Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[CH:13]=[CH:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[C:10]=1[CH3:24])=[O:8])C>O1CCCC1.O>[C:7]([C:9]1[CH:13]=[CH:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[C:10]=1[CH3:24])([OH:8])=[O:6]
Reactant: CCOC(=O)c1ccn(-c2ccnc3ccccc23)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)ccn1-c1ccnc2ccccc12
Yield: 98.6 %

Procedure:
2.226 g (53 mmol) of lithium hydroxide monohydrate, in portions of 0.742 g every 24 hours, are added at 20° C. to 2.48 g (8.4 mmol) of 3-ethoxycarbonyl-2-methyl-1-(quinol-4-yl)-1H-pyrrole dissolved in 75 mL of tetrahydrofuran and 75 mL of water. After stirring at reflux for 72 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 40 mL of water and then triturated with 10 mL of 5N hydrochloric acid for 0.2 hour. After filtering off and drying the solid residue under reduced pressure (2.7 kPa) at 40° C., 2.09 g of 3-carboxy-2-methyl-1-(quinol-4-yl)-1H-pyrrole are obtained in the form of a pinkish solid. Mass spectrum (EI): m/e 252 (M+.), m/e 207.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[CH3:16][O-:17].[Na+]>CO>[CH3:16][O:17][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:9]([CH3:11])[N:10]=2)[N:7]=1
Reactant: Cc1nc2ccc(Cl)nn2c1S(N)(=O)=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nc(C)c(S(N)(=O)=O)n2n1
Yield: 99.7 %

Procedure:
To a solution of 4.9 g of 6-chloro-2-methylimidazo [1,2-b]pyridazine-3-sulfonamide in 50 ml of methanol is added 2.2 g of sodium methylate, followed by refluxing for 4 hours. Methanol is distilled off and the residue after addition of water is neutralized with hydrochloric acid. The precipitated crystals are collected by filtration and dried to give 4.8 g of the title compound. mp. 251° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](F)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-:3])=[O:2].[NH2:13][NH2:14]>>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:11]=1[NH:14][N:13]=[C:9]2[NH2:10])([O-:3])=[O:2]
Reactant: NN
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Product: Nc1n[nH]c2c([N+](=O)[O-])cccc12
Temperature: 120 °C
Yield: 438.5 %

Procedure:
A mixture of 5-nitro-2-fluoro-benzonitrile (Aldrich, 1.00 g, 6.02 mmol) in 30% aqueous hydrazine (5.00 mL, 18.1 mmol) was heated to about 120° C. in a sealed tube for about 40 minutes. The mixture was cooled to ambient temperature and the precipitate was filtered off, washed with water (10 mL) and dried under reduced pressure to yield 7-nitro-1H-indazol-3-ylamine (0.470 g, 26.4 mmol); (DMSO-d6, 400 MHz) δ 12.16 (br, 1H), 8.90 (m, 1H), 8.05 (dd 1H), 7.35 (d, 1H), 5.98 (br, 2H); RP-HPLC (Table 1, Method j) Rt 8.07 min.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[C:13](=O)[O:14][C:15](O)([CH3:23])[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)CCC>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[C:13](=[O:14])[NH:2][N:3]=[C:15]([CH3:23])[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(O)OC(=O)C(c2c(F)cccc2F)=C1c1ccccc1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Cc1n[nH]c(=O)c(-c2c(F)cccc2F)c1-c1ccccc1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 60.9 %

