Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH2:11].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.CO[C:48](=O)[C:49]1[CH:54]=[CH:53][C:52](Cl)=[CH:51][C:50]=1[NH:56][C:57]([CH:59]1[CH2:64][CH2:63][CH2:62][CH2:61][N:60]1[C:65](=[O:73])[C:66]1[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=1)=O>CN(C=O)C>[CH2:50]([N:56]1[C:3](=[O:12])[C:4]2[C:5](=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=2)[N:11]=[C:57]1[CH:59]1[CH2:64][CH2:63][CH2:62][CH2:61][N:60]1[C:65](=[O:73])[C:66]1[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:48]=1
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)C1CCCCN1C(=O)c1ccc(C)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCCCC2c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)cc1
Yield: 21 %

Procedure:
In an ice bath at −15° C., pure compound of Formula 202 (7.2 g, 29 mmol) was combined with 2-amino-4-chloro-benzoic acid methyl ester (4.5 g, 24 mmol), PyBroP (2.3 g, 4.9 mmol) and diisopropylethylamine (0.95 mL, 5.4 mmol) in DMF (30 mL). The resulting mixture was stirred ovemight, allowing the temperature to rise to room temperature with the bath. The solution was concentrated under vacuum and the residue partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with water (3×100 mL) and concentrated under vacuum. The resulting residue was purified by silica gel chromatography using 40% ethyl acetate/hexanes as eluent to give 2.66 g (21% yield) of the desired product of Formula 203, 4-chloro-2-{[1-(4-methyl-benzoyl)-piperidine-2-carbonyl]amino}-benzoic acid methyl ester, as a crystalline solid. LRMS (MH+) m/z 472.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]=[C:21]=[O:22])[CH:15]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Br:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:22])[NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[CH2:9][C:10]([OH:12])=[O:11])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C=Nc1cccc(Br)c1
Reactant: Nc1cc(Cl)ccc1CC(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(O)Cc1ccc(Cl)cc1NC(=O)Nc1cccc(Br)c1
Reaction time: 1.5 h
Yield: 46.6 %

Procedure:
6-Chlorooxindole (2.5 g, 14.9 mmol) was suspended in 50 ml 4 M aqueous NaOH and the mixture was refluxed for 6 hours. The reaction mixture was allowed to cool and the product precipitated and filtered off with suction. The solid was dissolved in water (100 ml) and precipitated with 4 M aqueous HCl at 0° C. The solid was then filtered with suction and dried under vacuum to yield 2.0 g (72%) of white crystalline solid. (2-Amino-4-chloro-phenyl)-acetic acid (700 mg, 3.8 mmol) was then dissolved in 25 ml pyridine and 1-bromo-3-isocyanato-benzene (811 mg, 4.1 mmol) was added drop-wise and the solution was stirred for 90 minutes. The reaction mixture was diluted with 150 ml ethyl acetate and washed twice with 1 M aqueous HCl. The organic phase was reduced under vacuum and the product recrystallised from ethyl acetate/heptane to yield 680 mg of white crystalline solid (47%) (m.p. 195-196° C.)
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]([O-:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[Li+].[OH-].CO.Cl>O>[O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC1C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl (2S)-1-(1,2- dioxo-3,3-dimethylpentyl-2-pyrrolidinecarboxylate (2.10 g; 8.23 mmol), 1 N LiOH (15 mL), and methanol (50 mL) was stirred at 0° C. for 30 min and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87%) of snow-white solid which did not require further purification. 1H NMR (CDCl3):d 0.87 (t,3H); 1.22, 1.25 (s,3H each); 1.77 (dm,2H); 2.02 (m,2H); 2.17 (m, 1H); 2.25 (m,1H); 3.53 (dd, 2H, J=10.4, 7.3); 4.55 (dd, 1H, J=8.6, 4.1).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:9])[CH:7]=O)[CH2:2][CH2:3][CH3:4].[CH:10](=[O:13])[CH2:11][CH3:12].C(NCCCC)CCC>CCOCC>[CH2:1]([O:5][C:6](=[O:9])/[CH:7]=[C:11](\[CH:10]=[O:13])/[CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C=O
Reactant: CCC=O
Solvent: CCCCNCCCC
Solvent: CCOCC
Product: CCCCOC(=O)/C=C(/C)C=O
Temperature: 113.5 °C
Reaction time: 2 h

