Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2C(=O)[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][CH2:21][CH2:22][NH:23][S:24]([NH2:27])(=[O:26])=[O:25])=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8].C1COCC1.[OH-].[Na+].P(=O)(O)(O)O>O.C(OC)(C)(C)C>[NH2:27][S:24]([NH:23][CH2:22][CH2:21][NH:20][C:16]1[C:15]([C:10](=[N:11][OH:12])[NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=2)=[N:19][O:18][N:17]=1)(=[O:25])=[O:26]
Reactant: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Temperature: 20 °C
Reaction time: 0.12 h
Yield: 95.5 %

Procedure:
To a 20-L glass reactor was added N-[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]sulfamide (799.4 g, 1.72 mol) and THF (3.2 L). The resulting solution was stirred at 20° C. for 7 min. and then charged with water (1.6 L). The batch was cooled to 2° C. and was charged with 30 wt % sodium hydroxide solution (475 mL, 666.4 g, 4.99 mol, 2.9 equiv.) over 8 minutes. The batch was warmed to 20° C. and the temperature was maintained for 16 h. The batch was then charged with methyl tert-butyl ether (8.0 L) over 23 minutes. Water (2.7 L) was added and the batch was cooled to about 0° C. The batch was then charged with 85 wt % phosphoric acid (370.7 g, 3.22 mol, 1.9 equiv.) over 9 minutes. The batch was warmed to 20° C. and stirred for 1 h. The batch was allowed to settle and phases were separated. The organic layer was retained in the reactor and charged with water (2.9 L) and 85 wt % phosphoric acid (370.7 g, 3.22 mol) and stirred at 20° C. for 1 h. The batch was allowed to settle and phases were separated. The organic layer was retained in the reactor and charged with water (3.2 L) and stirred at 20° C. for 1 h. The batch was allowed to settle and phases were separated. The organic solution was retained in the reactor and distilled under reduced pressure at 20° C. to remove 3.4 Kg of distillate. Ethanol (4.8 L) was charged to the batch and the batch was distilled to a volume of 3.2 L. This distillation process was repeated one more time. Ethanol (0.6 L) was added to the batch to adjust the batch volume to 4 L. The batch was stirred at 20° C. for 16 h and then charged with water (6.39 L). The resultant slurry was stirred at 20° C. for 5 h. The product was collected by filtration and was washed twice with a mixture of ethanol (529 mL) and water (1059 mL). The product was dried under reduced pressure at 45° C. for 65 h to afford the desired product (719.6 g, 95.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.51 (s, 1 H), 8.90 (s, 1 H), 7.17 (t, J=8.8 Hz, 1 H), 7.11 (dd, J=6.1, 2.7 Hz, 1 H), 6.76 (m, 1 H), 6.71 (t, J=6.0 Hz, 1 H), 6.59 (s, 2 H), 6.23 (t, J=6.1 Hz, 1 H), 3.35 (dd, J=10.9, 7.0 Hz, 2 H), 3.10 (dd, J=12.1, 6.2 Hz, 2 H); C11H13BrFN7O4S (MW 438.23), LCMS (EI) m/e 437.9/439.9 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](Cl)=[O:41]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:40](=[O:41])[C:39]3[CH:43]=[CH:44][CH:45]=[C:37]([O:36][CH3:35])[CH:38]=3)=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)N(Cc2ccc3ccc(C#N)cc3c2)c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)c1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, 3-methoxybenzoyl chloride.
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([N:15]2[CH2:20][CH2:19][C@:18]([CH2:27][C:28]([OH:31])([CH3:30])[CH3:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:17][C:16]2=[O:32])[CH3:14])=[CH:9][CH:8]=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C([O-])([O-])=O.[K+].[K+]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[C:33]([O:37][C:38]([N:40]1[CH2:41][CH:42]=[C:43]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]([N:15]3[CH2:20][CH2:19][C@:18]([CH2:27][C:28]([OH:31])([CH3:29])[CH3:30])([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:17][C:16]3=[O:32])[CH3:14])=[CH:9][CH:8]=2)[CH2:44][CH2:45]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Dimethylformamide (5 mL) was added to a flask charged with a stir bar, 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (0.30 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.22 g), K2CO3 (0.29 g), and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (57 mg) under argon atmosphere. The resulting mixture was stirred at 80° C. overnight. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 40:60→0:100) to afford the title compound.
Reaction SMILES: [CH2:1]([O:5][CH:6]([C:24]([F:27])([F:26])[F:25])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=CC=CC=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]>C(O)C.[Pd]>[CH2:1]([O:5][CH:6]([C:24]([F:25])([F:26])[F:27])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(CCCc1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCCCOC(CCCc1ccc(O)cc1)C(F)(F)F
Reaction time: 5 h
Yield: 99.2 %

