Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].BrC[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.C(O)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:37]4[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Reactant: BrCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCc3ccncc3)cc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
The phenol was dissolved in DMF (5 mL) at room temperature. Sodium hydride (60% in oil) was added and the mixture allowed to stir 30 min. 4-Bromomethyl-pyridine was added and the reaction was allowed to stir over night. Ethanol was added and the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (2/98 methanol/dichloromethane—5/95 methanol/dichloromethane gradient) to afford the product.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(#N)C.O>[N:12]1([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1O
Temperature: 50 °C
Reaction time: 40 h
Yield: 86.7 %

Procedure:
5-Fluoro-2-nitro-phenol (3.05 g, 19.4 mmol; Alfa Aesar) in Acetonitrile (20 mL) was treated with Morpholine (3.6 mL, 41 mmol) under an atmosphere of Nitrogen. After 40 h at rt, the mixture was heated at 50° C. for 6 h to drive to completion. The mixture was concentrated to ca. ½ volume, precipitate formed and the mixture was diluted with 100 mL water. The solids were collected and washed 2×50 mL water then dried to afford 5-Morpholin-4-yl-2-nitro-phenol as a yellow solid (3.77 g, 87%). 1H-NMR (DMSO): 7.88 (d, 1H, J=9.6 Hz), 6.64 (dd, 1H, J=2.4, 9.6 Hz), 6.43 (d, 1H, J=2.4 Hz), 3.70 (t, 4H, J=4.8 Hz), 3.41 (t, 4H, J=4.8 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[N:20][CH:19]=3)[C:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C:10]=3[C:4]=2[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>ClCCl>[CH3:15][N+:12]1([O-:33])[CH2:13][CH2:14][C:9]2[N:8]([CH2:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[C:10]=2[CH2:11]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C)C1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CC[N+](C)([O-])C1
Reaction time: 24 h
Yield: 41.9 %

Procedure:
Dimebon (500 mg) was dissolved in 10 mL dichloromethane. To this was added a solution of mCPBA (65%, 536 mg) in 5 mL dichloromethane drop wise at 25 deg C. The reaction mixture was stirred at 25 deg C. for 24 h at which point it was found complete (by TLC and LCMS). The solvent was removed under reduced pressure (below 30 deg C.) and the residue was purified by column chromatography on neutral alumina eluting with methanol-dichloromethane gradient to obtain 220 mg of product as light brown oil. TLC Rf 0.5 in 5% MeOH-DCM. This compound also exhibited the following inhibition profile:
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43](O)=[O:44])=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[NH2:55][C@@H:56]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([O:68][CH:69]([CH3:71])[CH3:70])=[CH:64][CH:63]=1)[C:57]([O:59][CH3:60])=[O:58]>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:55][C@@H:56]([CH2:61][C:62]3[CH:63]=[CH:64][C:65]([O:68][CH:69]([CH3:71])[CH3:70])=[CH:66][CH:67]=3)[C:57]([O:59][CH3:60])=[O:58])=[O:44])=[CH:31][CH:32]=2)[N:27]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC(C)C)cc1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OC(C)C)cc1)NC(=O)c1ccc2c(N3CCN(C)CC3)nc(N)nc2c1
Reaction time: 0.17 h
Yield: 39.5 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (20 mg, 0.052 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) in N,N-dimethylformamide (2 mL) and N,N-diisopropylethylamine (12 uL, 0.070 mmol). The reaction was stirred for 10 min, and the methyl (2S)-2-amino-3-(4-isopropoxyphenyl)propanoate (16 mg, 0.070 mmol) was added. The reaction mixture was stirred for 2 h. at r.t. and was purified by RP-HPLC (pH=2) to afford the desired product (6 mg, 30%) as a white solid TFA salt. Analytical LCMS (M+H)+: m/z=507.0.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>O1CCCC1>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:35]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: COc1ccccc1N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-methoxyphenyl isocyanate (0.162 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 219 mg (68.2%) of the desired product as a solid.
Reaction SMILES: [NH3:1].C1COCC1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22](Cl)=[O:23])[N:15]=1>O1CCCC1>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([NH2:1])=[O:23])[N:15]=1
Reactant: N
Reactant: O=C(Cl)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Solvent: C1CCOC1
Product: NC(=O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Saturated NH3/THF solution (130 ml) cooled to 0° C. via cannula slowly over 10 min is then added to a suspension of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoyl chloride (Compound A2, 8.0 g, 26.43 mmol) in anhydrous tetrahydrofuran (80 mL) cooled to −78° C. The mixture is stirred for 30 minutes, warmed to room temperature and stirred for 16 h. The solvent is concentrated in vacuo and the resulting white residue is washed several times with water. The wet solid is dried in a vacuum oven for two days to give 7.06 g (94%) of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzamide (Compound A3) as a white solid: mp 231-234° C.; 1H NMR (300 MHz, DMSO-d6) δ 6.10 (br d, J=9.7 Hz, 2H) 7.28-7.39 (m, 2H), 7.64 (t, J=7.8 Hz, 2H), 8.07 (d, J=7.8 Hz, 1H), 8.24 (t, J=7.5 Hz, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.58 (t, J=1.8 Hz, 1H); MS m/z 284.12, calcd for C15H10FN3O2 (MH+) 284.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[O:14])[N:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccccc2n1
Reaction time: 4 h

