Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C([Cl:9])=O)=CC=1.C(N(CC)CC)C.CN(C(C1C=CC=CC=1)C1CCCCC1O)C.[OH-].[K+].[CH3:38][N:39]([CH:41]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH:43]1[O:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)[CH3:40]>C(Cl)Cl>[ClH:9].[CH3:38][N:39]([CH:41]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH:43]1[O:48][C:49](=[O:58])[C:50]1[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=1)[CH3:40]
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: CN(C)C(c1ccccc1)C1CCCCC1O
Agent: COc1ccc(C(=O)OC2CCCCC2C(c2ccccc2)N(C)C)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cl
Reaction time: 15 h

Procedure:
1.06 g (6.43 mmole) of 4-methoxybenzoyl chloride were dissolved in 4 ml methylene chloride, and 870 mg (8.57 mmole) triethylamine were added at −10° C. (methanol/ice cooling bath). 1.0 g (4.29 mmole) of the 2-(dimethylamino-phenylmethyl)cyclohexanol prepared according to Example 2 (1st stage), dissolved in 2 ml methylene chloride, was then added dropwise, and the mixture was subsequently stirred for 15 hours. For working up, 2 ml potassium hydroxide solution (0.5 N) were added, and the organic phase was separated, dried over sodium sulfate, filtered and concentrated on a rotary evaporator (500 to 10 mbar). 1.78 g of crude base were obtained. 1.00 g of the hydrochloride of [2-(dimethylaminophenylmethyl)-cyclohexyl]4-methoxybenzoate (58% of theoretical) with a melting point above 230° C. was obtained from the crude base in accordance with Example 1 (4th stage) using chlorotrimethylsilane/water in 2-butanone.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([NH:15][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NC1CCCC1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Clc1ncc(Br)c(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.2 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (45.6 g, 200 mmol) in dioxane (400 mL) was added N-cyclopentylamine (20.4 g, 240 mmol) at room temperature. The mixture thus obtained was stirred at room temperature for 6 h. The reaction mixture was then diluted with ethyl acetate and washed with brine and dried over MgSO4. The solvent was evaporated to give the title compound as a light yellow solid (56 g, 100%) which was used in next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 8.23 (1H, s), 7.37 (1H, d, J=7.3 Hz), 4.31 (1H, m), 1.92 (2H, m), 1.71 (2H, m), 1.53-1.59 (4H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 276.0, Calculated 275.9.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)[N:3]=1.Br[CH2:17][CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:21][O:20][CH:19]([O:22][CH3:23])[CH2:18][CH2:17][N:12]1[CH:13]=[C:8]([C:4]2[N:3]=[N:2][CH:7]=[CH:6][CH:5]=2)[C:9](=[O:15])[NH:10][C:11]1=[O:14]
Reactant: COC(CCBr)OC
Reactant: O=c1[nH]cc(-c2cccnn2)c(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(CCn1cc(-c2cccnn2)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.7 %

Procedure:
A mixture of 5-pyridazin-3-yl-1H-pyrimidine-2,4-dione hydrochloride (Prep121, 656 mg, 2.89 mmol), 3-bromo-1,1dimethoxy-propane (609 mg, 3.33 mmol) and K2CO3 (400 mg, 2.89 mmol) in DMSO (10 ml) was stirred for 24 hours at room temperature. 3-Bromo-1, 1dimethoxy-propane (100 mg, 0.55 mmol) was then added and the reaction was left for 11 days at room temperature. 3-Bromo-1,1dimethoxy-propane (100 mg, 0.55 mmol) was further added and stirring continued for additional 6 days. The mixture was lyophilized and the residue washed with diethyl ether and filtrate. The solid washed with ethyl acetate. After evaporation of the organic phase, 200 mg of the title compound as a light brown powder was obtained (24% yield).
Reaction SMILES: [C:1]([C:3]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[N:2].[OH-].[K+].O>CC(O)C>[C:1]([C:3]1([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][C:12]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)C1(c2ccccc2)CCN(C2CCC(C#N)(c3ccc(F)cc3)CC2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: N#CC1(c2ccc(F)cc2)CCC(N2CCC(C(=O)O)(c3ccccc3)CC2)CC1
Yield: 66.4 %

