Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)([OH:20])[CH3:19]
Reactant: CC(O)(C1CCN(Cc2ccccc2)CC1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CC(O)(C1CCNCC1)C(F)(F)F

Procedure:
To a stirred solution of 2-(1-benzylpiperidin-4-yl)-1,1,1-trifluoropropan-2-ol in methanol (25 mL), palladium on carbon (150 mg, 3.26 mmol) was added under hydrogen atmosphere. The resulting mixture was stirred under reflux for 6 h at 65 C. After completion of the reaction, the mixture was filtered and concentrated under vacuum to afford 1,1,1-trifluoro-2-(piperidin-4-yl)propan-2-ol. [M+H]=198.06
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[C:8]([CH:10]=1)[NH2:9])[CH3:2].CC(C)([O-])C.[K+].[F:25][C:26]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:27]=1[CH2:28]Br.O>CN(C)C=O>[F:25][C:26]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:27]=1[CH2:28][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:10][C:8]=2[NH2:9])=[CH:13][CH:14]=1
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: CCOc1ccc(Oc2ccc(O)cc2)c(N)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(Oc2ccc(OCc3cc(F)ccc3F)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 5-ethoxy-2-(4-hydroxyphenoxy)aniline (3.68 g, 15 mmol) in N,N-dimethylformamide (50 ml) were added potassium tert-butoxide (2.02 g, 18 mmol) and 2,5-difluorobenzyl bromide (3.11 g, 15 mmol), followed by stirring at room temperature overnight. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and after drying, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate-hexane (1:4)] to give the title compound (4.29 g).
Reaction SMILES: [CH2:1]([C:3]1([CH2:33][CH3:34])[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([NH:16][CH3:17])[CH3:15])=[CH:10][CH:9]=2)[N:5]([C:18]([NH:20][C@H:21]([CH2:29][CH2:30][CH3:31])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:19])[C:4]1=[O:32])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:44][O:45][CH2:46][C:47](Cl)=[O:48]>C(Cl)Cl>[CH2:33]([C:3]1([CH2:1][CH3:2])[C@H:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]([CH3:17])[C:47](=[O:48])[CH2:46][O:45][CH3:44])[CH3:15])=[CH:12][CH:13]=2)[N:5]([C:18]([NH:20][C@H:21]([CH2:29][CH2:30][CH3:31])[C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)=[O:19])[C:4]1=[O:32])[CH3:34]
Reactant: COCC(=O)Cl
Reactant: CCC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc([C@H](C)NC)cc1)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc([C@H](C)N(C)C(=O)COC)cc1)c1ccc(C)cc1
Reaction time: 0.25 h
Yield: 97 %

Procedure:
The residue from Step B was taken up in methylene chloride (150 mL) and cooled in an ice bath and diisopropylethylamine (7.0 mL, 40 mmol) was added. A solution of methoxyacetyl chloride (3.5 gm, 32 mmol) in methylene chloride (20 mL) was added over 10 min. The reaction was stirred another 15 min before it was quenched into a mixture of ice water, 2N hydrochloric acid (40 mL) and methylene chloride. The layers were separated and the aqueous layer was extracted with another portion of methylene chloride. The methylene chloride layers were each washed with brine, combined, dried over sodium sulfate and evaporated. The residue was purified by preparative chromatography with 5% methanol/25% ethyl acetate/70% hexanes to give 28 gm (97%) of the title compound.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][N:4]=1.[CH3:9][N:10]([CH2:12][CH2:13][NH2:14])[CH3:11]>C1(C)C(C)=CC=CC=1>[CH3:9][N:10]([CH3:11])[CH2:12][CH2:13][NH:14][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: COc1ccncn1
Reactant: CN(C)CCN
Solvent: Cc1ccccc1C
Product: CN(C)CCNc1ccncn1