Procedure:
To a solution of ethyl 4-chloroquinazoline-2-carboxylate (0.6 g, 2.53 mmol) in THF (6 mL) at −40° C., was added dropwise a 1 M solution of 4-fluorophenylmagnesium bromide in THF (3 mL, 3.0 mmol, 1.2 eq). The mixture was stirred at −40 C for 4 h. The reaction was quenched by adding 0.5 N HCl solution (5 mL) and the mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine and dried over MgSO4. The crude product was purified on a silica gel column using a mixture of EtOAc-hexanes as eluent. (4-chloroquinazoline-2-yl)(4-fluorophenyl)methanone was obtained as a light yellow solid (440 mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ 7.45-740 (m, 2H), 8.07-8.03 (m, 1H), 8.17-8.13 (m, 2H), 8.23 (m, 2H), 8.42 (d, 1H); LC-MS (ESI) m/z 287 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(Oc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, phenol and DBU in dioxane. EI-MS m/e (%): 333 (M{81Br}+, 64), 331 (M{79Br}+, 68), 252 ([M—Br]+, 100), 159 (98).
Reaction SMILES: [CH3:1][O:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5]>CO>[CH:7]1([C@@H:3]([O:2][CH3:1])[C:4]([OH:6])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CO[C@@H](C(=O)O)c1ccccc1
Solvent: CO
Product: CO[C@@H](C(=O)O)C1CCCCC1
Reaction time: 1 h

Procedure:
An autoclave is charged with a solution of 1.00 g of (R)-α-methoxy-phenyl acetic acid in 20 ml methanol. 0.100 g of Nishimura catalyst are added and the mixture is hydrogenated at 4 bar and 20° C. for 1 hour. The mixture is filtered over Hyflo and the filtrate concentrated by evaporation to provide the title compound as a colourless oil. The crude material is used without further purification. Rf=0.84 (150:54:10:1 dichloromethane-methanol-water-acetic acid)
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([S:56]([NH:59][CH3:60])(=[O:58])=[O:57])[CH:44]=[CH:45][C:46]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([S:56]([NH:59][CH3:60])(=[O:58])=[O:57])[CH:44]=[CH:45][C:46]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CNS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNS(=O)(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c(OC)c1
Yield: 80.4 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with 3-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (72 mg, 0.22 mmol), sodium carbonate (23 mg, 0.22 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (21 mg, 0.03 mmol) in 1,2-dimethoxyethane (1.60 ml) and water (0.40 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 46 mg (73% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4](F)[C:3]=1[N+:23]([O-:25])=[O:24].C([O-])(=[O:28])C.[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([OH:28])[C:3]=1[N+:23]([O-:25])=[O:24]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c([N+](=O)[O-])c2F)c1=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c([N+](=O)[O-])c2O)c1=O
Temperature: 100 °C

Procedure:
30 g of 3-[4-chloro-2,6-difluoro-3-nitrophenyl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione were dissolved in 100 ml of absolute dimethylformamide, admixed with 25.2 g of sodium acetate and heated at 100° C. for four hours. After cooling, the solvent was removed under reduced pressure and the residue was admixed with water; by addition of dilute hydrochloric acid, the pH was taken into the acidic range, and the mixture was extracted with methyl tert-butyl ether (three times 75 ml). The product of value was obtained as a mixture with the isomer formed by exchange of the fluorine atom which is in the position para to the nitro group. Total yield: 28.3 g. The crude product was purified at the subsequent stage (intermediate 7).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:22]([Cl:25])=[CH:23][N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])=[O:6].[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>>[Cl:25][C:22]1[C:4]([C:5]([NH:7][CH:8]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=2)[CH3:9])=[O:6])=[CH:3][C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])=[N:24][CH:23]=1
Reactant: CCC(=O)Cl
Reactant: CC(NC(=O)c1cc(N)ncc1Cl)c1ccc(OCC(F)(F)F)nc1
Product: CCC(=O)Nc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)c(Cl)cn1
Yield: 44 %