Procedure:
A mixture of 10.9 parts of ethyl 1-[4-cyano-4-(4-fluorophenyl)-1-cyclohexyl]-4-phenyl-4-piperidinecarboxylate, 11.2 parts of potassium hydroxide, 50 parts of water and 96 parts of 2-propanol is stirred and refluxed for 4 hours. The reaction mixture is filtered hot over Hyflo and the filtrate is poured onto 300 parts of water. The whole is neutralized with acetic acid to pH 6-7. The precipitated product is filtered off, washed three times with water and converted into the hydrochloride salt in ethanol and 2-propanol. The salt is filtered off and suspended in a solution of 1.4 parts of potassium hydroxide in 150 parts of water. The free base is extracted four times with 70 parts of 1,1'-oxybisethane. The aqueous phase is separated and stirred for a while on a rotavapor to remove all traces of 1,1'-oxybisethane. The clear aqueous phase is acidified with a 10% acetic acid solution to pH 6. The precipitated product is filtered off, washed with water and dried overnight at about 105° C., yielding 5.4 parts (66.4%) of 1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-4-phenyl-4-piperidinecarboxylic acid; mp. 281.1° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[N:3]1[CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][N:25]2[S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>ClCCl.C(O)(C(F)(F)F)=O>[S:30]([N:25]1[C:26]2[C:22](=[C:21]([CH2:20][N:3]3[C:4]4([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]4)[CH2:5][CH2:6][CH2:7][C:2]3=[O:1])[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1)([C:33]1[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=1)(=[O:31])=[O:32]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCN(C(=O)OC(C)(C)C)CC5)cccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCNCC5)cccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 116 %

Procedure:
To a stirred solution of tert-butyl 2-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,9-diazaspiro[5.5]undecane-9-carboxylate (0.12 g, 0.21 mmol) in dichloromethane (5.0 mL), TFA (0.5 mL) was added at 0° C. and the reaction mixture was stirred for 16 h at rt under a nitrogen atmosphere. The reaction mixture was concentrated to yield the title compound as colourless oil (0.11 g, 95%) which was used in the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:21]1[O:29][CH:22]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[ClH:30]>C(OCC)(=O)C.CS(C)=O>[ClH:30].[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:21][CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:29])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: OC(COC1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 5.00 g of 1-benzyl-4-hydroxypiperidine, 1.97 g of potassium tert-butoxide and 4 ml of dimethyl sulfoxide was heated to 80° C. Thereto was dropwise added 2.10 g of styrene oxide over 40 minutes. The resulting mixture was stirred for 3 hours at the same temperature. The reaction mixture was added to a mixture of 100 ml of ice water and 80 ml of ethyl acetate. The mixture was adjusted to pH 11.5 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=10/1). The resulting oily product was dissolved in 8 ml of ethanol. To the solution were added 1 ml of a 6N dry hydrogen chloride-ethanol solution and 20 ml of diethyl ether. The mixture was stirred for 30 minutes at room temperature. The resulting crystals were collected by filtration, washed with a mixture of 2 ml of ethanol and 2 ml of diethyl ether, and dried to obtain 930 mg of 2-(1-benzylpiperidin-4-yloxy)-1-phenylethanol hydrochloride (compound No. 113).
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([OH:17])[C:15](Br)=[C:8]3[C:9]=2[C:4](=[CH:5][CH:6]=[CH:7]3)[C:3]1=[O:18].C=O.CN.[CH2:23]([N:25](CC)[CH2:26]C)C>O1CCOCC1>[OH:1][N:2]1[C:3](=[O:18])[C:4]2[C:9]3[C:8]([CH:7]=[CH:6][CH:5]=2)=[C:15]2[N:25]([CH3:26])[CH2:23][O:17][C:14]2=[CH:13][C:10]=3[C:11]1=[O:12]
Reactant: CCN(CC)CC
Reactant: O=C1c2cccc3c(Br)c(O)cc(c23)C(=O)N1O
Agent: C=O
Agent: CN
Solvent: C1COCCO1
Product: CN1COc2cc3c4c(cccc4c21)C(=O)N(O)C3=O
Temperature: 25 °C
Reaction time: 220 h
Yield: 32.5 %