Procedure:
A solution of 4-methoxypyrimidine (12.9 g, 0.117 mole) and unsym-dimethylethylene diamine (20.7 g, 0.23 mole) in 40 ml of xylene is heated under reflux for 64 hours. The reaction is concentrated and the oil is distilled at 15 mm of Hg. 4-(2-Dimethylaminoethylamino) pyrimidine, boiling at 164°-169° C., is collected.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7](=[O:17])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:4][CH3:5])[CH3:2].[OH-].[K+].Cl[CH2:21][CH2:22][OH:23]>C(O)C>[CH2:1]([CH:3]([NH:6][C:7](=[O:17])[CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:21][CH2:22][OH:23])=[CH:14][CH:15]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)NC(=O)C=Cc1ccc(O)cc1
Reactant: OCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCC(CC)NC(=O)C=Cc1ccc(OCCO)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
N-(1-Ethyl-propyl)-3-(4-hydroxy-phenyl)-acrylamide (example 76a) (0.44 mmol, 103 mg) was dissolved in absolute ethanol with KOH (0.7 mmol, 37 mg). The mixture was stirred at 80° C. for 1 hr. Then 2-chloro-ethanol (1.76 mmol, 118 μL) was added dropwise and the mixture was refluxed overnight. Following evaporation the crude product was dissolved in dichloromethane and washed with water and 5% citric acid. The organic phase was evaporated and the residue was purified by chromatography on silica gel to give 73 mg of desired product (60%). 1H NMR (500 MHz, CDCl3): δ 0.92-0.95 (t, 6H), 1.25 (s, 1H), 1.40-1.46 (m, 2H), 1.59-1.64 (m, 2H), 3.93-3.94 (m, 1H), 3.95-3.98 (m, 2H), 4.09-4.11 (m, 2H), 5.28-5.30 (d, 1H), 6.26-6.29 (d, 1H), 6.88-6.90 (d, 2H), 7.43-7.45 (d, 2H), 7.56-7.59 (d, 1H). MS (M+H, 278.1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:16][CH:15]([O:17][Si](C(C)(C)C)(C)C)[CH:14]([CH2:25][O:26][Si](C(C)(C)C)(C)C)[C:13]1=[CH2:34].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:16][CH:15]([OH:17])[CH:14]([CH2:25][OH:26])[C:13]1=[CH2:34]
Reactant: C=C1C(CO[Si](C)(C)C(C)(C)C)C(O[Si](C)(C)C(C)(C)C)CC1n1cnc2c(Cl)nc(N)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C1C(CO)C(O)CC1n1cnc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 57 (180 mg, 0.344 mmol) in THF (2 mL) was added tetrabutylammonium fluoride (2 mL of 1 M solution in THF). The reaction mixture was stirred at room temperature for 1 hour. It was poured into DCM (50 mL), washed with water (3×10 mL), dried over sodium sulfate, and concentrated in vacuo to give the title compound (55 mg, 54%).
Reaction SMILES: C([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14])(=O)C.Cl>CO>[NH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(=O)Nc1ccc(C=O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: Nc1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 97.5 %

Procedure:
4-Acetamido-3-nitrobenzaldehyde (2.08 g, 10 mmol) was dissolved in methanol (200 mL). The solution was added with aqueous 2 N HCl (50 mL), and refluxed by heating at 80° C. for 8 hours under an argon flow. The reaction mixture was concentrated under reduced pressure to remove the methanol, and the residue was made basic with aqueous 2 N NaOH, and extracted 5 times with dichloromethane. The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the target compound as yellow solid (1.62 g, yield: 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[C:14]([C:18]([C:23]2[N:24]=[CH:25][N:26]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]=2)([OH:22])[CH:19]([CH3:21])[CH3:20])[CH:15]=[CH:16][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[CH:17]=[CH:12][CH:13]=[C:14]([C:18]([C:23]3[N:24]=[CH:25][N:26]([C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:27]=3)([OH:22])[CH:19]([CH3:20])[CH3:21])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)C(O)(c1cccc(-c2ccc(Cl)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 69.9 %

Procedure:
By the reaction in the same manner as in Example 1-(i) using 4-chlorophenylboronic acid (0.49 g) and 1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.04 g), the title compound (0.77 g) was obtained as a coloress solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>CN(C=O)C.CCOC(C)=O>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[CH:9]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 70 °C
Reaction time: 0.12 h

