Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:19])(=[O:18])/[C:14](=[CH:16]/[CH3:17])/[CH3:15].[CH3:20][C:21]([CH3:23])=[O:22]>O1CCCC1>[OH:22][C:21]([C:14]([CH3:15])([CH:16]=[CH2:17])[C:13]([OH:19])=[O:18])([CH3:23])[CH3:20]
Reactant: CC(C)=O
Reactant: C/C=C(\C)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CC(C)(C(=O)O)C(C)(C)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
A cooled (−78° C.) solution of N,N-diisopropylamine (12.5 g, 123 mmol) in anhydrous tetrahydrofuran (100 mL) was treated with n-butyllithium (2.5 M solution in hexanes, 49 mL, 123 mmol). Temperature was raised to 0° C. for 30 minutes, then re-cooled down to −78° C. Tiglic acid (5.00 g, 49.4 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise. Temperature was raised to room temperature for 1 h then re-cooled down to −78° C. Acetone (2.86 g, 49.4 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise. After stirring for 3 h, the reaction was quenched with a saturated solution of ammonium chloride and allowed to warm up to room temperature. The pH was adjusted to pH 2 by addition of concentrated hydrochloric acid and diethyl ether (400 mL) was added. The organic layer was separated, and the volatiles removed in vacuo. The residue was partitioned between diethyl ether (200 mL) and a saturated solution of sodium bicarbonate (300 mL). The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid, then re-extracted with diethyl ether (2×100 mL). The organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Biotage cartridge eluted with a continuous gradient of iso-hexanes/acetone 1:0 to 3:2 to afford the title compound (5.129 g, 66%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 1.27 (s, 3H), 1.31 (s, 3H), 1.38 (s, 3H), 5.28 (d, J=17.6 Hz, 1H), 5.34 (d, J=10.9 Hz, 1H), 6.25 (dd, J=17.6, 10.9 Hz, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:19]([OH:26])[CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](=[O:26])[CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCCO2)cc2cccnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(CC1CCCO1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a solution of 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-furan-2-yl)-ethanol (0.9 g, 2.4 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (2.56 g, 6 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (100 mL). The mixture was extracted with dichloromethane (50 mL), washed with a saturated aqueous sodium bicarbonate solution (3×100 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-furan-2-yl)-ethanone (0.5 g, 56%) as a light yellow solid: LC/MS m/e calcd for C19H18N2O4S [M+H]+ 371.43, observed 371.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[F:11][C:12]1[CH:13]=[C:14]([CH:24]([NH:26][C:27]([C:29]2[N:30]=[C:31](Cl)[O:32][CH:33]=2)=[O:28])[CH3:25])[CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:16]1[CH:15]=[C:14]([CH:24]([NH:26][C:27]([C:29]2[N:30]=[C:31]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[O:32][CH:33]=2)=[O:28])[CH3:25])[CH:13]=[C:12]([F:11])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2ccccc2Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 30.4 %

Procedure:
2-Chlorophenylboronic acid (40.7 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (18 mg, 30%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=O)=[C:8]([F:21])[C:7]([O:22][CH3:23])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1N=C(C2C=C(O)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH:18]([C:16]1[N:17]=[C:13]([C:11]2[CH:2]=[C:1]([OH:3])[C:4]3[C:9](=[C:8]([F:21])[C:7]([O:22][CH3:23])=[CH:6][CH:5]=3)[N:10]=2)[S:14][CH:15]=1)([CH3:20])[CH3:19]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1F
Agent: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1F
Yield: 90 %