Procedure:
836 G. of the obtained glyoxalic acid butyl ester are introduced into 376 g. of propionaldehyde. The mixture is treated dropwise at 60° C. with 40.8 g. of di-n-butylamine. In so doing, the reaction temperature should not rise higher than 105° C. The reaction mixture is then stirred for 2 hours at 116-111° C., cooled and taken up in ether. The diethyl ether extract is washed successively with 500 ml. of 1 N sulphuric acid, 700 ml. of water, 1000 ml. of 5% by weight aqueous sodium bicarbonate solution and subsequently with 1000 ml. of water, dried over sodium sulphate and evaporated under reduced pressure. The remaining 3-formylcrotonic acid butyl ester boils, after rectification, at 93°-105° C./14 mm. Hg.; nD25 =1.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:67]1([CH2:73][NH2:74])[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1>ClCCl>[CH:67]1([CH2:73][NH:74][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([N:13]3[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH:7]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:15][CH2:14]3)[CH:17]=2)[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCCC1)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
The compound (0.12 g) prepared in step (c) of Example 1 was dissolved in dichloromethane (5 ml), and a BOP reagent (0.16 g) and diisopropylethylamine (0.078 ml) were added to the solution. The mixture was stirred at room temperature for 30 min. Cyclohexanemethylamine (0.057 ml) was then added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate=1:1) to give 0.13 g (91.6%) of N-cyclohexylmethyl-3-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]benzamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].ClCCl.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(N(CC)CC)C>[CH3:12][S:13]([O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccs1
Reaction time: 1 h

Procedure:
A mixture of 12.8 g. of 2-(2-thienyl)ethanol, 450 ml. of dichloromethane and 20.2 g. of triethylamine is chilled to -10° C. and 12.8 g. of cold methanesulfonyl chloride is added dropwise over 30 minutes. After stirring for 1 hour, the mixture is washed with 300 ml. of cold water, 300 ml. of cold 10% hydrochloric acid, 300 ml. of cold saturated sodium bicarbonate, and 300 ml. of cold saturated sodium chloride solution. The organic layer is dried over magnesium sulfate and concentrated under vacuum to give the product as an oil.
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[C:7]([CH3:19])=[CH:6][C:5]=1[OH:20])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>O>[CH3:19][C:7]1[C:8]2[C:9](=[O:18])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[O:16][C:17]=2[C:4]2[CH2:1][CH:2]([C:36]([OH:37])=[O:39])[O:20][C:5]=2[CH:6]=1
Reactant: C=CCc1c(O)cc(C)c2c(=O)c3ccccc3oc12
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(c3oc4ccccc4c(=O)c13)CC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.9 %