Procedure:
To a suspension of 175 mg (0.57 mmol) of 2,5-dihydroxy-6-bromo-benzo[de]isoquinoline-1,3-dione (from Example 125) in 4 mL dioxane was added 0.6 mL (22 mmol) of 37% aqueous formaldehyde, 0.2 mL (2.32 mmol) of 40% aqueous methylamine, and 0.078 mL (0.57 mmol) of triethyl amine. The reaction mixture was stirred at room temperature for 220 hours and quenched with 20 mL water. The precipitate was isolated, washed with water, and dried to yield 50 mg of the title compound, mp 263-265° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[N:4]([NH:14][CH2:15][CH3:16])[C:3]=1[CH3:17].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[C:60](=O)([O-:62])[O-:61].[Na+].[Na+].[C]=O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:15]([NH:14][N:4]1[C:3]([CH3:17])=[C:2]([C:60]([OH:62])=[O:61])[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13])[CH3:16]
Reactant: CCNn1c(C)c(Br)c2cccc(F)c2c1=O
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CCNn1c(C)c(C(=O)O)c2cccc(F)c2c1=O
Temperature: 122 °C
Reaction time: 19 h
Yield: 14.8 %

Procedure:
A stirred suspension of 4-bromo-2-ethylamino-8-fluoro-3-methyl-2H-isoquinolin-1-one (1.526 g, 4.847 mmol), palladium acetate (108.8 mg, 0.4847 mmol), 4,5-bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene (=Xantphos, 280.5 mg, 0.4847 mmol) and sodium carbonate (1.541 g, 14.54 mmol) in toluene (10 mL) was filled with carbon monoxide to 5 bars (6 times). It was stirred on hot oil bath (122° C., P=6 bar) for 19 hours, allowed to cool and the excess CO was released. It was quenched with 20 ml EtOH, filtered and partitioned between 3:1 Ether-EtOAc (3×100 ml) and 5% aq. NaHCO3 (100 ml). Each organic layer was washed with 2×5 ml 5% aq. NaHCO3. The organic solution contained crude unreacted starting material (865 mg). The combined aq. solution was acidified with 3M aq. HCl (pH=0) at 0° C., extracted with ethyl acetate (4×50 ml), each organic layer was washed with sat. aq. NaCl (2×5 ml). The combined org. solution was dried (Na2SO4) and rotovaped to give the pure title compound (190 mg; yield=15%) as a dark solid. LC-MS (m/z) 265.2 (MH+), fragments: 221.4 (M—CO2), 178.7 (M—CO2-EtNH); tR0.74. 1H NMR (500 MHz, DMSO-d6): 1.09 (t, J=7.2 Hz, 3H, Me of Et), 2.51 (s, 3H, Me (overlapped with dmso-d5)), 2.9 (br., 2H, CH2 of Et), 3.4 (very br., H2O+CO2H), 6.18 (br., 1H, NH), 7.25 (dd, J=8.0 Hz, J (H—F)=11.7 Hz, 1H, C7H), 7.44 (d, J=8.2 Hz, C5H), 7.74 (dt, J (d, H—F)=5.1 Hz, J (t)=8.2 Hz, 1H, C6H). 19F NMR (470 MHz, CFCl3=0 ppm): −110.78 (dd, J=4.9 Hz, J=11.5 Hz). 13C APT (125 MHz, DMSO-d5=39.87 ppm): 12.89 (Me of Et), 17.18 (Me), 44.69 (CH2 of Et), 110.46 (s, C), 112.76 (d, J=5.8 Hz, C), 113.18 (d, J=21 Hz, C7H), 120.01 (d, J=3.6 Hz, C5H), 134.44 (d, J=9.9 Hz, C6H), 135.94 (C), 143.13 (C), 157.79 (d, J=4.8 Hz, C), 161.64 (d, J=262 Hz, C8-F), 168.57 (C).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH3:21]>O>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[N:3]1[CH2:20][CH3:21]
Reactant: CCI
Reactant: Cc1ccc2c(c1)NC(C)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCN1c2cc(C)ccc2CCC1C
Yield: 77.6 %