Procedure:
0.60 g of hydrazine monohydrate was added dropwise to a mixture of 2.83 g of 3-(2,6-difluorophenyl)-5-hydroxy-5-methyl-4-phenyl-2(5H)-furanone and 15 ml of 1-butanol, followed by stirring at a bath temperature of 110° C. for 2.5 hours. Next, the reaction mixture was cooled to 0° C. The obtained solid was collected by filtration. The collected solid was washed with a mixed solvent (1:1) of hexane and t-butyl methyl ether, and dried under reduced pressure, thereby obtaining 1.70 g of 4-(2,6-difluorophenyl)-6-methyl-5-phenyl-2H-pyridazine-3-one. 1H-NMR (DMSO-d6, TMS) δ (ppm): 2.02 (3H, s), 6.92-6.98 (2H, m), 7.11-7.12 (2H, m), 7.27-7.36 (4H, m), 13.2 (1H, br s)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[N:30]=[CH:29][C:28]2[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=2)[C:22]1=[O:36])(=[O:3])[CH3:2].[N:37]1([CH2:41][C:42]2[N:46]([CH3:47])[N:45]=[C:44]([NH:48][C:49]3[C:50](=[O:57])[N:51]([CH3:56])[N:52]=[C:53](Cl)[CH:54]=3)[CH:43]=2)[CH2:40][CH2:39][CH2:38]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl-].[NH4+]>C(O)CCC.O>[N:37]1([CH2:41][C:42]2[N:46]([CH3:47])[N:45]=[C:44]([NH:48][C:49]3[C:50](=[O:57])[N:51]([CH3:56])[N:52]=[C:53]([C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([N:21]5[N:30]=[CH:29][C:28]6[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:33])([CH3:34])[CH3:32])[CH:27]=6)[C:22]5=[O:36])[C:6]=4[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:54]=3)[CH:43]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1nc(Nc2cc(Cl)nn(C)c2=O)cc1CN1CCC1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CCCCO
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc(CN4CCC4)n(C)n3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
A solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (498 mg, 1.01 mmol), 4-(5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-ylamino)-6-chloro-2-methylpyridazin-3(2H)-one (183 mg, 0.59 mmol), potassium phosphate (315 mg, 1.48 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (28.3 mg, 0.06 mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before (bis[dibenzylideneacetone]dipalladium) (17.0 mg, 0.03 mmol) was added and the resulting solution heated at 100° C. in for 2 h. The resulting mixture was cooled, poured into a saturated solution of ammonium chloride and extracted with methylene chloride (2×100 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was dissolved in dioxane (10 mL) and treated with a lithium hydroxide solution (0.5 mL, 2.0 M), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was poured into a saturated ammonium chloride solution and extracted with methylene chloride (2×150 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 1% to 10% methanol in dichloromethane) to give acetic acid 2-[5-(5-azetidin-1-ylmethyl-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzyl ester (112 mg, 32%) as an off white solid: mp. 214-217° C.; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.55 (m, 10H) 1.72-2.08 (m, 2H) 2.90-3.67 (m, 11H) 4.28-4.62 (m, 3H) 6.08 (s, 1H) 7.22-8.08 (m, 6H) 8.50 (d, J=1.89 Hz, 1H) 9.15 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]1([F:30])[C:27]([F:29])([F:28])[CH2:26][NH:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH2:26][C:27]([F:29])([F:28])[C:23]([F:30])([F:22])[CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: FC1(F)CNCC1(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC(F)(F)C(F)(F)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 3,3,4,4-tetrafluoropyrrolidine hydrochloride (1810-13-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=410.5 [MH+].
Reaction SMILES: [N:1]1([C:9]([CH2:11][N:12]2[C:18]3[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]([CH:24]=O)=[N:15][CH:14]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)=[O:28])[C:13]2=[O:37])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:39]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[N:1]1([C:9]([CH2:11][N:12]2[C:18]3[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]([C:24]#[N:39])=[N:15][CH:14]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)=[O:28])[C:13]2=[O:37])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: Cc1cccc(NC(=O)NC2N=C(C=O)c3cccc(C)c3N(CC(=O)N3CCCCCCC3)C2=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cccc(NC(=O)NC2N=C(C#N)c3cccc(C)c3N(CC(=O)N3CCCCCCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 27.1 %

