Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([CH2:14][NH2:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:1]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][NH:15][S:30]([CH3:29])(=[O:32])=[O:31])([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(C2CCCCC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNS(C)(=O)=O)(C2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 92.8 %

Procedure:
A 15-mL, round-bottomed flask was purged with nitrogen and then charged with the amine from Step A (0.063 g, 0.213 mmol), 1.7 mL of methylene chloride, and triethylamine (0.045 mL, 0.320 mmol). The reaction mixture was cooled at 0° C. in an ice-water bath and then methanesulfonyl chloride (0.018 mL, 0.23 mmol) was added dropwise via syringe. The resulting mixture was stirred at 0° C. for 50 min, warmed to room temperature, and stirred for 16.5 h. The reaction mixture was then diluted with methylene chloride and washed with two portions of 1N HCl solution, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (1:1 methylene chloride-acetone) to give the desired product (0.074 g) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[NH:16][CH2:17][CH2:18][CH3:19].[Li+].[OH-]>C1COCC1.CO>[CH2:17]([NH:16][C:7]1[CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:20])=[O:2])[CH2:18][CH3:19]
Reactant: CCCNc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCNc1cc(C(F)(F)F)ccc1C=CC(=O)O
Yield: 85.9 %

Procedure:
3-(2-Propylamino-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (67.3 mg, 0.234 mmol) was reacted with aqueous 1N LiOH solution (5 ml) in THF/CH3OH (10 ml/5 ml) for 1 hr. The reaction solvent removed in vacuo. Water (30 ml) was added to the resulting residue, which was neutralized with 1N HCl solution, an then extracted with ethyl acetate (30 ml×3). The combined organic layer was dried over MgSO4 and concentrated in vacuo to yield title compound (55 mg, 0.201 mmol, 86%).
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:27])[CH2:8][CH:9]([C:13]2[C:18]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:17]([CH3:23])[C:16]([CH3:24])=[C:15]([CH3:25])[C:14]=2[CH3:26])[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:29]([O:31][NH2:32])[CH3:30]>>[CH2:29]([O:31][N:32]=[C:1]([C:6]1[C:7](=[O:27])[CH2:8][CH:9]([C:13]2[C:18]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:17]([CH3:23])[C:16]([CH3:24])=[C:15]([CH3:25])[C:14]=2[CH3:26])[CH2:10][C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4])[CH3:30]
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)c(C)c(C)c(C)c2S(C)(=O)=O)CC1=O
Reactant: CCON
Agent: Cl
Product: CCCC(=NOCC)C1=C(O)CC(c2c(C)c(C)c(C)c(C)c2S(C)(=O)=O)CC1=O

Procedure:
2-[1-(Ethoxyimino)butyl]-3-hydroxy-5-(6-methylsulfonyl-2,3,4,5-tetramethylphenyl)cyclohex-2-en-1-one (57) was prepared from 2-butyryl-3-hydroxy-5-(6-methylsulfonyl-2,3,4,5-tetramethylphenyl)cyclohex-2-en-1-one and ethoxyamine hydrochloride following essentially the same procedure as that described in Example 1, part (iv). The product was characterized by proton nuclear magnetic resonance spectroscopy and the spectroscopic data is reported in Table 5, Example 37.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:43])([C:39]([F:42])([F:41])[F:40])[C:21]([F:38])([F:37])[C:22]([F:36])([F:35])[O:23][C:24]([F:34])([F:33])[C:25]([F:32])([F:31])[C:26]([F:30])([F:29])[CH2:27][OH:28]>>[CH2:1]([O:8][CH2:9][C@@H:10]([OH:12])[CH2:11][O:28][CH2:27][C:26]([F:29])([F:30])[C:25]([F:31])([F:32])[C:24]([O:23][C:22]([F:35])([F:36])[C:21]([F:37])([F:38])[C:20]([F:43])([F:19])[C:39]([F:42])([F:41])[F:40])([F:34])[F:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: c1ccc(COC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O[C@H](COCc1ccccc1)COCC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 120 °C
Reaction time: 3 h

