Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[C:5]2Cl.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cnnc2ccc(Br)cc12
Reactant: Nc1ccccc1
Solvent: CO
Product: Brc1ccc2nncc(Nc3ccccc3)c2c1
Yield: 62 %

Procedure:
A solution of Example 34D (500 mg; 2.5 mmol) and aniline (1.5 mL) in MeOH (11 mL) was stirred at r.t. for 2.5 hrs, the resulting precipitate was collected, rinsed with water and dried under vacuum to provide the desired product (400 mg; 62%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([Cl:23])[CH:14]=1)[CH2:5][C@H:6]1[CH2:10][CH2:9][C:8]([F:12])([F:11])[CH2:7]1.O.[OH-].[Li+]>C(O)C.O>[Cl:23][C:15]1[CH:14]=[C:13]([CH:4]([CH2:5][C@H:6]2[CH2:10][CH2:9][C:8]([F:12])([F:11])[CH2:7]2)[C:3]([OH:24])=[O:2])[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:20])=[O:21]
Reactant: COC(=O)[C@H](C[C@H]1CCC(F)(F)C1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(F)(F)C2)C(=O)O)cc1Cl
Temperature: 25 °C
Yield: 85.7 %

Procedure:
(R)-2-(3-Chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-propionic acid methyl ester (294 mg, 0.77 mmol) was dissolved in ethanol (8 mL) and treated with a solution of lithium hydroxide monohydrate (81 mg, 1.9 mmol) in water (2 mL) at 25° C. It was stirred at 25° C. until the starting material was all consumed by TLC (˜1 hr). The reaction was then concentrated in vacuo to remove the ethanol. The remaining aqueous layer was then acidified to pH=2 with an aqueous 1N hydrochloric acid solution. This was then extracted with ethyl acetate (3×20 mL), the organic layers combined and dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-propionic acid (242 mg, 86%) as a mixture of two diastereomers as a light yellow foam: ES-HRMS m/e calcd for C15H17O4SClF2 (M+Na)+ 389.0396, observed 389.0394; 1H NMR (300 MHz, CDCl3) δ 1.06-2.38 (m, 9H, CH and 4×CH2), 3.28 (s, 3H, SO2CH3), 3.65 (m, 1H, ArCH), 7.42 (m, 1H, Ar), 7.54 (m, 1H, Ar), 8.14 (m, 1H, Ar).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=2)[C:7]1=[O:18])[CH3:4].[C:19]1([N:25]2[C:29]3([CH2:34]CNC[CH2:30]3)[C:28](=[O:35])[NH:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:19]1([N:25]2[C:29]3([CH2:30][CH2:2][N:3]([CH2:5][CH:6]4[CH2:15][CH2:14][C:13]5[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=5)[C:7]4=[O:18])[CH2:4][CH2:34]3)[C:28](=[O:35])[NH:27][CH2:26]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc2c(c1)C(=O)C(CN(C)C)CC2
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)C(=O)C(CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
A mixture of 15.0 g of 2-[(dimethylamino)methyl]-3,4-dihydro-7-methoxy-1(2H)-naphthalenone, hydrochloride (1:1), 13.0 g of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, and 250 ml of absolute ethanol is heated on a steam bath until all solids dissolve. The resulting solution is stirred for 16 hours at room temperature under nitrogen. The resulting precipitates are collected and washed with additional absolute ethanol to give 16.7 g of the title compound.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+].CCCCCC>C1COCC1>[O:14]1[CH2:15][CH2:16][CH2:17][N:11]([CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH2:12][CH2:13]1
Reactant: C1COCCN(C2CCC3(CC2)OCCO3)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CCC(N2CCCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a cooled (<15° C.) solution of 3 (10.31 g, 42.75 mmol) in THF (216 mL) was added 7 N aqueous HCl (86 mL, 0.602 mol) over a period of 5 min. Cooling bath was then removed and the reaction mixture was stirred overnight at r.t. Then, the reaction mixture was basified to pH 8 by dropwise addition of 50% aqueous NaOH (48 g, 0.602 mol) over a period of 30 min while maintaining the internal temperature at 10-13° C. using an external cooling bath (0° C.). Hexane (50 mL) was added and the organic layer was separated, dried over MgSO4 and concentrated to afford yellowish liquid (7.21 g). The aqueous layer was extracted with AcOEt (4×50 mL). The extracts were combined, dried (MgSO4) and concentrated to afford the second portion of crude product (1.58 g). Both portions of crude product were combined and distilled in vacuum to afford ketone (VII-b) (7.27 g, 86%) as colorless liquid b.p. 98° C./5.3·10−3 mbar; 1H NMR (400 MHz, CDCl3) δ 1.73-1.85 (m, 2H), 1.89 (quintet, J=5.9 Hz, 2H), 2.05-2.15 (m, 2H), 2.30-2.42 (m, 2H), 2.43-2.52 (m, 2H), 2.79-2.85 (m, 4H), 3.03 (tt, J=10.4, 6.6 Hz, 1H), 3.72-3.77 (m, 2H), 3.82 (t, J=6.0 Hz, 2H).
Reaction SMILES: C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.S[CH2:22][CH2:23][OH:24].[C:25]1(CS(F)(=O)=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.S([O-])([O-])(=O)=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+].OCC(CO)O>[CH3:22][C@@H:23]([OH:24])[CH2:29][CH2:30][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: OCCS
Reactant: O=S(=O)(F)Cc1ccccc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: OCC(O)CO
Product: CCCCCC[C@@H](C)O