Procedure:
The title compound is prepared in 44% yield (10 mg) from 2-amino-5-chloro-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide (20 mg, 0.053 mmol, single enantiomer, Step-1) and propionyl chloride (6 mg, 0.080 mmol) by the similar manner in Step-2 of Example-8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH2:12][CH:11]([C:13]([OH:15])=O)[C:8]2([CH2:10][CH2:9]2)[C:7]1=[O:16].[CH2:23]([C@@H:30]1[CH2:34][O:33][C:32](=[O:35])[NH:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.Cl.O>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:23]([C@@H:30]1[CH2:34][O:33][C:32](=[O:35])[N:31]1[C:13]([CH:11]1[C:8]2([CH2:9][CH2:10]2)[C:7](=[O:16])[N:6]([CH2:5][C:4]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:3]=2[O:2][CH3:1])[CH2:12]1)=[O:15])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: COc1ccc(CN2CC(C(=O)O)C3(CC3)C2=O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(CN2CC(C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)C3(CC3)C2=O)c(OC)c1
Reaction time: 4 h

Procedure:
To a solution of 5-(2,4-dimethoxybenzyl)-4-oxo-5-azaspiro[2.4]heptane-7-carboxylic acid (1.59 g) in chloroform (16 ml) were sequentially added (R)-4-benzyl-2-oxazolidinone (1.11 g), WSC.HCl (1.20 g) and N,N-dimethyl-4-aminopyridine (318 mg) at room temperature, and the mixture was stirred for 4 hours. To this reaction mixture was added water, and the organic layer was separated from the solution, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to separate a low-polarity component as the titled compound (1.39 g).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][C:9]1([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17](C2CCCCO2)[N:16]=[C:15]3[C:27]2[N:32]=[C:31]([O:33][C@H:34]3[CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38][C:35]43[CH2:37][CH2:36]4)[CH:30]=[N:29][CH:28]=2)[CH2:11][CH2:10]1>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH2:37]1[C:35]2([CH2:38][CH2:39][NH:40][CH2:41][C@@H:34]2[O:33][C:31]2[N:32]=[C:27]([C:15]3[C:14]4[C:18](=[CH:19][CH:20]=[C:12]([C:9]5([CH3:8])[CH2:11][CH2:10]5)[CH:13]=4)[NH:17][N:16]=3)[CH:28]=[N:29][CH:30]=2)[CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C5(C)CC5)cc34)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2ccc3[nH]nc(-c4cncc(O[C@H]5CNCCC56CC6)n4)c3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
TFA (1.7 mL, 22.07 mmol) was added to a solution of (4R)-tert-butyl 4-(6-(5-(1-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (96.3 mg, 0.172 mmol) in DCM (1.7 mL) and the resulting solution was stirred at 25° C. for 2 h. The mixture was concentrated in vacuo and the residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% CH3CN/H2O+0.1% TFA, 15 min, 254 nm) to provide 3-(6-((4R)-6-azaspiro[2.5]oct-4-yloxy)-2-pyrazinyl)-5-(1-methylcyclopropyl)-1H-indazole 2,2,2-trifluoroacetate (64.6 mg, 0.132 mmol, 77% yield) as a yellow solid: 1H NMR (400 MHz, MeOH) δ ppm 9.02 (1 H, s), 8.26-8.33 (1H, m), 8.17-8.22 (1 H, m), 7.54 (1 H, d, J=8.8 Hz), 7.43 (1 H, dd, J=8.7, 1.5 Hz), 5.09 (1H, s), 3.90 (1 H, d, J=13.1 Hz), 3.60 (1 H, d, J=12.3 Hz), 3.47-3.55 (1 H, m), 3.33-3.39 (1 H, m), 2.65-2.77 (1 H, m), 1.49 (3 H, s), 1.23 (1 H, d, J=14.7 Hz), 1.01 (1 H, dt, J=9.7, 5.1 Hz), 0.90-0.95 (2 H, m), 0.82-0.90 (3 H, m), 0.75-0.81 (1 H, m), 0.64-0.73 (1 H, m). 19F NMR (377 MHz, MeOH) δ ppm −77.48 (3 F, s). MS (ESI, pos. ion) m/z: 376.3 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1.[CH2:15]([O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[O:21][CH2:22][CH:23]([OH:26])[CH2:24][NH2:25])[CH:16]=[CH2:17]>C(O)(C)C>[CH2:15]([O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[O:21][CH2:22][CH:23]([OH:26])[CH2:24][NH:25][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:14])=[C:9]([C:10](=[O:11])[NH2:12])[CH:13]=1)[CH:16]=[CH2:17]
Reactant: NC(=O)c1cc(OCCBr)ccc1O
Reactant: C=CCOc1ccccc1OCC(O)CN
Solvent: CC(C)O
Product: C=CCOc1ccccc1OCC(O)CNCCOc1ccc(O)c(C(N)=O)c1
Reaction time: 1 h