Procedure:
A mixture of 2,7-dimethyl-1,2,3,4-tetrahydroquinoline (48.3 g. 0.3 m), potassium carbonate (41.4 g, 0.3 m), and iodoethane (100 g) was heated at reflux for 4 hrs. Water (200 ml) was added and then the organic layer was extracted using chloroform (100 ml). The organic layer was separated and dried over sodium sulfate. Chloroform and excess iodoethane were distilled off to leave essentially pure product (44 g), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6](CC1C=CC=CC=1)[CH:7]2[CH3:12]>C(O)C.[Pd]>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[CH3:12]
Reactant: CC1c2cccc(N)c2C=CN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC1NCCc2c(N)cccc21
Reaction time: 24 h
Yield: 43.4 %

Procedure:
5-Amino-2-benzyl-1-methyl-1,2-dihydroisoquinoline (4.5 g, 17.9 mmol) was dissolved in ethanol (250 ml); 10% palladium catalyst on activated carbon (1 g) was then added and the mixture hydrogenated at atmospheric pressure for 24 h. The catalyst was then removed by filtration through Kieselguhr and the solvent removed in vacuo to afford a brown solid. This residue was then subjected to column chromatography eluting with 5 to 10% methanol-dichloromethane. The relevant fractions were combined and concentrated in vacuo to afford a brown solid (1.26 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:8]#[N:9])([CH3:3])[CH3:2].O.[SH2:18].[Na].O.O.O.O.O.O.[Cl-].[Mg+2].[Cl-].C(OCC)(=O)C.CCCCCC>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)[C:8](=[S:18])[NH2:9])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C#N)cc(C(F)(F)F)c1
Reactant: S
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc(C(N)=S)cc(C(F)(F)F)c1
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
3-Isopropoxy-5-(trifluoromethyl)benzonitrile (1000 g, 4.3 moles) was dissolved in DMF (4000 mL) and sodium hydrogensulfide hydrate (636 g; 8.6 moles) was added followed by magnesium chloride hexahydrate (960.2 g, 4.7 moles). The reaction mixture was stirred for 1 hr at 25 to 30° C. Reaction completion was monitored by TLC using ethyl acetate:hexane (2:8) as the mobile phase. The reaction mixture was quenched in an ice-water slurry (250 mL) and the pH was adjusted to 5 by addition of 10% aqueous HCl. The reaction mixture was extracted with MTBE and was washed with 20% brine solution. The organic layer was concentrated under vacuum to give 1136 g (4.3 moles; 100%) of the title compound, which was taken as such to next step. HPLC purity—97.37% a/a.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15][NH2:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]#[CH:13].C(N(CC)C(C)C)(C)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:40])[CH2:34][CH:35]([OH:39])[C:36](O)=[O:37])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](=[O:40])[CH2:34][CH:35]([OH:39])[C:36]([NH:16][CH2:15][CH2:14][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]#[CH:13])=[C:4]([O:3][CH3:2])[CH:5]=2)=[O:37])=[CH:31][CH:32]=1
Reactant: C#CCOc1ccc(CCN)cc1OC
Reactant: O=C(CC(O)C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCOc1ccc(CCNC(=O)C(O)CC(=O)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(3-Methoxy-4-prop-2-ynyloxy-phenyl)-ethylamine hydrochloride (5.4 g, 22 mmol) and N,N-diisopropylethylamine (11 g, 83 mmol) are dissolved in 70 ml of N,N-dimethylformamide. To this solution 4-(4-chloro-phenyl)-2-hydroxy-4-oxo-butyric acid (4.8 g, 21 mmol) and (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (10 g, 23 mmol) are added successively. The reaction mixture is stirred for 16 hours at room temperature, subsequently poured on ice-water and extracted several times with ethyl acetate. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated in vacuum. The remaining oil is purified by chromatography on silicagel (ethyl acetate/hexane 6:4) to give 4-(4-chloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-4-oxo-butyramide (Compound E1.10).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:7][CH:6]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C1COCC1>[C:15]([O:14][C:12](=[O:13])[NH:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][OH:3])=[CH:6][N:7]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CO)cn1
Reaction time: 6 h
Yield: 68.1 %

Procedure:
To a stirred solution of 6-tert-butoxycarbonylamino-nicotinic acid ethyl ester (3.50 g, 13.1 mmol) in THF (20 mL) under nitrogen was added LiAlH4 (0.91 g, 24.0 mmol) in THF (20 mL) over a period of 2 h. The reaction mixture was stirred for 6 h, then NH4Cl (sat.) was added (carefully) until neutral solution. The mixture was filtered and concentrated under reduced pressure to give (5-hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (2.00 g 68%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][NH:40][CH3:41]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:40]([CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])[CH3:41])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNCCN(C)C
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CN(C)CCN(C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Yield: 55.8 %