Procedure:
Candida utilis IFO 0988 strain was cultured in 3.6 L of medium B and the microbial cells were prepared by centrifugation. Obtained microbial cells were suspended in 100 mM potassium phosphate buffer (pH 8.0), 10% glycerol, 1 mM ethylenediaminetetraacetic acid 2Na (EDTA·2Na), 0.01% 2-mercaptoethanol, and 2 mM phenyl methane sulfonylfluoride (PMSF) and homogenized with bead beater (Biospec). After that, microbial cell debris were removed by centrifugation and cell-free extract was obtained. Protamine sulphate was added to this cell-free extract, and supernatant was obtained by centrifugation to remove nucleic acid. Ammonium sulfate was added to the supernatant, and the supernatant which was crude enzymatic solution was obtained in 30% saturation. The solution was dialyzed with standard buffer including 30% saturated ammonium and added to phenyl-sepharose HP (2.6 cm×10 cm) equilibrated with the same buffer. The gradient elution was conducted with 30% to 0% saturated ammonium sulfate. The fraction having selectivity of (R)-2-octanol among extracted fractions was recovered and concentrated by ultrafiltration. Composition of medium B used are followings:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]([CH3:8])([OH:7])[C:5]#[CH:6].N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd]>[CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]([CH3:8])([OH:7])[CH:5]=[CH2:6]
Reactant: [H][H]
Reactant: C#CC(C)(O)C(OC)OC
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Product: C=CC(C)(O)C(OC)OC

Procedure:
198 G. of 4,4-dimethoxy-3-methyl-but-1-yn-3-ol are dissolved in 960 ml. of high-boiling petroleum ether and, after the addition of 19.35% palladium catalyst and 19.3 g. of quinoline, hydrogenated under normal conditions. After the uptake of 33.5 l. of hydrogen, the hydrogenation is stopped. The catalyst is filtered off. The filtrate is evaporated under reduced pressure. The remaining 4,4-dimethoxy-3-methyl-but-1-en-3-ol boils, after rectification, at 70°-72° C./18 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:20]=[CH:21][N:22]=2)[CH:5]=[C:6]([C:17](O)=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16].[OH:23][C:24]1([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:27][NH:26][CH2:25]1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:4]([CH:20]=[CH:21][N:22]=2)[CH:5]=[C:6]([C:17]([N:26]2[CH2:27][C:24]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([OH:23])[CH2:25]2)=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C1(O)CNC1
Reactant: O=C(O)c1cn2ccnc2c(Cl)c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1C1(O)CN(C(=O)c2cn3ccnc3c(Cl)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.3 %

