Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][NH:54][CH2:55][CH:56]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)[OH:57])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][N:54]([CH2:55][CH:56]([C:58]2[CH:59]=[CH:60][C:61]([Cl:64])=[CH:62][CH:63]=2)[OH:57])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCC(O)c2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CC(O)c2ccc(Cl)cc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.6 %

Procedure:
To a solution of 50 mg (0.26 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 80 mg of TBTU (0.26 mmol) in 4 ml DMF, were added 0.22 ml (1.28 mmol) of N,N-diisopropyl-ethyl amine. After stirring for 5 min at rt, 81 mg (0.26 mmol) of [rac]-(4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 30 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 2:1) to give 60 mg (42%) of a light yellow solid. MS (ISP): 495.4 (M+H)+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([CH2:12][P:13]([CH3:18])(=[O:17])[O:14][CH2:15][CH3:16])[CH2:11][CH2:10]1.C[O:20][C:21](=O)[CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(O)(=O)C>O1CCCC1.ClCCl>[C:27]([O:26][C:24]([NH:23][CH2:22][C:21](=[O:20])[CH2:18][P:13]([CH2:12][CH:9]1[CH2:11][CH2:10]1)(=[O:17])[O:14][CH2:15][CH3:16])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOP(C)(=O)CC1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOP(=O)(CC(=O)CNC(=O)OC(C)(C)C)CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6.97 g of lithium diisopropylamide in 100 ml of anhydrous tetrahydrofuran is cooled to -78° under an inert atmosphere. With constant stirring, a -78° solution of 10.5 g of ethyl cyclopropylmethyl(methyl)phosphinate in 30 ml of absolute tetrahydrofuran is added over 15-20 minutes via a canula under a positive pressure of inert gas. The resulting pale yellow solution is stirred for 1 hour at -78° and a pre-cooled (-78°) solution of 2.06 g of N-tert.-butoxycarbonyl glycine methyl ester in 20 ml absolute tetrahydrofuran is added over 5-10 minutes via a canula. Chromatographic analysis after 15 minutes stirring at -78° C. indicated the reaction to be complete. At -78° 3.75 ml of glacial acetic acid is added and the mixture allowed to warm to room temperature. The reaction mixture is diluted with dichloromethane and washed with water. Drying of the solvent and removal under reduced pressure affords a pale yellow oil. Removal of the excess starting material by distillation and chromatography of the residue on silica gel gives ethyl 3-(N-tert.-butoxycarbonylamino)-2-oxo-propyl(cyclopropylmethyl)phosphinate as a pale yellow oil; 1H-NMR (CDCl3): δ (ppm)=5.40 (1H, Br t, Exch. D2O, NH), 4.14 (4H, m, CH2OP+CH2N) 3.17 (2H, d, J=17.5 Hz, CH2C=O), 1.93-1.68 (2H, m, PCH2), 1.45 (9H, s, tBu), 1.35 (3H, t, CH3), 0.93 (1H, m, CH), 0.62 (2H, m, CH2), 0.27 (2H, m, CH2).
Reaction SMILES: [C:1]([NH:8][CH:9]([C:20]([NH:22][C@@H:23]([C:28]([O:30]C)=[O:29])[CH2:24][CH2:25][S:26][CH3:27])=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[OH-].[Li+].S(=O)(=O)(O)[O-].[K+]>CO.O>[C:1]([NH:8][CH:9]([C:20]([NH:22][C@@H:23]([C:28]([OH:30])=[O:29])[CH2:24][CH2:25][S:26][CH3:27])=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H](CCSC)NC(=O)C(Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CSCC[C@@H](NC(=O)C(Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
To a solution of 4.27 g of methyl Boc-2,6-dimethyl-DL-tyrosyl-D-methioninate in 14 ml of methanol is added a solution of 1.18 g of lithium hydroxide hydrate in 14 ml of water. The reaction mixture is stirred for 3 hours in the cold then 100 ml of a 5% solution of potassium bisulfate is added to bring the pH to 2.5 The gummy product which forms is extracted with ethyl acetate. The ethyl acetate layers are collected and combined, then washed with water and dried over magnesium sulfate. The solution is filtered to remove the magnesium sulfate and the solvent is removed under reduced pressure to give Boc-2,6-dimethyl-DL-tyrosyl-D-methionine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[N+:13]([O-])=O>[Pd].C(O)C>[NH2:13][C:4]1[CH:5]=[C:6]([CH2:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CC(C)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CC(C)=O)cc1N
Reaction time: 3 h
Yield: 94 %