Procedure:
A mixture of 4-allyl-3-hydroxy-1-methyl-9-oxo-9H-xanthene (3.0 g), m-chloroperbenzoic acid (8 g) and chloroform (500 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (20 g) and water (400 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (500 ml) and, to the stirred solution, a mixture of chromium trioxide (5.5 g), water (25 ml) and concentrated sulfuric acid (8.5 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.5 g of 1,2-dihydro-5-methyl-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 231°-234° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 298.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1C=CC(S(O[CH2:24][CH2:25][Cl:26])(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:24][CH2:25][Cl:26])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1OCCCl
Temperature: 65 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
To a solution of methyl 5-chloro-2-hydroxybenzoate (54.06 g, 0.29 mol) in 300 mL of anhydrous DMF was added 2-chloroethyl 4-methylbenzenesulfonate (81.6 g, 0.35 mol) and Cs2CO3 (142 g, 0.44 mol). The mixture was stirred at 60-70° C. overnight, then water was added. A white solid precipitated from the solution, which was collected by filtration and coevaporated with toluene to afford 76.1 g (88%) of methyl 5-chloro-2-(2-chloroethoxy)benzoate. 1H NMR (400 MHz, CDCl3) δ: 7.76 (d, 1H), 7.40 (dd, 1H), 6.91 (d, 1H), 4.27 (t, 2H), 3.87 (s, 3H), 3.83 (t, 2H).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[C:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])(=[O:13])[CH3:12].Cl>O1CCCC1.C(OCC)(=O)C>[C:17]([C:16]1[CH:15]=[C:14]([C:11](=[O:13])[CH2:12][C:3]([O:7][CH2:8][CH3:9])=[O:10])[CH:21]=[CH:20][CH:19]=1)#[N:18]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cccc(C#N)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1cccc(C#N)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a suspension of sodium hydride (1.2 g of 60% suspension in mineral oil, hexane-washed, 30.3 mmol) in 40 mL of tetrahydrofuran was added diethyl carbonate (3.7 mL, 30.3 mmol) and 3-acetyl benzonitrile (2.2 g, 15.2 mmol). The resulting suspension was stirred at 65° C. for 1 h and then was cooled to room temperature. There was added 40 mL of 10% aqueous HCl and the reaction mixture was diluted with ethyl acetate and the layers were separated. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to afford 3.2 g (96%) of the title compound, which was sufficiently pure to be used without purification. MS(NH3—CI) 218.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.[Li+].[OH-]>C1COCC1.CO>[NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoate (104 mg, 0.314 mmol) in THF (698 μL) and MeOH (349 μL) was added LiOH (1 M solution) (565 μL, 0.565 mmol). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with 1N HCl solution up to pH 5, and worked up with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The crude product was used for the next step. LCMS (m/z): 318.3 (MH+), 0.5 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]1>C(O)(C)C>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]2)[N:3]=1
Reactant: CC(=O)N1CCC(N)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2c(F)ccc(OC)c2F)c(N)n1
Solvent: CC(C)O
Product: COc1ccc(F)c(C(=O)c2cnc(NC3CCN(C(C)=O)CC3)nc2N)c1F

Procedure:
A suspension of (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(2,6-difluoro-3-methoxy-phenyl)-methanone (20.0 mg, 0.056 mmol, Example 89) and 1-(4-amino-piperidin-1-yl)-ethanone (21.1 mg, 0.148 mmol, prepared as described in U.S. Pat. No. 5,817,828) in isopropyl alcohol (2.5 mL) was heated at 120° C. in a sealed tube under microwave conditions for 0.3 to 1 hour. The resulting reaction mixture was evaporated in vacuo and crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give 1-[4-[4-amino-5-(2,6-difluoro-3-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid (18.3 mg). MS (M+H)+, 406.
Reaction SMILES: [CH:1]([P:4]([CH:12]([CH3:14])[CH3:13])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH:15]O>C(Cl)Cl>[CH:12]([P:4]([CH:1]([CH3:3])[CH3:2])([C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:15])([CH3:14])[CH3:13]
Reactant: Cc1ccc(P(C(C)C)C(C)C)cc1
Reactant: OO
Solvent: ClCCl
Product: Cc1ccc(P(=O)(C(C)C)C(C)C)cc1
Temperature: 25 °C

Procedure:
To a solution of diisopropyl-p-tolyl-phosphane (2.6 g, 12.48 mmol) in DCM (5 mL) at 0° C. was added hydrogen peroxide (4.08 mL, 13.31 mmol) dropwise. The reaction mixture was allowed to warm to RT. The reaction was diluted with DCM, washed with water, brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The material was used without further purification. MS: cal'd 225 (MH+), exp 225 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[S:9][C:10]([C:27](=[O:29])[CH3:28])=[CH:11][C:12]=1[S:13](=[O:26])(=[O:25])[N:14]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH3:15])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Si:38](OS(C(F)(F)F)(=O)=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[S:9][C:10]([C:27]([O:29][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[CH2:28])=[CH:11][C:12]=1[S:13](=[O:25])(=[O:26])[N:14]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)c(NC(=O)OC(C)(C)C)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)c(NC(=O)OC(C)(C)C)s1
Reaction time: 0.5 h