Procedure:
A solution of 8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid (78 mg, 0.18 mmol) (prepared using procedures similar to those described in US 2006030610 and US 2005054701), 1,1-dimethylethyl 2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate (46.7 mg, 0.18 mmol), 4-(dimethylamino)pyridine (66 mg, 0.55 mmol), and finally 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42 mg, 0.21 mmol) in dimethylformamide (2 mL) was stirred at room temperature for 15 hours. The reaction mixture was partition between 5% aqueous lithium chloride and ethyl acetate and the aqueous portion was extracted twice using ethyl acetate. The combined organic portion was washed with 1 N HCl, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by column chromatography. Eluting with ethyl acetate, the isolated product was concentrated in vacuo to afford 101 mg, 0.15 mmol (83%) of 1,1-dimethylethyl 2-[1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate as a white solid. The solid was immediately dissolved in methanol (5 mL) and 4 N HCl in dioxane was added. The solution was briefly heated to reflux and then was concentrated in vacuo. The resultant residue was purified by preparative reverse phase HPLC. Isolated product was concentrated in vacuo to afford 36 mg, 0.06 mmol (40%) of 1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-piperidin-2-ylazetidin-3-ol acetate as a white solid. 1H NMR (400 MHz, DMSO): 8.78 (s, 1H), 8.19 (s, 0.5H), 8.15 (s, 0.5H), 8.00 (s, 1H), 7.62 (s, 1H), 7.55 (d, 1H), 7.31 (d, 1H), 6.54-6.49 (m, 1H), 4.24-4.12 (m, 1H), 3.97-3.86 (m, 2H), 3.63-3.56 (m, 1H), 2.98-2.90 (m, 1H), 2.50-2.40 (m, 1H), 1.72-1.61 (m, 1H), 1.56-1.43 (m, 2H), 1.32-1.14 (m, 2H), 1.07-0.94 (m, 1H); MS (EI) for C22H22ClFIN5O2: 570 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH:13]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=2)[C:28]([CH2:36][CH2:37][S:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:48]=[C:49]([CH:54]=[CH:55][CH:56]=3)[C:50]([O:52][CH3:53])=[O:51])=[CH:43][CH:42]=2)(=[O:40])=[O:39])=[C:27]1[CH2:57][CH2:58][OH:59])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)Cl>[CH:13]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=2)[C:28]([CH2:36][CH2:37][S:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:48]=[C:49]([CH:54]=[CH:55][CH:56]=3)[C:50]([O:52][CH3:53])=[O:51])=[CH:43][CH:42]=2)(=[O:40])=[O:39])=[C:27]1[CH2:57][CH2:58][O:59][S:2]([CH3:1])(=[O:4])=[O:3])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cccc(-c2ccc(S(=O)(=O)CCc3c(CCO)n(C(c4ccccc4)c4ccccc4)c4ccc(Cl)cc34)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2ccc(S(=O)(=O)CCc3c(CCOS(C)(=O)=O)n(C(c4ccccc4)c4ccccc4)c4ccc(Cl)cc34)cc2)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
CH3SO2Cl (2 eq) and Et3N (2.5 eq) were added to a solution of methyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (1 eq) in CH2Cl2 (0.02M) at 0° C. under N2. After 1 hour the reaction was warmed to room temperature. After an additional hour water was added and extracted with CH2Cl2 and washed with brine and dried over sodium sulfate. Removed solvent to obtain methyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)benzoate (light-yellow solid) in 99% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([CH2:10][CH3:11])[CH:3]=1.P(Br)(Br)[Br:13]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:13])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: CCc1cc(Br)ccc1CO
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of (4-bromo-2-ethyl-phenyl)-methanol (7.9 g, 36.7 mmol) in anhydrous CHCl3 (122 mL) was added PBr3(4.2 mL, 44.1 mmol). The resulting mixture was stirred at room temperature for 2 hours before it was quenched by the addition of water. The organic layer was washed with NaHCO3, brine and dried over MgSO4. The solvent was removed in vacuo and the residue was filtered through a pad of silica gel with 20% EtOAc in hexanes. The solvent was removed in vacuo to afford the desired product (8.4 g, 83%). 1H NMR (300 MHz, CDCl3): δ 1.29 (t, J=7.5 Hz, 3 H), 2.71-2.78 (m, 2 H), 4.48 (s, 2H), 7.17-7.20 (m, 1H), 7.29-7.32 (m, 1 H), 7.36-7.38 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[N:23]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[N:22]=[C:21]([CH:34]([CH3:36])[CH3:35])[CH:20]=3)=[O:17])=[C:11]([F:37])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl>[C:44]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[N:23]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[N:22]=[C:21]([CH:34]([CH3:35])[CH3:36])[CH:20]=3)=[O:17])=[C:11]([F:37])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:46])[CH3:45]
Reactant: CC(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(N)c3)cc2F)n(-c2ccc3ncccc3c2)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)C)nn3-c3ccc4ncccc4c3)c(F)c2)ccn1
Reaction time: 60 h
Yield: 76 %