Procedure:
2-(4-Isopropylthiazol-2-yl)-8-fluoro-7-methoxyquinolin-4-ol 218c was synthesized from compound 217c as a yellow solid in 90% yield, according to the procedure as described for compound 218a. MS (ESI, EI+): m/z=319 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>C1COCC1.CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(Br)cc1F
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.1 mmol) in THF (24 mL) and methanol (6 mL) at 0° C. was added a solution of (trimethylsilyl)diazomethane in hexanes (2.0 M, 5.46 mL, 10.9 mmol). The yellow solution was allowed to gradually warm to room temperature over 1 h. The volatile materials were removed and the residue was treated with aqueous hydrochloric acid (1 M). The aqueous mixture was extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, filtered, and concentrated to provide crude methyl 4-bromo-2-fluorobenzoate (2.7 g, quantitative yield). This material was used in the subsequent step without further purification. 1H NMR (400 MHz, CDCl3): 7.85-7.81 (m, 1H), 7.38-7.33 (m, 2H), 3.93 (s, 3H); MS (EI) for C8H6BrFO2: 232, 234 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:43]([NH2:49])[CH:44]1[O:48][CH2:47][CH2:46][CH2:45]1>O1CCCC1.O.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:49][CH2:43][CH:44]4[CH2:45][CH2:46][CH2:47][O:48]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: NCC1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC1CCCO1)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
The title compound was prepared as described in Example 76. To a solution of 3-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.200 g, 0.781 mmol) in tetrahydrofuran (5 mL) was added 1-hydroxybenzotriazole hydrate (0.316 g, 2.34 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.449 g, 2.34 mmol), tetrahydrofurfurylamine (0.242 mL, 2.34 mmol) and N,N-dimethylformamide (2 mL). The solution was stirred for 16 h at room temperature. Water (40 mL) was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (10-90% acetonitrile/water). The pure fractions were made basic with ammonium hydroxide, the solution evaporated under reduced pressure, diluted with water and filtered which gave the title compound (0.198 g, 74% yield): 1H NMR (DMSO-d6) δ 13.43 (s, 1H), 8.71 (t, 1H), 8.56 (m, 1H), 8.08 (AB quartet, 2H), 7.92 (dd, 1H), 7.62 (dd, 1H), 7.40 (t, 2H), 4.01 quartet, 1H), 3.79 (q, 1H), 3.63 (q, 1H), 3.36 (m, 2H), 1.97 (m, 1H), 1.83 (m, 2H), 1.62 (m, 1H); ES-MS (m/z) 340 [M+1]+.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=3)[C:17]([NH:19][C:20]3[C:21](O)=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])=[O:18])=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([C:17]4[O:18][C:21]5[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=[CH:29][C:20]=5[N:19]=4)[CH:31]=[CH:32][CH:33]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(NC(=O)c2cccc(C(=O)N3CCN(C(=O)C4CC4)CC3)c2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2nc(-c3cccc(C(=O)N4CCN(C(=O)C5CC5)CC4)c3)oc12
Yield: 85.7 %

Procedure:
Methyl 3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzamido)-2-hydroxybenzoate (160 mg, 0.35 mmol) and 4-methylbenzenesulfonic acid monohydrate (200 mg, 1 mmol) were added to toluene (10 mL) and the mixture was stirred at reflux for 16 hr. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated to yield methyl 2-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)benzo[d]oxazole-7-carboxylate as a solid (130 mg, yield: 85%). LC-MS (ESI) m/z: 434 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[N:4]([CH3:12])[C:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH:6]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:13])[N:4]([CH3:12])[CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1
Reactant: COC(=O)N(C)C1=CC(=O)CCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)N(C)C1CCCC(=O)C1

Procedure:
A solution of methyl-(3-oxo-cyclohex-1-enyl)-carbamic acid methyl ester (412 mg, 2.2 mmol) in methanol (20 ml) is hydrogenated with Pd/C (10%, 80 mg, 1 bar). After filtration the crude product is chromatographed on silica gel (30 g) with hexane/ethyl acetate (1:1 v/v) as eluent. Methyl-(3-oxo-cyclohexyl)-carbamic acid methyl ester is obtained as a colorless oil. NMR (400 MHz; CDCl3): 4.23 (br, 1H), 3.69 (s, 3H), 2.83 (br,s, 3H), 2.57-2.34 (m, 3H), 2.21 (td, J=14 Hz, J=6 Hz, 1H), 2.05 (m, 1H), 1.91 (m, 1H), 1.80 (qd, J=12.5 Hz, J=3.5 Hz, 1H), 1.6 (m, 1H).
Reaction SMILES: [CH2:1]([C@@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH3:24])[C:4]1=[O:25])[CH3:2].C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH3:24])[C:4]1=[O:25])[CH3:2]
Reactant: CC[C@H]1C(=O)N(C)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: CC[C@H]1C(=O)N(C)c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Yield: 87 %