Procedure:
The mixture of compound 10 (3.0 g, 14.3 mmol) and 10% palladium on carbon (1.6 g) in ethanol (230 ml) was stirred under hydrogen for 3 hours. Filtration of the catalyst and evaporation of solvent gave desired product 11 (2.41 g, 94%).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[C:19]2[NH:18][C:17](=[O:20])[CH2:16][CH2:15][C:14]=2[C:13]([CH:21]=[O:22])=[CH:12][CH:11]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C.O>[CH2:23]([N:18]1[C:19]2[C:10]([O:9][CH3:8])=[CH:11][CH:12]=[C:13]([CH:21]=[O:22])[C:14]=2[CH2:15][CH2:16][C:17]1=[O:20])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(C=O)c2c1NC(=O)CC2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)c2c1N(Cc1ccccc1)C(=O)CC2
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Sodium hydride (60% in oil) (1.07 g) was added at 0° C. to a DMF solution (50 ml) of 8-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde (5.0 g), followed by stirring for 30 minutes. Benzyl bromide (3.47 ml) was added, and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The extract was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from an ethyl acetate-n-hexane mixed solvent to thereby obtain 6.6 g (yield: 92%) of 1-benzyl-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a white powder.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[CH:24](OC)(OC)OC>>[CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][N:4]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[CH:24]1
Reactant: CC(C)(CNc1c(N)cnc2ccccc12)CC1(C)OCCO1
Reactant: COC(OC)OC
Product: CC(C)(Cn1cnc2cnc3ccccc3c21)CC1(C)OCCO1
Yield: 270.4 %

Procedure:
The general method described in Step 6 of Example 22 was used to cyclize N4-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]quinoline-3,4-diamine (8.1 g, 25.7 mmol) by reaction with trimethyl orthoformate (3.3 g, 10 mmol) to provide 1-[2,2-dimethyl-3-(2-methyl[1,3]dioxolan-2-yl)propyl]-1H-imidazo[4,5-c]quinoline (8.8 g) as an oil that was used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a suspension of 10 g (46.66 mmol.) of cis-1-tert-butoxycarbonyl-3,5-dimethyl piperazine and 12.90 g (93.3 mmol.) of potassium carbonate in N,N-dimethylformamide (100 ml) was added, at room temperature, 11.97 g (70 mmol.) of benzyl bromide. The mixture was stirred for 16 hours at 120° C. To the reaction system was added water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a column chromatography (ethyl acetate/hexane 30%) to give the object compound as a pale yellow oily product. The yield was 13.56 g (95%).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26](Cl)=[O:27].C(N(CC)C(C)C)(C)C>>[CH3:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)=[O:27]
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC(=O)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Yield: 88 %

Procedure:
Prepared according to Method E from 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol), 3,3-dimethylbutanoyl chloride (0.167 mL, 1.2 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) to give 0.347 g of the title compound as a white solid, mp 74–75° C.;
Reaction SMILES: CS(O[CH2:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.CCOC(C)=O>[N:18]([CH2:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC/C=C/c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCC/C=C/c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.5 %

Procedure:
To a solution of Intermediate 2C (1.3 g, 4.4 mmol) in DMF (7 mL) was added NaN3 (0.86 g, 13 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc (100 mL). The organic layer was washed with 10% aqueous LiCl solution (3×200 mL), dried over Na2SO4 and dried in vacuo. The product was isolated by silica gel chromatography to obtain 570 mg (87% yield) of Intermediate 2D. HPLC/MS (Method C) RT=4.02 min, [M+Na]+ 263.2.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[Cl:21][CH2:22][CH2:23][C:24](OCC)=[O:25]>C1COCC1>[Cl:21][CH2:22][CH2:23][C:24](=[O:25])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)CCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisoproply amine (20 mmol, 2.02 g, 3.05 ml) in dry THF (20 ml) at -78° C. was added n-butyllithium (20 mmol), 7.7 ml; 2.6M solution in hexanes. After stirring for 30 minutes, t-butyl acetate (22 mmol, 2.56 g) was added dropwise and the resulting mixture was stirred for 15 minutes. A solution of the lithium enolate of t-butyl acetate was subsequently added by cannula to a solution of ethyl 3-chloropropanoate (10 mmol, 1.37 g) in THF (25 ml) at -78° C. over 15 minutes. After stirring for an additional 15 minutes, the reaction was quenched by addition of glacial acetic acid (10 ml). After heating to room temperature, the reaction mixture was diluted with water (50 ml) and extracted with ether (150 ml). The ethereal extract was washed with 20% aqueous K2CO3 (2×100 ml), the organic phase was dried (MgSO4) and then concentrated in vacuo. Purification of the resulting liquid by gradient flash chromatography (SiO2, 1) 5% Et2O/pentane, 2) 15% Et2O/pentane) afforded t-butyl 5-chloro-3-oxopentanoate as a clear, colorless oil (4.08 g, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7]1)[CH3:2].[S:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:35]3[CH2:36][CH2:37][S:33][CH2:34]3)=[NH:24])=[CH:19][C:18]=2[F:25])[CH2:10][CH2:11]1)[CH3:2]
Reactant: C1CSCN1
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C#N)cc2F)CC1
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCSC3)cc2F)CC1
Yield: 23 %

