., the reaction is allowed to stir at room temperature overnight. The solvent is removed in vacuo and the residue is dissolved in CH2Cl2 (100 mL). This solution is washed with 1 N HCl (50 mL), brine (30 mL) and dried over MgSO4. The solution is concentrated in vacuo and the crude product is purified by column chromatography (silica, 1% MeOH in CH2Cl2) to yield 1-[1-(3,4-dimethoxyphenylsulfanyl)-5-phenylpentyl]-cyclopentanecarboxylic acid (2.2 g, 65%). 1H NMR (300 MHz, CDCl3) δ 7.28-7.23 (m, 2H), 7.18-7.09 (m, 3H), 7.01-6.91 (m, 2H), 6.76 (d, J=8.1 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.31 (dd, J=10.0, 3.0 Hz, 1H), 2.58-2.51 (m, 2H), 2.18-2.08 (m, 2H), 1.89-1.40 (m, 12H); MS (EI) m/e 428 (M+).
Reaction SMILES: C([N:8]1[C:16]2[C:15]([Cl:17])=[N:14][C:13]([Cl:18])=[N:12][C:11]=2[CH:10]=[CH:9]1)C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-].C(Cl)(Cl)Cl>ClC1C=CC=CC=1Cl>[Cl:18][C:13]1[N:14]=[C:15]([Cl:17])[C:16]2[NH:8][CH:9]=[CH:10][C:11]=2[N:12]=1
Reactant: Clc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Clc1nc(Cl)c2[nH]ccc2n1
Temperature: 160 °C

Procedure:
To a suspension of 5-benzyl-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (177 mg, 0.64 mmol) in 1,2-dichlorobenzene (20 mL) was added AlCl3 (852 mg, 6.4 mmol). The reaction mixture was heated at 160° C. for 1.5 h, during which the reaction mixture became dark and homogeneous. Upon completion of the reaction, the reaction mixture was cooled, added CHCl3 and washed with NH4Cl. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Added Hexanes and filtered off the product as purple solids (100 mg, 80%) and used for the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:43]=[N:44][CH:45]=[C:46](Br)[CH:47]=1)[CH3:38]>>[CH2:37]([O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:43]=[N:44][CH:45]=[C:46]([C:27]2[CH:26]=[CH:25][C:17]([C:18](=[O:19])[NH:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:16][C:15]=2[CH2:14][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]([CH:11]2[CH2:12][CH2:13]2)=[O:10])[CH:47]=1)[CH3:38]
Reactant: CC(C)(C)NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Reactant: CCOC(=O)Cc1cncc(Br)c1
Product: CCOC(=O)Cc1cncc(-c2ccc(C(=O)NC(C)(C)C)cc2CN(Cc2ccccc2)C(=O)C2CC2)c1

Procedure:
3-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-N-tert-butyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide and (5-bromo-pyridin-3-yl)-acetic acid ethyl ester were reacted as described in Example 3, Step 6 to provide (5-{2-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-tert-butylcarbamoyl-phenyl}-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])(=[O:13])=[O:12])[CH2:8][C@H:7]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)=O)C.[NH2:33][C:34]1([C:37]#[N:38])[CH2:36][CH2:35]1>>[C:37]([C:34]1([NH:33][C:4]([C@@H:6]2[CH2:10][C@@H:9]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Cl:21])(=[O:13])=[O:12])[CH2:8][C@H:7]2[CH2:22][O:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[O:3])[CH2:36][CH2:35]1)#[N:38]
Reactant: N#CC1(N)CC1
Reactant: CCOC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)C[C@H]1COCc1ccc(OC)cc1
Product: COc1ccc(COC[C@@H]2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)cc1