Procedure:
To a solution of (3-Hydroxy-phenyl)-carbamic acid tert-butyl ester (2.4 g, 11.4 mmol) in 5 ml of dry DMF, anhydrous potassium carbonate (7.9 g, 57.416 mmol) was added. The mixture stirred for 5-10 minutes, added ethyl-2-bromo-isobutyrate (4.5 g, 22.9 mmol). The resulting mixture was heated at 70° C. for 12 hours. Upon completion (˜25 h), the solution was diluted with EtOAc (25 ml) and washed with saturated NH4Cl (5 ml). The aqueous layer was then extracted for two additional times with EtOAc (10 ml) and the combined organic fractions were washed with brine (2×5 ml). The solution was then dried over Na2SO4 and concentrated to give brown oil. Purification on silica gel (hexanes/acetone) yielded 1.8 g (49%). 1H-NMR (400 MHz, CDCl3): δ 1H NMR (400 MHz, CDCl3): 1.26 (t, J=7.2 Hz, 3H), 1.50 (s, 9H), 1.59 (s, 6H), 6.43 (s, 1H), 6.47-6.50 (m, 1H), 6.96 (t, J=8.4 Hz, 2H), 7.11 (t, J=8.0, 1H).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[O:17]=[C:6]1[C:5](=[CH:4][NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]3[N:30]=[CH:31][CH:32]=[CH:33][N:34]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7]1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-pyrimidin-2-yl-benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ11.18 (d, 1H), 10.94 (s, 1H), 9.28 (s, 1H), 8.52 (d, 1H) 8.08 (d, 1H), 7.99 (d, 1H), 7.84 (d, 1H), 7.6 (d, 1H), 7.13 (d, 1H), 7.06 (m, 1H), 7.01 (m, 1H),; APCI−MS m/z 449 (M−H)−.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](C)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([CH2:36][CH3:37])=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:36]([C:33]1[N:32]=[CH:31][C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:38])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:35][CH:34]=1)[CH3:37]
Reactant: CCc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M174) (287 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (184 mg, 82%).
Reaction SMILES: [CH3:1][C:2]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]2[CH:7]=[N:8][C:9]([CH2:19]Cl)=[C:10]([O:11]CC3C=CC=CC=3)[C:5]=2[CH2:4][O:3]1.[CH3:25][NH:26][CH3:27]>C1C=CC=CC=1>[CH3:1][C:2]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]2[CH:7]=[N:8][C:9]([CH2:19][N:26]([CH3:27])[CH3:25])=[C:10]([OH:11])[C:5]=2[CH2:4][O:3]1
Reactant: CNC
Reactant: CCCCC1(C)OCc2c1cnc(CCl)c2OCc1ccccc1
Solvent: c1ccccc1
Product: CCCCC1(C)OCc2c1cnc(CN(C)C)c2O
Yield: 48 %

Procedure:
The method of example 1 was repeated, but starting with 1,3-dihydro-3-methyl-3-n-butyl-6-chloromethyl-7-benzoxy-furo-(3,4-c)-pyridine and dimethylamine dissolved in benzene. Yield 48% of an oily product, elemental analysis of which showed a good correspondence with the formula C14H22N2O2.HCl.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:22]=[C:21]2[C:12]([N:13]3[C:18]([CH2:19][O:20]2)=[N:17][NH:16][C:15](=[O:23])[C@H:14]3[CH3:24])=[CH:11][C:10]=1[C@@H:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]1[CH3:31].C=O.[BH3-][C:35]#N.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:22]=[C:21]2[C:12]([N:13]3[C:18]([CH2:19][O:20]2)=[N:17][NH:16][C:15](=[O:23])[C@H:14]3[CH3:24])=[CH:11][C:10]=1[C@@H:25]1[CH2:30][CH2:29][N:28]([CH3:35])[CH2:27][C@@H:26]1[CH3:31]
Reactant: [BH3-]C#N
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4c(F)cccc4F)c([C@@H]4CCNC[C@@H]4C)cc3N21
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4c(F)cccc4F)c([C@@H]4CCN(C)C[C@@H]4C)cc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a mixture of (R)-7-(2,6-difluoro-phenyl)-4-methyl-6-((3R,4R)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.005 g, 0.012 mmol) in AcOH (0.2 mL) and MeOH (2 mL) was added paraformaldehyde (0.004 g, 0.117 mmol) and the reaction mixture was stirred at ambient temperature for 1 h. NaBH3CN (0.002 g, 0.029 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. Aqueous saturated NaHCO3 solution (30 mL) was added and the reaction mixture was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative TLC (eluting with 20% MeOH in EtOAc) to give (R)-7-(2,6-difluoro-phenyl)-6-((3R,4R)-1,3-dimethyl-piperidin-4-yl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.0041 g, 79%). 1H NMR (400 MHz, CD3OD): 7.47-7.54 (m, 1H), 7.13 (t, J=7.91 Hz, 2H), 6.96 (s, 1H), 6.89 (s, 1H), 4.94-4.96 (m, 1H), 4.67 (m, 2H), 3.58 (m, 1H), 2.89-3.11 (m, 3H), 2.82 (s, 3H), 2.44-2.60 (m, 2H), 2.26-2.42 (m, 1H), 1.94 (m, 2H), 1.51 (d, J=6.4 Hz, 3H), 0.94 (d, J=7.4 Hz, 3H). LC/MS (Table 1, Method 4) Rt=1.656 min.; MS m/z: 441 [M+H]+. SFC (Table 2, Method 28), Rt=4.708 min.
Reaction SMILES: [NH2:1][C:2]([CH2:8][O:9][CH3:10])([CH2:5][O:6][CH3:7])[CH2:3][OH:4].[Cl:11][C:12]1[S:16][C:15]([C:17](Cl)=[O:18])=[CH:14][CH:13]=1>C1COCC1>[OH:4][CH2:3][C:2]([NH:1][C:17]([C:15]1[S:16][C:12]([Cl:11])=[CH:13][CH:14]=1)=[O:18])([CH2:8][O:9][CH3:10])[CH2:5][O:6][CH3:7]
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: COCC(N)(CO)COC
Solvent: C1CCOC1
Product: COCC(CO)(COC)NC(=O)c1ccc(Cl)s1
Temperature: 0 °C