Procedure:
The same procedure as in Example 45 was performed with ethyl-N-(N-(4-cyano-2-fluorobenzoyl)-β-ethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (1.48 g, 3.3 mmol) by using thiazolidine (2.5 ml) as an amine to yield the titled compound (314 mg, 23%).
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].C[O:10][C:11]([C:13]1[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]2[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:22][O:23][C:24]=2[CH2:25][OH:26])[CH:14]=1)=O>CCCCCC.O1CCOCC1>[CH:5]([NH:8][C:11]([C:13]1[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]2[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:22][O:23][C:24]=2[CH2:25][OH:26])[CH:14]=1)=[O:10])([CH3:7])[CH3:6]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)no1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CC(C)NC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)no1
Temperature: 80 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
Trimethylaluminum (0.57 mL of a 2 M solution in hexane, 1.15 mmol) was slowly added to a solution of isopropylamine (68.2 mg, 1.15 mmol) in dioxane (5.0 mL) and stirred at 80° C. for 1 h. Then a solution of 3-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.29 mmol) in dioxane (5.0 mL) was added dropwise. The mixture was stirred at 85° C. overnight. After cooling to room temperature and extractive workup (ethyl acetate/aqueous saturated Seignette's salt solution) the organic phase was dried (Na2SO4) and filtered. Purification by chromatography (silica, ethyl acetate:heptane=3:7 to 1:1) afforded the title compound (50 mg, 46%) as a white solid. MS: m/e=373.9 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1.[F:22][C:23]1[C:31]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:35])=[O:34])=[CH:30][CH:29]=[C:28]([F:39])[C:24]=1[C:25](O)=[O:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:22][C:23]1[C:31]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:34])=[O:35])=[CH:30][CH:29]=[C:28]([F:39])[C:24]=1[C:25]([NH:12][C:9]1[CH:10]=[C:11]2[C:3]([O:2][CH3:1])=[N:4][N:5]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]2=[N:7][CH:8]=1)=[O:26]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reactant: COc1ccc(Cn2nc(OC)c3cc(N)cnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(OC)nn3Cc2ccc(OC)cc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
3-Methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (0.0118 g, 0.0414 mmol), 2,6-difluoro-3-(propylsulfonamido)benzoic acid (0.0127 g, 0.0455 mmol), EDCI (0.00873 g, 0.0455 mmol), and HOBt (0.00615 g, 0.0455 mmol) were dissolved in DMF (1.5 mL) and stirred overnight at room temperature. The solution was partitioned between water and EtOAc. The organic layer was washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil, which was purified by column chromatography (4:1 to 3:2 hexane/EtOAc to give 2,6-difluoro-N-(3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.003 g, 13.3%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.FC(F)(F)C(O)=O.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=[C:4]([NH:35][CH:32]2[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: Nc1nc(Cl)ccc1C(=O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2ccc(C(=O)c3ccc(F)cc3)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-amino-6-chloro-pyridin-3-yl)-(4-fluorophenyl)methanone (Example 37) and 1-methanesulfonyl-piperidin-4-ylamine (Step A, Example 6) using the procedure described in Step B. Example 6. HRMS, observed: 393.1391, Calcd for (M+H)+: 393.1391.
Reaction SMILES: [Cl-].[NH4+].[NH2:3][C:4]1[C:9]([N+:10]([O-])=O)=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=3)=[O:22])=[C:16]([S:35][CH3:36])[CH:15]=2)[CH:7]=[CH:6][N:5]=1>C(O)C.O.[Fe]>[NH2:3][C:4]1[C:9]([NH2:10])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:34])([F:32])[F:33])[CH:25]=3)=[O:22])=[C:16]([S:35][CH3:36])[CH:15]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CSc1cc(Oc2ccnc(N)c2[N+](=O)[O-])ccc1NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CSc1cc(Oc2ccnc(N)c2N)ccc1NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 59 %