Procedure:
A mixture of N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-formyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (300 mg), hydroxylamine hydrochloride (41 mg) and sodium acetate (51 mg) in acetic acid (1.5 ml) was stirred at ambient temperature for 2.5 hours. Acetic anhydride (0.4 ml) was added to the reaction mixture, and the resultant mixture was stirred at 90° C. for 11.5 hours. After the reaction mixture was allowed to cool to ambient temperature, ethyl acetate and aqueous sodium hydrogen carbonate were added into the mixture successively under stirring. The separated organic layer was washed with aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to afford a residue, which was subjected to column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (4:1) to give N-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-5-cyano-2,3-dihydro-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea as crystalline powder (80 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1.[C:13]1([C@@H:19]2[O:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CS(C)=O.O.C(Cl)Cl>[OH:21][C@@H:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20][NH:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1
Reactant: NCCCc1ccc(C(N)=O)s1
Reactant: c1ccc([C@H]2CO2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: NC(=O)c1ccc(CCCNC[C@@H](O)c2ccccc2)s1

Procedure:
5-(3-Aminopropyl)-2-thiophenecarboxamide was heated with (S)-phenylethylene oxide at b 95° in dimethyl sulphoxide. The mixture was diluted with water and methylene chloride and the aqueous phase was extracted twice with methylene chloride. The methylene chloride phases were washed with water, dried over sodium sulphate and evaporated in vacuo. Chromatography of the residue with methanol on silica gel gave 5-[3-[[(S)-β-hydroxyphenethyl]amino]propyl]-2-thiophenecarboxamide of melting point 94°-96°; [α]589 =+19° (c=0.1% in dioxan); ε256 =8490; ε275 =10780.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:36]=[C:37]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)[CH3:38].C(O)(=O)C(O)=O>CN(C=O)C.C1COCC1.[Cu]I>[F:45][C:42]1[CH:43]=[CH:44][C:39](/[C:37](/[CH3:38])=[CH:36]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:18][CH2:17][C:5]2=3)=[CH:40][CH:41]=1
Reactant: CN1CCc2[nH]c3ccc(C(F)(F)F)cc3c2C1
Reactant: CC(=CBr)c1ccc(F)cc1
Agent: [Cu]I
Agent: O=C(O)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C/C(=C\n1c2c(c3cc(C(F)(F)F)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (127 mg, 0.5 mmol) was dissolved in DMF. Copper (I) iodide (9.5 mg, 0.05 mmol), L-proline (11.5 mg, 0.1 mmol) and potassium phosphate (212 mg, 1 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (118 mg, 0.55 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 90° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-3% MeOH-DCM. The free base was converted into oxalate salt by treatment of oxalic acid (1 equiv) in THF. Yield: 65 mg as the oxalate salt. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.90 (s, 1H), 7.70 (t, 2H), 7.50 (d, 1H), 7.40 (d, 1H), 7.20 (t, 2H), 7.0 (s, 1H), 4.60 (m, 2H), 3.78 (m, 2H), 3.20 (m, 2H), 3.10 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: CC1(C)COB([C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:10][CH:9]=2)OC1.Br[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[Cl:32])[NH:28][CH:27]=[C:26]2[CH:33]=[O:34].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[Cl:32][C:31]1[CH:30]=[C:29]2[C:25]([C:26]([CH:33]=[O:34])=[CH:27][NH:28]2)=[CH:24][C:23]=1[C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:19][CH:20]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Reactant: CC(=O)NCCOc1ccc(B2OCC(C)(C)CO2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)NCCOc1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Temperature: 110 °C
Yield: 64.1 %