Procedure:
(R)-Benzylglycidyl ether (2.0 g, 12.2 mmol, prepared essentially as described by Byun et al. in Tet. Lett. 30, 2751 (1989)) was added dropwise to a 120° C. solution of potassium carbonate (0.17 g, 1.2 mmol) in 4-nonafluorobutoxy-2,2,3,3,4,4-hexafluoro-1-butanol (5.1 g, 12.2mmol). The resulting mixture was stirred for 3 hours at 120° C. and was then cooled to ambient temperature and distilled (0.6 torr, 110°-130° C.) to give 6.25 g of 1-benzyloxy-(R)-2-hydroxy-3-(4-(nonafluorobutoxy)-2,2,3,3,4,4-hexafluorobutoxy)propane.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:19][CH:18]=1>CN(C=O)C>[CH2:3]([C:7]1[N:8]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[CH:21][CH:22]=2)[C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under protective gas, 1.6 g (0.053 mol) of sodium hydride (80% strength) are suspended in 50 ml of DMF, 10 g (0.053 mol) of 2-butyl-5-formyl-4-chloroimidazole (preparation according to EP 324,377) in 100 ml of DMF are added dropwise at 0° C., then the mixture is stirred at 0° C. for 15 min and 18.9 g (0.053 mol) of tertbutyl 2-(4-bromomethylphenyl)-2-cyclopentylacetate in 100 ml of DMF are added dropwise. The mixture is stirred for 2 h at 0° C., the solvent is evaporated, the residue is taken up in diethyl ether, the solid is filtered off and, after concentration, the residue is chromatographed on silica gel 60 using dichloromethane. Yield: 16.2 g (66.7% of theory) Solidification point: 101°-102° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].FC(F)(F)S(O[C@@H:22]([CH2:30][CH3:31])[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])(=O)=O.C(OCC)(=O)C>C(#N)C>[CH:11]([C:10]1[CH:9]=[C:8]([CH:15]=[CH:14][CH:13]=1)[O:7][C@H:22]([CH2:30][CH3:31])[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[O:12]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCCOC(=O)[C@H](CC)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCOC(=O)[C@@H](CC)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (473 mg) was added to a solution of 3-hydroxybenzaldehyde (418 mg) in acetonitrile (10 mL). Subsequently, n-butyl (S)-2-trifluoromethanesulfonyloxybutyrate (1.0 g) was added to the mixture, followed by stirring at room temperature for 12 hours. Ethyl acetate was added to the reaction mixture, and the resultant mixture was washed sequentially with water and saturated brine, followed by drying over sodium sulfate anhydrate. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate=4/1), to thereby yield 904 mg of a colorless, oily substance (99.9%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH2:4][C:5]#[N:6].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.O=P(Cl)(Cl)Cl>CCOCC>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:1][CH2:2][C@@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH2:4][C:5]#[N:6]
Reactant: C1=COCCC1
Reactant: N#CC[C@@H](CO)c1ccccc1F
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC[C@@H](COC1CCCCO1)c1ccccc1F
Reaction time: 0.08 h

Procedure:
To a solution of β(R)-(hydroxymethyl)-β-(2-fluorophenyl)-propionitrile (210 g, 1.18 mol) in Et2O (200 ml), is added 3,4-dihydro-2H-pyran (225 ml, 2.68 mol) at ambient temperature. The mixture is stirred for 5 minutes and POCl3 (5 mL) is added dropwise. The reaction mixture is stirred for 30 minutes at ambient temperature and then refluxed for 2 hours. The resulting solution is allowed to cool and the solvent is removed in vacuo. The residue is then chromatographed (EtOAc/hexane, 1:4) to give β(R)-[[(tetrahydropyran-2-yl)oxy]methyl]-β(2- fluorophenyl)-propionitrile as an oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:9][C:8]=1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)=O.[C:28]([C@:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)#[CH:29].C(N(CC)CC)C.N>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.[Cu]I.CN(C)C=O>[CH2:19]([C:8]1[CH:9]=[C:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:11]=[CH:12][C:7]=1[C:29]#[C:28][C@:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: O=C1CCCN1c1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCCN1c1ccc(C#C[C@@]2(O)CN3CCC2CC3)c(Cc2ccccc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 32.9 %

Procedure:
To a mixture of 200 mg of 2-benzyl-4-[2-pyrrolidinon-1-yl]phenyl trifluoromethanesulfonate (Production Example 5), 80 mg of (3R)-3-ethynyl-3-quinuclidinol (Production Example 22), 30 mg of tetrakis(triphenylphosphine)palladium (0), 5 mg of copper (I) iodide and 0.2 ml of triethylamine was added 1 ml of N,N-dimethylformamide, followed by heating under stirring under nitrogen atmosphere in an oil bath at 80° C. for 3 hours. After standing to cool, aqueous ammonia was added to the reaction mixture, which then was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by NH-silica gel column chromatography with ethyl acetate, to give 66 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([NH2:17])=O)=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]#[N:17])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: NC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Yield: 39 %