Procedure:
A solution of the above 1-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (44 mg, 0.061 mmol theory) and pyridine (0.30 mL, 3.7 mmol) in CH2Cl2 (1 mL) was treated with acetic anhydride (0.040 mL, 0.39 mmol). The reaction was stirred for 60 h and then partitioned between EtOAc and 2 M aq Na2CO3. The organic layer was washed with water and brine. The aqueous phases were back extracted with EtOAc. The combined organic phases were dried (Na2SO4), concentrated in vacuo and purified by reverse-phase chromatography to provide 1-(4-(2-acetamidopyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (25 mg, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 9.01 (s, 1H), 8.96-8.94 (m, 2H), 8.49 (m, 1H), 8.18-8.11 (m, 4H), 7.95 (dd, J=8.8, 2.4 Hz, 1H), 7.64-7.59 (m, 2H), 7.21 (dd, J=11.8, 2.7 Hz, 1H), 6.98 (m, 1H), 6.65 (dd, J=5.8, 2.4 Hz, 1H), 6.43 (s, 1H), 2.93 (m, 1H), 2.03 (s, 3H), 1.26 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 540.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:40])[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:22])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)C)=[CH:13][CH:12]=3)[C:3]=12.Cl.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:40])[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:22])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)[C:3]=12
Reactant: CC(=O)Nc1ccc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(N)cc2)c2c(N)ncnc21
Yield: 27.3 %

Procedure:
To a solution of Example 107 (0.080 g, 0.149 mmoles) in ethanol (5 ml), Con.HCl (0.5 ml) was added and refluxed for 2 h. The reaction mixture was basified with sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.020 g, 27% yield). MP: 91-94° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.04 (dd, J=8.3, 1.5 Hz, 1H), 8.02 (s, 1H), 7.85 (m, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.53 (t, J=7.6 Hz, 2H), 7.29 (m, 3H), 7.06 (dt, J=8.7, 2.3 Hz, 1H), 6.91 (br s, 1H), 6.68 (d, J=8.4 Hz, 2H), 6.00 (q, J=7.0 Hz, 1H), 5.42 (s, 2H), 1.87 (d, J=7.0 Hz, 3H). Mass: 492.83 (M+).
Reaction SMILES: Cl[C:2]1[C:3]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=O)=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[N:7]=1.O.[NH2:27][NH2:28]>C(O)C>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[C:3]2[C:2](=[N:7][C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[CH:5][N:4]=2)[NH:28][N:27]=1
Reactant: NN
Reactant: O=C(c1ccccc1Cl)c1ncc(Oc2ccc(F)cc2F)nc1Cl
Solvent: CCO
Solvent: O
Product: Fc1ccc(Oc2cnc3c(-c4ccccc4Cl)n[nH]c3n2)c(F)c1
Yield: 42.1 %

Procedure:
To a solution of [3-chloro-5-(2,4-difluorophenoxyl)pyrazin-2-yl]-(2-chlorophenyl)methanone (0.73 g, 1.9 mmol, 1.0 eq) in ethanol was added hydrazine hydrate (0.19 mL, 3.8 mmol, 2.0 eq). The resulting mixture was refluxed under nitrogen for 0.5 hours. The reaction mixture was cooled and filtered to give 3-(2-chlorophenyl)-6-(2,4-difluorophenoxy)-1H-pyrazolo[3,4-b]pyrazine (0.285 g, 0.8 mmol, 42% yield) as a solid. MP=240.5-241.5° C. Mass spec., M+1=359.
Reaction SMILES: COC([N:5]1[N:12](C(OC)=O)[CH:11]2[CH:6]1[CH:7]1[CH:17]([O:18]C(=O)C)[CH:10]2[CH:9]=[CH:8]1)=O.[OH-].[Na+].[O-]Cl.[Na+]>>[OH:18][CH:17]1[CH:10]2[CH:9]=[CH:8][CH:7]1[CH:6]1[CH:11]2[N:12]=[N:5]1
Reactant: COC(=O)N1C2C3C=CC(C3OC(C)=O)C2N1C(=O)OC
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Product: OC1C2C=CC1C1N=NC21
Reaction time: 1 h