Procedure:
The title compound was prepared in analogy to example 68 step 10 and 11 using (1R,2R,4S)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(4-methoxy-benzyloxymethyl)-cyclopentanecarboxylic acid ethyl ester (example 153 step 8) and 1-amino-cyclopropanecarbonitrile. Light yellow oil (80%). MS (EI): 521.2 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]=2[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3].C(N(CC)CC)C.[CH2:33](Br)[CH:34]=[CH2:35]>CN(C=O)C>[CH2:35]([N:18]1[CH2:17][CH2:16][N:15]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5][N:4]3[CH2:2][CH3:3])=[CH:9][C:10]=2[F:21])[CH2:20][CH2:19]1)[CH:34]=[CH2:33]
Reactant: C=CCBr
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)CC1
Reaction time: 3 h
Yield: 30.3 %

Procedure:
A mixture of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3carboxylic acid hydrochloride (0.18 g), triethylamine (0.12 g), allyl bromide (0.09 g), and DMF (3 ml) was heated with stirring at 90° for 3 hours and the solvent was evaporated. The residue was dissolved in 2N sodium hydroxide solution. The alkaline solution was adjusted to pH 7 with aqueous acetic acid and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was recrystallized from a mixture of DMF and ethanol to give 7-(4-allyl-1-piperazinyl)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.055 g), mp 227°-230° C. (decomp.).
Reaction SMILES: N[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[BrH:13].N([O-])=O.[Na+]>O.[Cu]Br>[Br:13][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)Cc2cccc(N)c2O1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)Cc2cccc(Br)c2O1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, 10.0 grams (0.061 mole) of 7-amino-2,3-dihydro-2,2-dimethylbenzofuran was stirred and cooled in an ice-water bath. To this was added 17.4 mL (0.153 mole) of aqueous 48% hydrobromic acid, followed by the dropwise addition of a solution of 4.2 grams (0.061 mole) of sodium nitrite in 50 mL of water. The reaction mixture temperature was maintained at below 10° C. throughout the addition. In a separate reaction vessel, a stirred mixture of 4.8 grams (0.034 mole) of copper(I) bromide and 4.2 mL (0.037 mole) of aqueous 48% hydrobromic acid was heated to 60°-70° C., and the diazonium salt prepared above was added slowly dropwise. Upon completion of addition, the reaction mixture was warmed to 80° C. where it was stirred for one hour. After this time the reaction mixture was allowed to cool to ambient temperature as it stirred for about 18 hours. The reaction mixture was poured into 300 mL of water and the mixture was extracted with two 200 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 7.0 grams of 7-bromo-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=1[CH2:31][C:32]([O:34][CH3:35])=[O:33].CCN(C(C)C)C(C)C.[CH2:45]([Si:47]([C:52]#[CH:53])([CH2:50][CH3:51])[CH2:48][CH3:49])[CH3:46]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:48]([Si:47]([C:45]#[C:46][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=1[CH2:31][C:32]([O:34][CH3:35])=[O:33])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH3:49]
Reactant: COC(=O)Cc1c(Br)cccc1C(F)(F)F
Reactant: C#C[Si](CC)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[Si](C#Cc1cccc(C(F)(F)F)c1CC(=O)OC)(CC)CC
Temperature: 90 °C

Procedure:
A mixture of CuI (0.005 g, 0.03 mmol), PdCl2(PPh3)2 (0.009 g, 0.01 mmol), PPh3 (0.017 g, 0.065 mmol) and methyl 2-(2-bromo-6-(trifluoromethyl)phenyl)acetate (A91) (0.213 g, 0.717 mmol) in DMF (2.0 mL) was degassed with nitrogen for several minutes before the addition of DIPEA (2.00 mL, 11.5 mmol) and (triethylsilyl)acetylene (0.50 mL, 2.8 mmol). The resulting mixture was then degassed with nitrogen before heating under microwave irradiation at 90° C. for 2×20 minutes. The volatiles were evaporated under reduced pressure and the residue purified using silica gel column chromatography (0-10% EtOAc in petroleum benzine 40-60° C.) to give a mixture of product and starting material. To this material, CuI (0.013 g, 0.068 mmol), PdCl2(PPh3)2 (0.013 g, 0.019 mmol), PPh3 (0.030 g, 0.114 mmol), DMF (4.0 mL), DIPEA (2.00 mL, 11.5 mmol) and (triethylsilyl)acetylene (0.50 mL, 2.8 mmol) were added. The resulting mixture was heated at 100° C. for 30 minutes then concentrated under reduced pressure and the residue purified using silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 5-10% EtOAc in petroleum benzine 40-60° C.) to give the title compound A92 (0.175 g, 69%); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=7.7 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.35 (m, 1H), 4.09 (m, 2H), 3.68 (s, 3H), 1.03 (t, J=7.9 Hz, 9H), 0.67 (q, J=7.9 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([NH2:34])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:23]=2)=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=1>>[CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([NH:34][C:41]([C:38]2[CH:39]=[CH:40][C:35]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:36][CH:37]=2)=[O:42])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:23]=2)=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(Cc1cc(Cl)c2cccnc2c1OCc1ccccc1)c1cccc(CN2CCCC2)c1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: O=C(NC(Cc1cc(Cl)c2cccnc2c1OCc1ccccc1)c1cccc(CN2CCCC2)c1)c1ccc(-c2ccccc2)cc1
Yield: 18 %