Procedure:
To a solution of N-{2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]ethyl}acetamide (100 mg, 0.35 mmol) in ethanol (1.4 mL) were added 5-bromo-6-chloro-1H-indole-3-carbaldehyde (107 mg, 0.42 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg, 0.036 mmol), 2M aqueous potassium carbonate (2 mol/L, 0.7 mL) and toluene (4.2 mL). The mixture was degassed with nitrogen for 3 min and heated to 110° C. by microwave irradiation for 1 h. The mixture was concentrated in vacuo to give a residue, which was dissolved with ethyl acetate (50 mL) and washed with brine (2×15 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a brown residue, which was purified by flash chromatography (petroleum ether/ethyl acetate=10:1 to 2:1) to give N-{2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]ethyl}acetamide (80 mg, 65%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH2:29][O:28][CH2:27][CH2:26][C:11]=3[N:12]([C:14]([NH:16][C@@H:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]([NH:20]C)=[O:19])=[O:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].N[C@H](C(N)=O)C(C)(C)C>>[NH2:20][C:18](=[O:19])[C@@H:17]([NH:16][C:14]([N:12]1[C:11]2[CH2:26][CH2:27][O:28][CH2:29][C:10]=2[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[N:13]1)=[O:15])[C:22]([CH3:25])([CH3:23])[CH3:24]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(C)(C)C
Agent: CC(C)(C)[C@H](N)C(N)=O
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(N)=O

Procedure:
Compound 99 was prepared according to the procedure for the synthesis of compound 28 by replacing tert-leucine methylamide with tert-leucine amide.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][C:15]3([F:18])[F:17])=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(C(C)C)C(C)C)C.CCCCO>CC#N.O>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][C:15]3([F:18])[F:17])=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CC1(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4(F)F)c23)C1
Temperature: 120 °C
Reaction time: 5 h
Yield: 35.1 %