Procedure:
(3S)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3S)-3-Ethyl-6-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (87%). [α]D25=+301° (c=0.0107 G/ML, CHCl3); MS (ESI) m/z 329 ([M+H]+); MS (ESI) m/z 327 ([M−H]−); HRMS: calcd for C18H17FN2O3, 328.1223; found (ESI_FT), 329.12904;
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=1>C1(C)C=CC=CC=1.CCOC(C)=O.[Cu]I>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:27]2[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=2)=[CH:4][CH:3]=1
Reactant: Fc1c(Cl)ccc2cc[nH]c12
Reactant: CCCn1cc(Br)cn1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCn1cc(-n2ccc3ccc(Cl)c(F)c32)cn1
Temperature: 140 °C
Reaction time: 20 h
Yield: 72.2 %

Procedure:
To a stirred solution of compound 2 (1.1 g, 6.48 mmol) in toluene (15 mL) under inert atmosphere were added N,N′-dimethyl ethylene diamine (229 mg, 2.60 mmol), potassium phosphate (3.44 g, 16.27 mmol), 4-bromo-1-propyl-1H-pyrazole (Intermediate B; 1.21 g, 6.50 mmol), CuI (124 mg, 0.65 mmol) at RT, degassed under argon for 15 min; heated to 140° C. and stirred for 20 h in sealed tube. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (30 mL), filtered and the filtrate was concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 8-10% EtOAc/Hexanes to afford compound 3 (1.3 g, 72%) as brown liquid. 1H NMR (500 MHz, CDCl3): δ 7.64 (s, 1H), 7.60 (s, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.12-7.07 (m, 2H), 6.60 (s, 1H), 4.13 (t, J=7.0 Hz, 2H), 1.99-1.91 (m, 2H), 0.97 (t, J=8.0 Hz, 3H); LC-MS (ESI): 93.5%; m/z 278.2 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.08 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[C:11]1([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:11]1([S:17]([NH:20][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:10][CH:9]=2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.4 %

Procedure:
5 g of 4-iodobenzoic acid is added to a solution of 3.3 g of benzenesulfonamide, 2.68 g of 4-dimethylaminopyridine and 4.04 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 100 ml of dichloromethane, and the suspension is stirred for 18 hours at room temperature. The reaction mixture is diluted with 400 ml of dichloromethane, washed in succession with 400 ml portions of 10% hydrochloric acid, water and saturated common salt solution, the organic phase is dried on sodium sulfate and concentrated by evaporation. The residue is suspended in diethyl ether/ethyl acetate=1/1, and the crystallizate is suctioned off. 3.15 g of N-benzenesulfonyl-4-iodobenzoic acid amide of melting point 192°-193° C. is obtained.
Reaction SMILES: CC1C2C(=NC(C3C=CC(O)=CC=3)=CC=2CN2CC(C)(C)NCC2(C)C)NN=1.[CH3:29][C:30]1[C:38]2[C:37]([C:39](O)=O)=[CH:36][C:35]([C:42]3[CH:47]=[CH:46][C:45]([O:48]C4CCCCO4)=[CH:44][CH:43]=3)=[N:34][C:33]=2[N:32](C2CCCCO2)[N:31]=1.C([N:68]1[CH2:73][C:72]([CH2:76][CH3:77])([CH2:74][CH3:75])[NH:71][CH2:70][C:69]1([CH3:79])[CH3:78])C1C=CC=CC=1>>[CH2:76]([C:72]1([CH2:74][CH3:75])[CH2:73][NH:68][C:69]([CH3:79])([CH3:78])[CH2:70][N:71]1[CH2:39][C:37]1[CH:36]=[C:35]([C:42]2[CH:43]=[CH:44][C:45]([OH:48])=[CH:46][CH:47]=2)[N:34]=[C:33]2[NH:32][N:31]=[C:30]([CH3:29])[C:38]=12)[CH3:77]
Reactant: CCC1(CC)CN(Cc2ccccc2)C(C)(C)CN1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)O)c12
Agent: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(CN3CC(C)(C)NCC3(C)C)c12
Product: CCC1(CC)CNC(C)(C)CN1Cc1cc(-c2ccc(O)cc2)nc2[nH]nc(C)c12