Procedure:
To a solution of (5-acetyl-3-{[2-(4-fluorophenyl)ethyl]methylsulfamoyl}thiophene-2-yl)-carbamic acid t-butyl ester (the compound of Preparation Example 111) (946 mg) in dichloromethane (8 mL) was added triethylamine (0.58 mL) and 0.71 mL of t-butyldimethylsilyltrifluoromethane sulfonate (0.71 mL) on an ice bath. After stirring for 30 minutes, an aqueous solution of saturated sodium bicarbonate was added, and the solution was extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the residue that was obtained upon removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate) and, the title compound (985 mg) was obtained as a colorless oily matter.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([C:18](=[O:20])[CH3:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:28]([O:32][C:33](Cl)=[O:34])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C>CN(C=O)C>[CH2:28]([O:32][C:33]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[C:17]([C:18](=[O:20])[CH3:19])=[C:12]([NH:11][C:8]3[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=3)[N:13]=[CH:14][N:15]=2)[CH2:23][CH2:24]1)=[O:34])[CH:29]([CH3:31])[CH3:30]
Reactant: CC(=O)c1c(Nc2ccc(S(C)(=O)=O)nc2)ncnc1OC1CCNCC1
Reactant: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1c(Nc2ccc(S(C)(=O)=O)nc2)ncnc1OC1CCN(C(=O)OCC(C)C)CC1
Temperature: 80 °C
Yield: 64.7 %

Procedure:
A mixture of 1-[4-(6-methanesulfonyl-pyridin-3-ylamino)-6-(piperidin-4-yloxy)-pyrimidin-5-yl]-ethanone (48 mg, 0.11 mmol), isobutylchloroformate (14.0 μL, 0.11 mmol), and triethylamine (45 μL, 0.34 mmol) in DMF (1.0 mL) was heated under microwave irradiation for 3 minutes at 80° C. The crude mixture was purified by HPLC to provide Compound A60 as a white solid (35 mg, 65%). 1H NMR (CDCl3, 400 MHz) δ 0.97 (d, 6H), 1.82-1.92 (m, 2H), 2.10-2.19 (m, 2H), 2.70 (s, 3H), 3.22 (s, 3H), 3.37 (m, 2H), 3.89-3.96 (m, 5H), 5.59 (h, 1H), 8.10 (d, 1H), 8.49-8.57 (m, 2H), 8.92 (d, 2H). Exact mass calculated for C22H29N5O6S 491.18, found 492.3 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1[C:19]([C:20]2[C:21](=[O:36])[NH:22][C:23](=[O:35])[C:24]=2[C:25]2[C:33]3[C:28](=[C:29]([CH3:34])[CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[C:8]2[CH:9]=[C:10]([CH2:13]OS(C)(=O)=O)[CH:11]=[CH:12][N:7]2[N:6]=1>>[CH3:1][N:2]([CH2:13][C:10]1[CH:11]=[CH:12][N:7]2[N:6]=[C:5]([CH3:4])[C:19]([C:20]3[C:21](=[O:36])[NH:22][C:23](=[O:35])[C:24]=3[C:25]3[C:33]4[C:28](=[C:29]([CH3:34])[CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)=[C:8]2[CH:9]=1)[CH3:3]
Reactant: CNC
Reactant: Cc1nn2ccc(COS(C)(=O)=O)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Product: Cc1nn2ccc(CN(C)C)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.6 %