Procedure:
A suspension of iron powder (4 equivalents, 78 mg, 1.4 mmol) and ammonium chloride (5.8 equivalents, 109 mg, 2 mmol) in ethanol (400 μL) and water (438 μL) was heated to reflux. 1-(4-(2-amino-3-nitropyridin-4-yl-oxy)-2-(methylthio)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (180 mg, 0.35 mmol) was added in portions and the mixture stirred at reflux for 24 hours. After cooling to room temperature, the slurry mixture was filtered and washed with ethanol. After removal of the solvent, the crude powder was dissolved into EtOAc, filtered to removed the precipitate, and evaporated to provide the title compound (100 mg, 59%) as a sticky dark oil. 1H-NMR (δ, ppm, DMSO-d6): 2.41 (s, 3H, CH3), 5.61 (s, 2H, NH2,Py), 6.06 (d, 1H, HPy,5, J=5.6 Hz), 6.79 (d, 1H, Harom, J=8.7 Hz), 7.01 (s, 1H, Harom), 7.26 (d, 1H, HPy,6, J=5.6 Hz), 7.58-7.69 (m, 4H, Harom), 8.12 (s, 2H, NH2,Py), 8.27 (s, 1H, NHurea1), 10.02 (s, 1H, NHurea3). LC-MS (m/z): 484 (M+H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[NH:33][C:34]([C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([O:41][CH3:42])=[O:40])=[N:35][N:36]=2)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[NH:33][C:34]([C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([O:41][CH3:42])=[O:40])=[N:35][N:36]=4)=[CH:30][CH:31]=3)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: COC(=O)C(F)(F)C(F)(F)c1nnc(-c2ccc(N)cc2)[nH]1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCC(C(=O)Nc1ccc(-c2nnc(C(F)(F)C(F)(F)C(=O)OC)[nH]2)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
87 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 88 mg (0.28 mmol, 1.1 eq.) of methyl 3-[5-(4-aminophenyl)-4H-1,2,4-triazol-3-yl]-2,2,3,3-tetrafluoropropanoate were reacted according to General Method 1. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 96 mg (purity 94%, 56% of theory)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH2:15][N:16]([C:19](=[O:21])[CH3:20])[CH2:17][CH2:18][C:13]=3[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.[F:24][C:25]1[CH:26]=[C:27]([F:35])[C:28]2[CH2:29][C@H:30]3[O:34][C@H:31]3[C:32]=2[CH:33]=1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[F:35][C:27]1[CH:26]=[C:25]([F:24])[CH:33]=[C:32]2[C:28]=1[CH2:29][C@@H:30]([OH:34])[C@@H:31]2[N:12]1[C:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][C:14]=2[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:22])[F:23])[CH:5]=2)=[N:11]1
Reactant: CC(=O)N1CCc2[nH]nc(-c3cccc(OC(F)(F)F)c3)c2C1
Reactant: Fc1cc(F)c2c(c1)[C@@H]1O[C@@H]1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CCc2c(c(-c3cccc(OC(F)(F)F)c3)nn2[C@@H]2c3cc(F)cc(F)c3C[C@H]2O)C1
Temperature: 50 °C
Reaction time: 24 h
Yield: 23.3 %

Procedure:
A mixture of 1-[3-(3-trifluoromethoxy-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (3e) (0.461 mmol), 0.44 g, 2.65 mmol), (1aS,6aR)-3,5-difluoro-6,6a-dihydro-1aH-1-oxa-cyclopropa[a]indene (6b) (0.077 g, 0.461 mmol) and K2CO3 (127 mg, 0.922 mmol) in 5 ml CH3CN was stirred at 50° C. for 24 h. Water was added, the mixture was extracted 3 times with CH2Cl2, the combined organic layers were dried over MgSO4, filtrated and the solution was evaporated to dryness. The crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 53 mg of 1-[1-((1R,2R)-4,6-difluoro-2-hydroxy-indan-1-yl)-3-(3-trifluoromethoxy-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (11a).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH2:18]([N:20]([C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1)[CH2:21][CH2:22][NH2:23])[CH3:19].CCOP(O)N(C(C)C)C(C)C>ClCCl>[CH2:18]([N:20]([C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1)[CH2:21][CH2:22][NH:23][C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH3:19]
Reactant: CCN(CCN)c1cc(C)ccn1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCN(CCNC(=O)/C=C/C(F)(F)F)c1cc(C)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (32 mg, 0.23 mmol) was dissolved in dichloromethane (0.5 ml containing one drop of dimethyl formamide), oxalyl chloride was added (20 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N-ethyl-N-(4-methyl-2-pyridyl)ethane-1,2-diamine dihydrochloride (38 mg, 0.15 mmol) and EDIPA (128 μl, 0.8 mmol) in anhydrous dichloromethane (2 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 29 mg of a solid (0.096 mmol, 64% yield).