Procedure:
4-[4-(2,2-diethyl-5,5-dimethyl-piperazin-1-ylmethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol was synthesized in analogy to Example 49 (4-[3-Methyl-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol) starting from 3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid and 1-benzyl-5,5-diethyl-2,2-dimethyl-piperazine.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([S:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=[N:22]2)[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:43])C=1>O1CCCC1>[C:29]1([S:28]([C:24]2[CH:23]=[N:22][N:21]([CH:7]([CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([NH:10][C:11]3[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[N:12]=3)=[O:9])[C:26](=[O:27])[CH:25]=2)=[O:43])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Sc3ccccc3)cc2=O)n1
Solvent: C1CCOC1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(S(=O)c3ccccc3)cc2=O)n1
Temperature: 25 °C
Yield: 23.1 %

Procedure:
A solution of 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-4-phenylsulfanyl-6H-pyridazin-1-yl)-propionamide (30 mg, 0.06 mmol) in tetrahydrofuran (1 mL) was treated with m-chloroperbenzoic acid (10.8 mg, 0.06 mmol). In a separate flask, a solution of 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-4-phenylsulfanyl-6H-pyridazin-1-yl)-propionamide (30 mg, 0.06 mmol) in tetrahydrofuran (1 mL) was treated with m-chloroperbenzoic acid (21.5 mg, 0.12 mmol). Both reactions were stirred at 25° C. for 3 nights. At this time, each reaction was individually concentrated in vacuo. Two separate HPLC purifications (30-100% acetonitrile/water, C18 Pursuit Agilient, 20×150mm, 30 ml/min) were combined to afford 2-(4-benzenesulfinyl-6-oxo-6H-pyridazin-1-yl)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (6.9 mg, 11%) as a white solid; ES+-HRMS m/e calcd for C25H31N5O4S [M+H+] 498.2170 found 498.2171. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (2×s, 6H), 1.19-1.70 (m, 9H), 1.88-2.01 (m, 1H), 2.10-2.26 (m, 1H), 3.87 (s, 2H), 4.66 (s, 1H), 5.47 (dd, J=10.6, 4.2 Hz, 1H), 6.35 (d, J=2.4 Hz, 1H), 7.51 (dd, J=2.4 Hz, 1H), 7.54 (dd, J=2.4 Hz, 1H), 7.73 (t, J=7.5 Hz, 2H), 7.85 (t, J=7.5 Hz, 1H), 8.14 (d, J=7.5 Hz, 2H), 8.47 (d, J=2.4 Hz, 1H), 10.87 (s, 1H); and 2-(4-benzenesulfonyl-6-oxo-6H-pyridazin-1-yl)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (14.9 mg, 23%) as a white solid; ES+-HRMS m/e calcd for C25H31N5O5S [M+H+] 514.2119 found 514.2121. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.04 (s, 3H), 1.20-1.70 (m, 9H), 1.86-2.02 (m, 1H), 2.07-2.31 (m, 1H), 3.87 (s, 2H), 4.66 (s, 1H), 5.47 (dd, J=10.4, 4.4 Hz, 1H), 6.35 (d, J=2.4 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.52 (d, J=2.4 Hz, 1H), 7.73 (t, J=7.5 Hz, 2H), 7.85 (t, J=7.5 Hz, 1H), 8.14 (d, J=7.5 Hz, 2H), 8.47 (d, J=2.4 Hz, 1H), 10.87 (s, 1H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[N:57]1([CH2:63][CH2:64][CH2:65][NH2:66])[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1.[OH-].[Na+]>O.ClCCl.C(N(CC)CC)C>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][CH2:65][CH2:64][CH2:63][N:57]5[CH2:62][CH2:61][O:60][CH2:59][CH2:58]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCCCN1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NCCCN2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 2 h