Procedure:
To a stirring solution of [8-(benzyloxy)-5-chloroquinolin-7-yl]acetaldehyde (10.54 mmol) in tetrahydrofuran (75 mL) at −78° C. was slowly added a 0.25M solution of [3-(1-pyrrolidinylmethyl)phenyl]magnesium bromide in tetrahydrofuran (12.50 mmol, 1.2 eq.) and stirring at −78° C. was continued for 20 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution (10 mL) and allowed to warm to room temperature. The mixture was then diluted with saturated aqueous ammonium chloride solution (65 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give 2-(8-benzyloxy-5-chloro-quinolin-7-yl)-1-(3-pyrrolidin-1-ylmethyl-phenyl)-ethanol as a yellow oil that was purified by column chromatography using 70/29/1 dichloromethane/acetone/diisopropylethylamine. The 2-(8-benzyloxy-5-chloro-quinolin-7-yl)-1-(3-pyrrolidin-1-ylmethyl-phenyl)-ethanol was subjected to the general conditions described above for conversion of alcohols to azides to give 7-[2-Azido-2-(3-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-8-benzyloxy-5-chloro-quinoline. 7-[2-Azido-2-(3-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-8-benzyloxy-5-chloro-quinoline (5.34 mmol) was subjected to the general conditions described above for Staudinger reduction of azides to give 2-(8-Benzyloxy-5-chloro-quinolin-7-yl)-1-(3-pyrrolidin-1-ylmethyl-phenyl)-ethylamine an amber oil and was used directly in the ensuing step. 2-(8-Benzyloxy-5-chloro-quinolin-7-yl)-1-(3-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (0.675 mmol) was subjected to the general conditions described above for N-acylation with 4-biphenylcarbonyl chloride to give an off-white solid which was purified by twice recrystallizing from dichloromethane/hexanes to give the title compound as a white solid (0.311 mmol, 18% for 4 steps). MS (ESI) m/z 652.5; HRMS: calcd for C42H38ClN3O2+H+, 652.27253; found (ESI, [M+H]+ Obs'd), 652.2730.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[NH:22][CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:17][CH:16]=1)=[O:13]>ClCCl>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][NH:22][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][C:12]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:6][CH2:7]2)=[O:13])=[CH:20][CH:19]=1)=[O:29]
Reactant: CC(C)(C)CCNC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: C1CN(CC2CC2)CCN1
Solvent: ClCCl
Product: CC(C)(C)CCNC(=O)c1ccc(OC(=O)N2CCN(CC3CC3)CC2)cc1
Reaction time: 16 h

Procedure:
The title product was prepared from 1-cyclopropylmethylpiperazine (0.35 mmol) dissolved in dichloromethane (5 ml). 4-(3,3-dimethyl-butylcarbamoyl)-phenyl chloroformate (0.35 mmol) was added at room temperature. The reaction mixture was stirred for 16 h and evaporated to dryness and subjected to preparative HPLC (metod C) (5%, white crystals). HPLC-MS m/z=388.2 (M+1), Rt: 2.43 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37].[O:38]1[CH2:40][CH2:39]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[OH:38][CH2:39][CH2:40][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: C1CO1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1OCCO
Yield: 14.8 %