Procedure:
Dimethylamine (approx. 50% solution in DMF, 0.04 ml, 0.27 mmol, 2.0 equiv) is added at room temperature under an atmosphere of argon to a solution of methanesulfonic acid 2-methyl-3-[4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-pyrazolo[1,5-a]pyridin-5-ylmethyl ester (80 mg, 0.17 mmol). The reaction mixture is stirred at room temperature for 20 minutes. After dilution with water, the mixture is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (CH2Cl2/MeOH 95:5) affords the title compound (44 mg, 62%). 1H NMR (400 MHz, d6-DMSO): δ=11.77 (s, 1H), 10.93 (s, 1H), 8.48 (d, J=6.9Hz, 1H), 7.94 (d, J=3.0 Hz, 1H), 6.79 (br s, 1H), 6.74 (d=7.1 Hz, 1H), 6.65 (dd, J=7.1/1.7 Hz, 1H), 6.45 (t, J=7.1 Hz, 1H), 6.11 (d, J=8.1 Hz, 1H), 4.10 (q, J=5.4 Hz, 2H), 3.18 (s, 3H), 3.17 (s, 3H), 2.39 (s, 3H), 2.20 (s, 3H). MS (ES+): 414 (M+H)+.
Reaction SMILES: ClC1N=NC(NC)=C(C2C=CC=CC=2)C=1.[Cl:16][C:17]1[N:22]=[N:21][C:20]([N:23]([CH3:40])[C:24](=[O:39])[C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:26]=2)=[C:19]([C:41]2[CH:46]=[CH:45][C:44](F)=[CH:43][C:42]=2OC)[CH:18]=1>CCCCCCC.C(OCC)(=O)C>[Cl:16][C:17]1[N:22]=[N:21][C:20]([N:23]([CH3:40])[C:24](=[O:39])[C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[C:27]([S:35]([CH3:38])(=[O:36])=[O:37])[CH:26]=2)=[C:19]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:18]=1
Reactant: COc1cc(F)ccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: CNc1nnc(Cl)cc1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1nnc(Cl)cc1-c1ccccc1
Yield: 20 %

Procedure:
The title compound was prepared in analogy to example 1, from (6-chloro-4-phenyl-pyridazin-3-yl)-methyl-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 1, intermediate d) after a reaction time of 18 hours and using a gradient of n-heptane:ethyl acetate (100:0 to 30:70) for the chromatographic purification. Another purification step using preparative HPLC (Gemini NX column) with a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2) gave the desired compound as a colorless solid (20%). MS (ESI+): m/z=470.054 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:23][C:24]1([F:38])[CH2:27][N:26]([C:28](=[O:37])[CH2:29][O:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:25]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:38][C:24]1([F:23])[CH2:27][N:26]([C:28](=[O:37])[CH2:29][O:30][CH:31]2[CH2:36][CH2:35][N:34]([C:4]([C:3]3[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=3[F:1])[CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)=[O:6])[CH2:33][CH2:32]2)[CH2:25]1
Reactant: O=C(COC1CCNCC1)N1CC(F)(F)C1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)N1CC(F)(F)C1
Reaction time: 1 h
Yield: 17.7 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), 1-(3,3-difluoroazetidin-1-yl)-2-(piperidin-4-yloxy)ethanone (88) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.215 g, 0.67 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.117 mL, 0.67 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compounds were evaporated to dryness to afford 4-(3-(4-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethoxy)piperidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (89) as a white solid (0.061 g, 17.7% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.67-1.48 (2H, m), 1.86-1.75 (1H, m), 2.01-1.89 (1H, m), 3.19-3.06 (1H, m), 3.56-3.39 (2H, m), 3.66-3.57 (1H, m), 4.17-3.95 (3H, m), 4.28 (2H, s), 4.39-4.33 (2H, m), 4.62-4.57 (2H, m), 7.02 (1H, t), 7.31-7.26 (2H, m), 7.79-7.70 (3H, m), 8.48-8.46 (1H, m), 10.53 (1H, s) m/z (LC-MS, ESI+), RT=1.83 (M+H 515). and 2-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidin-4-yloxy)acetic acid (90) as a white solid (0.016 g, 5.50%); 1H NMR (400.132 MHz, CDCl3) δ 1.68-1.60 (1H, m), 1.84-1.71 (2H, m), 2.05-1.96 (1H, m), 3.16-3.04 (1H, m), 3.53-3.45 (2H, m), 3.78-3.68 (1H, m), 4.23-4.04 (3H, m), 4.32-4.28 (2H, m), 7.07-7.02 (1H, m), 7.30-7.24 (2H, m), 7.86-7.74 (3H, m), 8.47-8.42 (1H, m), 11.12 (1H, s) COOH missing; m/z (LC-MS, ESI+), RT=0.91 (M+H 440).