Procedure:
To a mixture of 0.080 g (0.18 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.0849 g (0.22 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 2 mL of dichloromethane, 0.11 mL of triethylamine was added followed by 0.05 mL of 3-morpholin-4-yl-propylamine. After 2 hours, 6 mL of dichloromethane, 4 mL of water and 0.2 mL of 1M sodium hydroxide was added. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-methanol-ammonium hydroxide (91:9:0.8) to give 0.0608 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(3-morpholin-4-yl-propyl)-benzamide (I-79).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]([NH:34][C:35](=O)[O:36]C(C)(C)C)[CH2:15][C:16]2[CH:24]=[C:23]([CH3:25])[C:22]3[C:18](=[CH:19][N:20](COCC[Si](C)(C)C)[N:21]=3)[CH:17]=2)[CH:5]=[C:4]([CH3:42])[N:3]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH:56]1[CH2:61][CH2:60][CH:59]([N:62]2[CH2:71][C:70]3[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=3)[NH:64][C:63]2=[O:72])[CH2:58][CH2:57]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]([NH:34][C:35]([N:56]2[CH2:57][CH2:58][CH:59]([N:62]3[CH2:71][C:70]4[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=4)[NH:64][C:63]3=[O:72])[CH2:60][CH2:61]2)=[O:36])[CH2:15][C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([CH3:25])[CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH:5]=[C:4]([CH3:42])[N:3]=1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: Cc1cc(Cn2ccnc2C(Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)NC(=O)OC(C)(C)C)cc(Cl)n1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2ccnc2C(Cc2cc(C)c3[nH]ncc3c2)NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc(Cl)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
tert-Butyl 1-(1-((2-chloro-6-methylpyridin-4-yl)methyl)-1H-imidazol-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (100 mg, 0.16 mmol) was dissolved in a minimum amount of ethyl acetate, and treated with hydrochloric acid (4 N in dioxane, 2.0 mL). The mixture was stirred under nitrogen overnight. After removal of the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was filtered. The resulting solid was dissolved in dimethylformamide (1.0 mL), cooled to 0° C., and treated with carbonyl diimidazole (27.0 mg, 0.165 mmol, 1.05 equiv) and N′N-diisopropylethylamine (66.0 μL, 3.0 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (44.0 mg, 0.165 mmol, 1.05 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to afford 67.1 mg (65%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.43-1.62 (m, 4H), 2.27 (s, 3H), 2.46 (s, 3H), 2.65-2.77 (m, 3H), 3.22-3.30 (m, 1H), 3.95-4.07 (m, 2H), 4.19 (s, 2H), 4.30-4.38 (m, 1H), 5.14-5.37 (m, 3H), 6.61 (s, 1H), 6.70 (s, 1H), 6.80 (d, J=7.9, 1H), 6.88 (s, 1H), 6.96 (dd, J=7.6, 7.3, 1H), 7.10 (s, 1H), 7.13 (s, 1H), 7.14-7.20 (m, 2H), 7.28 (s, 1H). Mass spec.: 638.1 (MH)+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[CH2:6]2)[O:4]CC1>Cl>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH:7]2[CH2:8][CH2:9][CH2:10][C:5](=[O:4])[CH2:6]2)[CH2:13][CH2:14]1
Reactant: c1ccc(N2CCN(CC3CCCC4(C3)OCCO4)CC2)nc1
Agent: Cl
Product: O=C1CCCC(CN2CCN(c3ccccn3)CC2)C1
Yield: 88.5 %

Procedure:
From 1-(1,4-dioxaspiro[4.5]dec-7-ylmethyl)-4-(2-pyridinyl)piperazine (Step B) (8.4 g) and 50 mL of 10% aqueous hydrochloric acid solution using the procedure of Example A, Step D is obtained 6.4 g of the title compound as a white solid; mp 86°-90° C.