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and N,N,N′-trimethylethylenediamine (200 mg, 1.98 mmol) as starting materials to afford the title compound as a colourless oil (241 mg).
Reaction SMILES: [N+:1](/[C:4](/[CH3:13])=[CH:5]/[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6](/[CH:5]=[C:4](/[N+:1]([O-:3])=[O:2])\[CH3:13])[CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: C/C(=C\c1cccc(O)c1)[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C/C(=C\c1cccc(OCc2ccccc2)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate 1 (23.68 g, 0.13 mol) in dimethylformamide (175 mL) was slowly added sodium hydride (60%, 5.29 g, 0.13 mol). The mixture was stirred at room temperature for 1 hour. Then benzyl bromide (15.72 mL, 0.13 mol) was added into the mixture and was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. The title compound was obtained (26.46 g, 74%) and was used in the next step without further purification. MS (M+): 270.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:22]([NH:24][CH:25]([C:34](=[O:37])[CH2:35]Br)[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16].[F-].[K+].[F:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1.CCCCCC.CCOC(C)=O>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:22]([NH:24][CH:25]([C:34](=[O:37])[CH2:35][O:47][C:44]1[CH:45]=[CH:46][C:41]([F:40])=[CH:42][CH:43]=1)[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16]
Reactant: CC(C)Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CBr)C(C)C)n(C)c2ccccc12
Reactant: Oc1ccc(F)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc2ccc(F)cc2)C(C)C)n(C)c2ccccc12
Yield: 98.4 %

Procedure:
The titled product (72 mg, 100%) was prepared as a white solid as described in Example 82 using the product of Example 81 (68.0 mg, 0.12 mmol), potassium fluoride (15.6 mg, 0.27 mmol), and 4-fluorophenol (13.4 mg, 0.12 mmol) in DMF (2.0 ml) TLC (hexane/EtOAc, 50/50): Rf=0.48.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])[C:6]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH:29]([F:31])[F:30])=[N:5]1.[O:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.[BH3-]C#N.[Na+]>CO>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH:29]([F:30])[F:31])=[C:21]([C:6]2[C:7]([NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[N:17][C:16]=34)=[O:11])=[CH:8][N:4]([CH2:3][CH2:2][NH:1][CH2:37][C:33]3[O:32][CH:36]=[CH:35][N:34]=3)[N:5]=2)[CH:26]=1
Reactant: NCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: O=Cc1ncco1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1cn(CCNCc2ncco2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.3 %

Procedure:
To a solution of N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.22 mmol) in MeOH (15 mL) was added 1,3-oxazole-2-carbaldehyde (21.7 mg, 0.22 mmol), followed by NaBH3CN (16 mg, 0.25 mmol). The resulting solution was stirred at room temperature for 12 h. The resulting mixture was concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 5% MeOH in DCM. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge BEH130 Prep C18 OBD Column, 19&#65533; 100 mm 5 um 13 nm; mobile phase, Water with 10 mM NH4CO3 and ACN (20% ACN up to 50% in 6 min); Detector, UV 254/220 nm. 52.7 mg product was obtained. This resulted in 52.7 mg (45%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[(1,3-oxazol-2-ylmethyl)amino]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 20) [M+H]+=529.2, RT=2.42 min. 1H NMR (300 MHz, CD3OD-d4) δ: (ppm) 9.08 (dd, 1H, J=1.7, 7.1 Hz), 8.66-8.63 (m, 2H), 8.34 (s, 1H), 7.87 (d, 1H, J=0.6 Hz), 7.67 (d, 1H, J=2.7 Hz), 7.53 (dd, 1H, J=2.4, 8.7 Hz), 7.38 (d, 1H, J=8.7 Hz), 7.19 (dd, 1H, J=4.2, 7.2 Hz), 7.13 (d, 1H, J=0.6 Hz), 6.55 (t, 1H, J=73.5 Hz), 4.33 (t, 2H, J=6.0 Hz), 3.95 (s, 2H), 3.14 (t, 2H, J=6.0 Hz).