Procedure:
A solution of 7-chloro-3-(aminocarbonyl)pyrazolo[3,4-c[1]benzazepine-4,10(1H,9H)-dione (590 mg, 2.03 mmol) (compound of Example 14) in phosphorous oxychloride (2.56 mL) was refluxed for 70 minutes. The excess phosphorous oxychloride was distilled off at atmospheric pressure and 106° C. To the remaining dark brown residue was added water (40 mL). The aqueous phase was extracted with ethyl acetate (4×50 mL). The organic layers were combined and dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator to give the title compound as a broaqvgold solid (≈216 mg, 39% yield, m.p. 370° C. dec.).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]2[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([F:12])[C:5]=2[O:4][CH2:3]1.[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH:15]1([NH:1][C@@H:2]2[CH2:7][C:6]3[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([F:12])[C:5]=3[O:4][CH2:3]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCC1
Reactant: COc1ccc(F)c2c1C[C@@H](N)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(F)c2c1C[C@@H](NC1CCCC1)CO2
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a solution of (R)-3-amino-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (0.7 g, 3.4 mmol), cyclopentanone (0.7 g, 8.3 mmol) and HOAc (0.2 g, 3.5 mmol) in methanol (25 mL), NaCNBH3 (0.7 g, 10 mmol) was added in portions at room temperature. The solution was stirred at room temperature over night. The methanol was evaporated. The residue was dissolved in EtOAc and washed with water. The organic layer was dried with Na2SO4 and the solvent was evaporated to give 0.9 g (100% yield) of the title compound as a colourless oil. GC indicated 99.6 purity. GC/MS (70 eV) M=265 (30%).
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:19][C:20]1([CH2:24][OH:25])[CH2:23][O:22][CH2:21]1>>[CH3:19][C:20]1([CH2:24][O:25][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:23][O:22][CH2:21]1
Reactant: CC1(CO)COC1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Product: CC1(COc2ncc(C#Cc3ccccc3)cn2)COC1

Procedure:
The title compound, yellow solid, MS: m/e=281.1 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and (3-methyl-oxetan-3-yl)-methanol by using Cs2CO3 as base and dioxane as solvent for 16 hours at 100° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2/[CH:17]=[CH:18]/[CH3:19])[CH:5]=[CH:6][CH:7]=1.[CH2:21](C([Sn])=C(CCCC)CCCC)[CH2:22]CC>O1CCOCC1.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>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH:21]=[CH2:22])[C:3]2=[O:20])=[C:9](/[CH:17]=[CH:18]/[CH3:19])[CH:10]=1)([O-:16])=[O:15]
Reactant: C/C=C/c1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cccn(-c2ccc([N+](=O)[O-])cc2/C=C/C)c1=O

Procedure:
929 mg (2.77 mmol) of the compound from Example 44A are dissolved in 14 ml of anhydrous dioxane, and 64 mg (0.06 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. At room temperature, 1.06 g (3.33 mmol) of tributylvinyl tin are added slowly, and, after the addition has ended, the mixture is heated at reflux for 21 h. The reaction solution is allowed to cool and is filtered through kieselguhr. The filter cake is then washed with ethyl acetate, and the combined organic filtrates are concentrated to dryness under reduced pressure. The product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate=4:1). This gives 568 mg (70% of theory) of the desired product.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:42])[CH2:14][N:15]([CH2:38][CH2:39][CH2:40][CH3:41])[C:16]([N:18]([CH2:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@@H:27]1[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][N:18]([CH2:19][CH2:20][CH2:21][CH3:22])[C:16](=[O:17])[N:15]([CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:42])[CH2:38][CH2:39][CH2:40][CH3:41])([OH:33])=[O:32]
Reactant: CCCCN(CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)C(=O)N(CCCC)CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCN(CC(=O)N1CCC[C@@H]1C(=O)O)C(=O)N(CCCC)CC(=O)N1CCC[C@@H]1C(=O)O
Yield: 73.6 %

Procedure:
A solution of 278 mg (0.47 mmol) (R)-1 -[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-1,3-dibutyl-ureido]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 2 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue was dried to give 167 mg (74%) of the title compound as brown foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[C:45]([F:47])[CH:46]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][C:19]=1[NH:31][CH2:32][CH:33]1[CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]1)=[O:17].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:35]1[CH2:34][CH:33]([CH2:32][NH:31][C:19]2[CH:20]=[C:21]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)[CH:22]=[CH:23][C:18]=2[C:16]([NH:15][C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([CH2:5][C:4]4[CH:3]=[C:2]([F:1])[CH:46]=[C:45]([F:47])[CH:44]=4)[CH:7]=3)[NH:11][N:10]=2)=[O:17])[CH2:36]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCC3CN(C(=O)OC(C)(C)C)C3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCC3CNC3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
tert-butyl 3-({[2-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-5-(4-methylpiperazin-1-yl)phenyl]amino}methyl)azetidine-1-carboxylate (289 mg, 0.45 mmol) was dissolved in DCM (3 mL) and TFA (0.7 mL) was added. The resulting reaction solution was stirred overnight at room temperature. The mixture was diluted with DCM and extracted with 10% aqueous NH3. Organic phase was evaporated. Reverse phase column chromatography purification afforded 104 mg of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.ClC1C(C=O)=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:28][CH2:29]C)=[CH:21][CH:22]=2)[N:17]=1>>[CH3:29][O:28][C:20]1[CH:19]=[C:18]2[C:23]([CH:24]=[C:5]([C:4]([OH:3])=[O:14])[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:17]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCOc1ccc2cc(C=O)c(Cl)nc2c1
Product: COc1ccc2cc(C(=O)O)c(-c3ccccc3)nc2c1