Procedure:
1.14 g (6.16 mmol) 2-amino-3-methoxy-2-methoxymethyl-propan-1-ol are suspended in 9 ml THF, cooled in the ice bath and combined with 2.56 ml (18.4 mmol) TEA. 1.12 g (6.19 mmol) 5-chlorothiophene-2-carboxylic acid chloride are dissolved in 6 ml THF and added dropwise. After 1.5 h the mixture is filtered and the filtrate is concentrated by evaporation i.vac. Then it is purified by chromatography through RP material (Microsorb C18 Varian; eluant:water/acetonitrile/trifluoroacetic acid=90:10:0.1=>0:100:0.1).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]=1.[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH2:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:25]2[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:23][CH2:24]2)=[CH:5]1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: BrCCC1=CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(NC1CCN(CCC2=CCc3ccccc32)CC1)c1ccccc1

Procedure:
3-(2-Bromoethyl)indene (1.12 g.), 4-benzamidopiperidine (1.02 g.) and potassium carbonate (1.38 g.) were heated under reflux in isopropanol (25 ml.) for 24 hours. The mixture was filtered and the filtrate was evaporated. Trituration of the residue with ether gave a solid which was recrystallised twice from aqueous ethanol to provide the title compound, m.p. 148°-149° C. (Found: C, 79.7; H, 7.6; N, 8.0. C23H26N2O requires C, 79.7; H, 7.6; N, 8.1%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]([CH3:20])=[C:12]3[C:21]#[N:22])[CH:9]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=1.Cl[S:31]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[C:21]([C:12]1[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=[C:2]3[NH:1][S:31]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=[O:33])=[O:32])[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]=1[CH3:20])#[N:22]
Reactant: CCOC(=O)CCS(=O)(=O)Cl
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCS(=O)(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 200 mg (0.512 mmol) tert-butyl 3-amino-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 3A) in dichloromethane (4 ml) were added 309 mg (1.54 mmol) ethyl 3-(chlorosulfonyl)propanoate and 0.21 ml (1.54 mmol) triethylamine. The mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with saturated aqueous sodium hydrogencarbonate solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient) to yield 41 mg (14% of th.) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH3:16])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([N:15]([CH3:16])[C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=2)=[O:33])=[CH:22][CH:21]=1
Reactant: CN(C(=O)CN(C(=O)CN)c1ccccc1)c1ccc(F)cc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccc(F)cc2)c2ccccc2)c1
Yield: 48.7 %