Procedure:
A sealed tube was charged with N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-difluorocyclopropanecarboxamide (150 mg, 0.449 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (270 mg, 1.35 mmol), N-ethyl-N-isopropylpropan-2-amine (235 μL, 1.35 mmol) and n-BuOH (3 mL). Then N2 was bubbled through the mixture for 5 minutes. The tube was sealed under N2 and stirred at 120° C. for 5 hours and then at 130° C. for 48 hours. The mixture was concentrated in vacuo, and the residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-85% CH3CN/water, 23 CV) to yield tert-butyl(3R)-1-(5-bromo-3-(2,2-difluorocyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (81 mg, 35% yield) as a solid. LCMS (APCI+) m/z 514.1, 516.1 (M+H)+.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)(=[O:8])C1C=CC=CC=1.N1CCCC(C(OCC)=O)C1.ClC([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=O>>[CH2:35]([O:34][C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)=[O:8])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CCOC(=O)C1CCCNC1
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with ethyl nipecotate (209.9 mg; 1.33 mmol and benzyl chloroformate (190 μl; 1.33 mmol). The crude product was distilled at 220° C./0.1 torr, giving ethyl 1-benzyloxycarbonyl-3-piperidinecarboxylate (236.5 mg) as a colorless oil. MS m/Z (positive ion) 539 ([dimer-OEt]+; 50), 337 (M+2Na+; 25), 314 (M+Na+; 50), 292 (MH+; 100), 247.5 (M-OEt; 90), 158 (50).
Reaction SMILES: [N+:1]([CH:4]([CH3:6])[CH3:5])([O-:3])=[O:2].[CH3:7][O:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH:17]=[O:18])=[CH:13][CH:12]=1.[Na].Cl>CO>[CH3:7][O:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH:17]([OH:18])[C:4]([N+:1]([O-:3])=[O:2])([CH3:6])[CH3:5])=[CH:13][CH:12]=1
Reactant: COCCc1ccc(OCC=O)cc1
Reactant: CC(C)[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COCCc1ccc(OCC(O)C(C)(C)[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
39.5 g of 2-nitropropane and 27 g of 4-(2-methoxyethyl)-phenoxy-acetaldehyde are successively added dropwise to a solution of 2 g of sodium in 150 ml of methanol. After the mixture has been stirred at room temperature for 15 hours, the solution is poured onto water and acidified with 2N HCl. Extraction with CHCl3 gives, after crystallisation from diisopropyl ether, 23.3 g of the nitro compound mentioned in the title. Melting point: 92°-94° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:18]C)=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][NH2:27])=[O:25].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.O.C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][NH:27][C:12](=[O:14])[C@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:18])[C@@H:15]([OH:17])[CH3:16])=[O:25]
Reactant: CCc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1cccc(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2cccc(Cl)c2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-ethylphenylamino)-3-hydroxybutanoic acid (800 mg, 2.98 mmol), 3-Chlorobenzhydrazide (508 mg, 2.98 mmol) and anhydrous THF (40 mL) were placed in a 100 mL round bottomed flask and the mixture was cooled to −15° C. 1-Hydroxybenzotriazole hydrate (403 mg, 2.98 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N-ethylcarbodimide HCl (857 mg, 4.47 mmol) at −15° C. followed by triethylamine (0.62 mL, 4.47 mmol). The reaction mixture was maintained at −15° C. and stirred for 1 h after which, stirring continued overnight while the mixture slowly warmed to room temperature. Water (40 mL) was added to the reaction mixture followed by citric acid (4 g) while stirring. EtOAc (60 mL) was then added to the mixture and the phases were partitioned. The organic phase was then washed with saturated aqueous sodium bicarbonate (40 mL) and the organic phase dried (Na2SO4). EtOAc was removed under vacuum and replaced by chloroform (60 mL). The insoluble hydrazide was then separated from the mixture by filtration and dried under reduced pressure to furnish a white solid (855 mg, 68%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.7 (br s, 2H), 7.96 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.46-7.7 (m, 2H), 6.64 (d, J=8.6 Hz, 1H), 5.3 (d, J=7 Hz, 1H), 4.19-4.03 (m, 1H), 3.98-3.87 (m, 1H), 2.35 (s, 3H) and 1.26 (d, J=6.35 Hz, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:9]([C:12]1[C:20]2[O:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH2:27][CH2:28]Br)[CH2:10][CH3:11]>>[CH3:1][C@H:2]1[NH:6][C:5](=[O:7])[N:4]([CH2:28][CH2:27][CH2:26][O:25][C:13]2[CH:14]=[CH:15][C:16]3[C:17]([C:21]([F:23])([F:24])[F:22])=[N:18][O:19][C:20]=3[C:12]=2[CH2:9][CH2:10][CH3:11])[C:3]1=[O:8]
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: C[C@H]1NC(=O)NC1=O
Product: CCCc1c(OCCCN2C(=O)N[C@H](C)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
5(R)-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione was prepared as for Example 10 from 5(R)-methylimidazolidine-2,4-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1.C(N(CC)C(C)C)C.[N:28]1([CH2:34][CH2:35]O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[N:28]1([CH2:34][CH2:35][O:18][C:17]([C:9]2[NH:10][C:11]3[C:16]([C:8]=2[NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:19])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)c1[nH]c2ccccc2c1Nc1ccncc1
Reactant: OCCN1CCCCC1
Agent: CCN(CC)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(OCCN1CCCCC1)c1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 0 °C
Yield: 38.4 %

Procedure:
Stir under N2 at 0° C. a mixture of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid (0.25 g, 1 mmol), benzotriazol-1-yloxytris(pyrrlidino)-phosphonium hexafluorophosphate (0.52 g, 1 mmol), diethylisopropylamine (0.175 mL, 1 mmol) and 1-methyl-2-pyrrolidinone (4.0 mL). Add 1-piperidineethanol (0.50 mL, 3.8 mmol) in one portion and stir at ambient temperature for 18.5 h. Pour the reaction into 5% aqueous potassium carbonate and extract with ethyl acetate (2×20mL). Wash the combined extract with water (20 mL), brine (20 mL), dry over MgSO4, filter and concentrate under vacuum to a dark residue. Chromatograph over silica gel (Redisep cartridge, 30 g) and elute with a step gradient of 10% methanol/dichloromethane (150 mL) to 20% methanol/dichloromethane. Concentrate like fractions under vacuum to an oil. Dry the oil under high vacuum at ambient temperature and obtain 0.14 g of the title compound as a tan foam: MS 365(M+H), TLC (silica gel, 0.5/9.5/90 ammonium hydroxide/methanol/dichloromethane) Rf=0.25.