Procedure:
Following the procedure of Example 36 (a)-(b) substituting ethylbenzoylacetate in step 36 (a) gave the above named compound. LCMS m/e [M+H]+=280.2
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([C:21]#[N:22])([CH3:20])[CH3:19])[N:13]=2)[CH:3]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([C:21]#[N:22])([CH3:20])[CH3:19])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CC(C)(C#N)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C(C)(C)C#N)n2)c(C(N)=O)nn1
Temperature: 120 °C
Reaction time: 18 h
Yield: 35.2 %

Procedure:
A resealable pressure tube was charged with 6-chloro-4-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide (200 mg, 631 μmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (135 mg, 631 μmol) in NMP (2.00 mL). The reaction mixture was heated in an oil bath with stirring at 120° C. for 18 h. Then added more tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (135 mg, 631 μmol) in small portions during 7 hours and reaction continued for 18 h. The solvent was distilled off under high vacuum. The residue was dissolved in dichloromethane containing few drops of methanol and then purified by flash column (spherical silica 20-45 μM, 50 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2 to yield tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (110 mg, 222 μmol, 35.2% yield) as a yellow foam. 1H NMR (CHLOROFORM-d) δ: 11.48 (s, 1H), 8.82 (br. s., 1H), 8.00-8.11 (m, 1H), 7.62 (t, J=7.9 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 5.53-5.85 (m, 2H), 5.06 (d, J=8.3 Hz, 1H), 4.47 (br. s., 1H), 3.80-3.99 (m, 1H), 1.24-1.93 (m, 23H); LC-MS 495.1 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.O1CCCC1>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[O:8])=[CH:5][CH:4]=1
Reactant: C1=COCCC1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(OC1CCCCO1)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.6 %

Procedure:
In a mixed solvent of dichloromethane and tetrahydrofuran was dissolved 5 g of p-bromomethylbenzoic acid, and 10 g of dihydropyran and 585 mg of pyridinium p-toluenesulfonate were added to the solution and the mixture was stirred at room temperature for 6 hours. The thus-obtained solution was washed with a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of sodium chloride, dried on anhydrous magnesium sulfate and concentrated. The concentrate was recrystallized from a mixed solvent of n-hexane, ethyl acetate and chloroform to obtain 3.8 g of tetrahydropyranyl p-bromomethylbenzoate.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]2[S:18][C:19]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:20][C:21]=2[C:22]([NH2:24])=[O:23])[N:11]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:19]2[S:18][C:17]([NH:16][C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:7][CH3:6])[N:11]=3)=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=2)=[CH:26][CH:27]=1
Reactant: CN(Cc1cccc(Nc2sc(-c3ccc(F)cc3)cc2C(N)=O)n1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cccc(Nc2sc(-c3ccc(F)cc3)cc2C(N)=O)n1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl[(6-{[3-(aminocarbonyl)-5-(4-fluorophenyl)-2-thienyl]amino}pyridin-2-yl)methyl]methylcarbamate (90 mg, 0.197 mmol) in dichloromethane (0.4 mL) was added trifluoroacetic acid (0.4 mL) and the reaction was maintained at room temperature for 1 hour. The volatiles were removed in vacuo and the crude product was purified by reverse phase HPLC (20-90% acetonitrile/water with 0.05% trifluoroacetic acid). The appropriate fractions were diluted with ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (40 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (40 mL) and water (2×40 mL), dried over sodium sulfate, filtered and concentrated to yield the title compound.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:38])[C:29]3[N:33]=[C:32]([CH:34]4[CH2:36][CH2:35]4)[NH:31][C:30]=3[CH:37]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:34]1([C:32]2[NH:31][C:30]3[CH:37]=[C:26]([O:25][C:21]4[N:22]=[CH:23][N:24]=[C:19]([N:14]5[CH2:13][CH2:12][C:5]6([O:4][C:3](=[O:17])[NH:2][C:7]7[N:8]=[CH:9][CH:10]=[CH:11][C:6]6=7)[CH2:16][CH2:15]5)[CH:20]=4)[CH:27]=[C:28]([CH3:38])[C:29]=3[N:33]=2)[CH2:35][CH2:36]1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c(C3CC3)nc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2[nH]c(C3CC3)nc12

Procedure:
41 mg (0.16 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 40 mg (0.13 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-cyclopropyl-4-methyl-1H-benzo[d]-imidazole and 0.08 mL (0.48 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.