Procedure:
The procedure is analogous to that described in Example 1, but 2.6 g of 2-(2-amino-N-phenylacetamido)-N-(4-fluorophenyl)-N-methylacetamide and 1.1 g of 3-methylphenyl isocyanate are used as the starting material. The crude product obtained is purified by chromatography on 60 g of silica (0.065-0.200 mm) contained in a column 2.0 cm in diameter [eluent: ethyl acetate/cyclohexane (50-50 by volume)], collecting 30 cm3 fractions. Fractions 6 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from ethyl acetate, 1.8 g of N-(4-fluorophenyl)-N-methyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 135° C is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:26])[N:13]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[N:15]2)=[CH:10][C:9]=1[O:27][CH3:28].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37]Cl)[CH2:31][CH2:30]1>CN(C)C=O>[CH3:28][O:27][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:8]=1[O:7][CH2:37][CH2:36][CH2:35][N:32]1[CH2:33][CH2:34][O:29][CH2:30][CH2:31]1)[N:15]=[CH:14][N:13]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[C:12]2=[O:26]
Reactant: ClCCCN1CCOCC1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 65.4 %

Procedure:
Potassium carbonate (4.51 g) was added to 7-hydroxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (2.0 g) in dimethylformamide (50 ml) followed by 3-morpholinopropyl chloride (1.3 g) and the reaction was stirred at 100° C. for 6 hours. After cooling the solid was removed by filtration and the filtrate was evaporated and was purified by eluting through a silica column with 10% methanol in methylene chloride to yield 6-methoxy-7-(3-morpholinopropoxy)-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one as a solid (1.85 g, 65%); NMR: 1.1 (s, 9H), 1.9 (m, 2H), 2.4 (broad m, 6H), 3.55 (m, 4H), 3.88 (s, 3H), 4.16 (m, 2H), 5.89 (s, 2H), 7.13 (s, 1H), 7.47 (s, 1H), 8.32 (s, 1H); m/s: M+H+ 434.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[CH:29]12[O:34][CH:33]1[CH2:32][O:31][CH2:30]2>CCOC(C)=O>[OH:34][CH:29]1[CH2:30][O:31][CH2:32][CH:33]1[O:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: C1OCC2OC12
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC2COCC2O)cc(-c2ccc(C)cc2)c1
Temperature: 110 °C

Procedure:
A stirred mixture of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (370 mg, 1.4 mmol), potassium carbonate (421 mg, 3.05 mmol), DMSO (8 mL), and 3,6-dioxabicyclo[3.1.0]hexane (260 mg, 3.0 mmol) was heated at 110° C. overnight. After cooling, the reaction mixture was diluted with EtOAc. The organic phase was washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([NH2:11])[CH:9]=[CH2:10]>O1CCCC1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][NH:11][CH2:8][CH:9]=[CH2:10])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: C=CCN
Solvent: C1CCOC1
Product: C=CCNCC(=O)OCC
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 46.9 %

Procedure:
A solution of ethyl bromoacetate 52 (3 g, 18.0 mmol) in dry tetrahydrofuran (20 cm3) was added dropwise to an ice-cold solution of allylamine 53 (2.05 g, 36 mmol) in dry tetrahydrofuran (20 cm3) over 3 min. The solution was stirred at 0° C. for 2.5 h (a white precipitate was observed after 2 h), concentrated in vacuo and suspended in diethyl ether. The white suspension was filtered through Celite™ and the solvent removed to yield the crude product which was purified by chromatography (silica gel, 1:1, hexane:ethyl acetate) to give alkene 54 (1.209 g, 47%) as a light yellow oil: δH (300 MHz; CDCl3; Me4Si) 1.17 (3H, t, J 7.1, OCH2CH3), 1.70 (1H, br s, N—H), 3.16 [211, d, J 5.9, CH2(allyl)], 3.28 (2H, s, CH2Gly), 4.08 (2H, q, J 7.1, OCH2CH3), 4.98-5.12 (2H, m, ═CH2) and 5.70-5.85 (1H, m, C(H)═CH2); δC (75 MHz; CDCl3) 13.9 (CH3, OCH2CH3), 49.7 (CH2), 51.6 (CH2), 60.4 (CH2, OCH2CH3), 116.2 (CH2, ═CH2), 135.9 (CH, C(H)═CH2) and 172.2 (quat., CO).