Procedure:
The title compound was prepared according to the procedure described in Example 15 by using N-(4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (5 g, 10 mmol), oxirane (5.8 mL, 100 mmol) and K2CO3 (2.74 g, 2 mmol) in DMF/H2O (24 mL/6 mL). The crude product was purified by a silica gel column chromatography (DCM/MeOH=30/1) to give the title compound as a pale white solid (0.8 g, 15%).
Reaction SMILES: C([O:5][C:6](=[O:32])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[N:18]=[C:19]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[N:20]=[CH:21][C:22]=3[N:23]=2)=[CH:11][CH:10]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][C:19]1[N:20]=[CH:21][C:22]2[N:23]=[C:15]([C:12]3[CH:11]=[CH:10][C:9](/[CH:8]=[CH:7]/[C:6]([OH:32])=[O:5])=[CH:14][CH:13]=3)[O:16][C:17]=2[N:18]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc1
Yield: 122 %

Procedure:
A solution of 145 mg of (E)-3-{4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-phenyl}-acrylic acid tert-butyl ester in 2 ml of dichloromethane and 1 ml of trifluoroacetic acid was stirred at room temperature for 1.5 h. Then the mixture was concentrated in vacuo and freeze-dried. 154 mg of the title compound were obtained. LC/MS (method LC1): Rt=1.25 min; m/z=378.08 [M+H]+
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1([F:32])[O:25][C:24]2[CH:26]=[CH:27][C:28]([CH:30]=O)=[CH:29][C:23]=2[O:22]1>>[F:32][C:21]1([F:20])[O:25][C:24]2[CH:26]=[CH:27][C:28]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:29][C:23]=2[O:22]1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC1(F)Oc2ccc(CN3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2O1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2,2-difluoro-1,3-benzodioxole-5-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Phenomenex Luna C18 100A, 10 m silica, 21 mm diameter, 150 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][C:9]1[C:18]2[C:12]([CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][CH:10]=1.[S:19](=O)(=[O:22])([OH:21])[OH:20].[OH-].[Na+:25]>>[CH3:8][C:9]1[CH:10]=[C:11]([S:19]([O-:22])(=[O:21])=[O:20])[C:12]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2.[Na+:25]
Reactant: Cc1ccc2cccccc1-2
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(S(=O)(=O)[O-])c2cccccc1-2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Acetic anhydride in an amount of 10 ml is added to 1.0 g. of 1-methylazulene under cooling with ice-water, sulfuric acid in an amount of 3.4 g. is added dropwise and the reaction mixture is stirred for 4 hours at 0° C. Then, the reaction mixture is alkalized to pH8-9 by adding 40% of sodium hydroxide solution and the generated solid is collected and dried. The product is recrystalized from 95% ethanol to give 1.1 g. of the objective compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][CH:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[C:54]1([N:60]=[C:61]=[O:62])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][CH:47]1[CH2:51][CH2:50][N:49]([C:61]([NH:60][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:62])[CH2:48]1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(CC1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)Nc2ccccc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 44 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyrrolidin-3-ylacetamide tris(trifluoroacetate) and phenyl isocyanate as starting materials in 44% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.42 (m, 2H), 9.07 (s, 1H), 8.32 (m, 2H), 8.21 (s, 1H), 8.13 (s, 1H), 7.68 (s, 1H), 7.50 (d, 2H), 7.31 (d, 1H), 7.20 (m, 2H), 7.07 (d, 1H), 6.89 (m, 1H), 3.60 (m, 2H), 3.40 (m, 1H), 3.12 (m, 1H), 2.99 (m, 4H), 2.60 (m, 1H), 2.09 (m, 2H), 1.67 (m, 2H). LCMS for C30H30ClN8O2 (M+H)+: m/z=569.2.