Procedure:
92 parts of 3,4-dimethoxycarbonyl-9-acetoxy-3,4-diazatricyclo[4,2,1,02,5 ]non-7-ene and 570 parts of 20 percent strength aqueous NaOH were stirred for 3 hours at 70° C., after which 356 parts of 13 percent strength by weight aqueous NaOCl were added dropwise at 40° C. and stirring was continued for 1 hour at 40° C. The reaction mixture was extracted continuously for 12 hours with 300 parts of CH2Cl2, the organic phase was dried with MgSO4, treated with active charcoal and evaporated down, and the residue was digested with 200 parts of petroleum ether. 36.4 parts (86 mol %) of 9-hydroxy-3,4-diazatricyclo[4,2,1,02,5 ]nona-3,7-diene of melting point 128° C. (from cyclohexane) were obtained. ##STR13##
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([C:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH:27]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=3)[OH:25])=[C:11]([C:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH:27]=3)[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC(C)c1nc2c(c(C3=CCC(F)(F)CC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(C3=CCC(F)(F)CC3)c1[C@H](O)c1ccc(C(F)(F)F)cn1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-(4,4-difluorocyclohex-1-enyl)-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 2-bromo-5-(trifluoromethyl)pyridine.
Reaction SMILES: [C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([C:40]([O:42]C)=[O:41])[CH:34]=3)=[O:31])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+]>O1CCCC1>[C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:29][C:30](=[O:31])[NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH:34]=3)[C:40]([OH:42])=[O:41])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(NC(=O)NC2CN(C(=O)CC(C)(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1ccc(C)c(C(=O)O)c1)CN2C(=O)CC(C)(C)C
Temperature: 45 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-methylphenyl)urea (0.94 g) was dissolved in tetrahydrofuran (20 ml), aqueous lithium hydroxide monohydrate (0.32 g) solution (10 ml) was added, the mixture was stirred at 40-50° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was weakly acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(chloroform:methanol=30:1), to thereby obtain 0.56 g of the title compound as colorless powder (Yield: 61%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:25][CH2:24]2)=[CH:4][C:5]([N:20]([CH3:22])[CH3:21])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].[CH:36]1([C:39]2[O:40][CH:41]=[C:42]([C:44](O)=[O:45])[N:43]=2)[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH3:21][N:20]([CH3:22])[C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:19][C:2]([NH:1][C:44]([C:42]2[N:43]=[C:39]([CH:36]3[CH2:38][CH2:37]3)[O:40][CH:41]=2)=[O:45])=[C:3]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:27][CH2:28]2)[CH:4]=1
Reactant: Cc1ccccc1N1CCN(c2cc(N(C)C)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Reactant: O=C(O)c1coc(C2CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1N1CCN(c2cc(N(C)C)c(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2coc(C3CC3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
5-Amino-2-dimethylamino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 7c (111.4 mg, 0.23 mmol, 100 mol %), 2-cyclopropyl-oxazole-4-carboxylic acid 1h (53.5 mg, 0.35 mmol, 150 mol %) and N,N-diisopropylethylamine (0.12 ml, 0.70 mmol, 300 mol %) were combined in N,N-dimethylformamide (2.0 ml) and HATU (132.7 mg, 0.35 mmol, mol %) was added and the reaction was stirred at room temperature for 16 h. The reaction was then diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate and then concentrated to a residue that was purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to afford 2-cyclopropyl-oxazole-4-carboxylic acid [4-dimethylamino-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 7e (100.0 mg; 0.16 mmol, 70.0%) as a white solid.