Procedure:
A mixture of 6.5 g of 5-(2-bromoethoxy)salicylamide and 8.9 g of 1-(2-allyloxyphenoxy)-3-aminopropan-2-ol is melted in an oil bath at 100° and stirred for 1 hour using a magnetic stirrer. The working up is carried out analogously to Example 11 and yields 1-(2-allyloxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]propan-2-ol having a melting point of 147°-148° (from isopropanol).
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([O:24]C)=[O:23])[CH:17]=[CH:18][C:19]=1[OH:20]>CO.O>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([OH:24])=[O:23])[CH:17]=[CH:18][C:19]=1[O:20][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: CC(C)Cc1ccc(CCl)cc1
Solvent: CO
Solvent: O
Product: CC(C)Cc1ccc(COc2ccc(CC(=O)O)cc2Cl)cc1

Procedure:
3-chloro-4-(4'-isobutylbenzyloxy) phenylacetic acid was prepared in accordance with the procedure designated (f) above by reacting 4-isobutylbenzyl chloride and methyl 3-chloro-4-hydroxyphenylacetate. The resultant product evidenced a melting point of 97°-99° C. (methanol-water 4:1), the yield being 61%.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][CH:16]=[CH:15][C:14]=3[C:18]=2[OH:19])=[O:9])=[CH:4][CH:3]=1.[Cl-].[CH2:23]=[N+:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:15][C:14]=3[C:18]=2[OH:19])=[O:9])=[CH:20][CH:21]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1ccc2sccc2c1O
Reactant: C=[N+]1CCOCC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(NCc1ccc(Cl)cc1)c1ccc2sc(CN3CCOCC3)cc2c1O
Yield: 71.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-4-hydroxy-1-benzothiophene-5-carboxamide (Preparation 14, 0.15 g), 4-methylenemorpholin-4-ium chloride (0.13 g), and anhydrous acetonitrile (5 mL) is heated at reflux for 2 hours. Upon cooling, a saturated solution of sodium bicarbonate is added until the pH=9 and this solution is partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated to give a pink oil. Chromatography on a Biotage column eluting with 20% ethyl acetate in heptane (250 mL) and 50% ethyl acetate in heptane (500 mL) affords 140 mg (76%) of the title compound as a white solid. Physical characteristics: Mp 200° C.; MS (ESI+) for C21H21ClN2O3S m/z 417 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:9][CH:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:44][N:43]1[C:39]([C:2]2[S:6][CH:5]=[C:4]([C:7]([NH:9][CH:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])[CH:3]=2)=[CH:40][CH:41]=[N:42]1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: CC(C)(C)OC(=O)NCC(NC(=O)c1csc(Br)c1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1cc(C(=O)NC(CNC(=O)OC(C)(C)C)c2ccccc2)cs1
Temperature: 80 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
To a solution of 1,1-dimethylethyl (2-{[(5-bromo-3-thienyl)carbonyl]amino}-2-phenylethyl)carbamate (250 mg, 0.588 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (325 mg, 2.35 mmol), tetrakistriphenylphosphine Pd(0) (34 mg, 29.4 μmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (126 mg, 0.647 mmol). The reaction mixture was heated to 80° C. in a sealed tube. After 5 h, additional tetrakistriphenylphosphine Pd(0) (34 mg, 29.4 μmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (126 mg, 0.647 mmol) were added. After 12 h, the reaction solution was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organics were dried (Na2SO4), concentrated under vacuum and purified on silica gel (1% MeOH in DCM) to give the title compound (250 mg, quant.) as an orange oil: LCMS (ES) m/z=427.