Procedure:
0.95 g (2.5 mmol) of the product (22-1) of Preparation Example 39 was dissolved in 50 ml of ethanol, and the solution was added with 0.1 g of 10% Pd/C and stirred vigorously under hydrogen pressure of 1-1.2 atm. for 5 hours. After the reaction, Pd/C was filtered out and the filtrate was concentrated under reduced pressure to give 0.72 g of (+)-4-(4-butoxy-5,5,5-trifluoropentyl)phenol (3-23). Yield: 99%; [α]D20 =-2.9° (c=1, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12](O)=[O:13].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][OH:13]
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1c[nH]c2ccc(F)cc12
Reaction time: 0.5 h
Yield: 102.5 %

Procedure:
To a solution of 5-fluoro-indol-3-acetic acid (4.3 g, 0.022 mol) in anhydrous THF (35 ml) was added LiAlH4 (1.0 M, 33 ml, 0.033 mol) at 0° C. The mixture was allowed to stir for 0.5 hours and, then quenched by saturated NH4Cl solution. The mixture was then filtered through celite. The filtrate was washed with 1N NaOH (3×100 ml) and extracted with ethyl acetate (3×100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride) afforded 4.04 g (100%) of product as an off-white solid: mp 59-61° C.
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([NH2:8])[C:4]=1[CH3:9].[CH3:10][N:11]([CH3:24])[C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:22][CH3:23]>C(O)(=O)C>[Cl-:1].[CH3:10][N:11]([CH3:24])[C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH:16]=[N:2][N+:3]2[CH:7]=[CH:6][N:5]([N:8]=[CH:16][C:15]3[CH:18]=[C:19]([O:20][CH3:21])[C:12]([N:11]([CH3:10])[CH3:24])=[C:13]([O:22][CH3:23])[CH:14]=3)[C:4]=2[CH3:9])=[CH:14][C:13]=1[O:22][CH3:23]
Reactant: COc1cc(C=O)cc(OC)c1N(C)C
Reactant: Cc1n(N)cc[n+]1N
Agent: [Cl-]
Solvent: CC(=O)O
Product: COc1cc(C=Nn2cc[n+](N=Cc3cc(OC)c(N(C)C)c(OC)c3)c2C)cc(OC)c1N(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.2 g of 1,3-diamino-2-methylimidazolium chloride and 6.9 g of 4-dimethylamino-3,5-dimethoxy-benzaldehyde are dissolved in 100 ml of glacial acetic acid, whereupon the solution is stirred at room temperature for 48 hours. The glacial acetic acid is distilled off in vacuo and the residue is dissolved in 100 ml of ethyl acetate. After crystallization sets in a further 300 ml of ethyl acetate are added thereto, whereupon the mixture is cooled to 10°. The crystallized-out material is filtered off under suction, washed with 100 ml of ethyl acetate and dried over potassium hydroxide in vacuo at 80°. There is obtained 1,3-bis[[4-(dimethylamino)-3,5-dimethoxybenzylidene]amino]-2-methylimidazolium chloride of decomposition point 226°.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1)[CH3:2].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:11][CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(C#N)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: CC(Br)c1ccc(C#N)cn1
Temperature: 25 °C

Procedure:
A solution of 6-ethyl-nicotinonitrile (synthesis described in WO2008/71404, 1000 mg, 7.57 mmol), N-bromosuccinimide (1632 mg, 9.08 mmol) and 2,2′-azo-bis(isobutyronitrile) (62 mg, 0.38 mmol) in chloroform (12 mL) is heated at reflux for 7 min. After cooling to room temperature, the reaction mixture is filtered and the volatiles are removed under reduced pressure (260 mbar, 55° C.) to yield the product which was used without further purification. Yield: 1597 mg (quant.); ESI mass spectrum: [M+H]+=211 (Br pattern); Retention time HPLC: 0.92 min (Z018_S04).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15](=[O:22])(=[O:21])[NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:23]Br>C(Cl)(Cl)(Cl)Cl.[W]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15](=[O:22])(=[O:21])[NH:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH:5]=[CH:6][C:7]=1[CH2:8][Br:23]
Reactant: Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Reactant: BrBr
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)c(F)c1
Yield: 81.8 %

Procedure:
A solution of 1.08 g (3.36 mmol) of 3-fluoro-4-methyl-2'-(N-t-butyl-sulfamoyl)biphenyl (from Step A) in 20 mL of CCl4 was stirred at reflux under irradiation from a 100-watt tungsten lamp as a solution of 3.5 mmol of bromine in approximately 13 mL of CCl4 was added dropwise over 1.5 hour. After being stirred at reflux overnight, the solution was cooled and concentrated. The residue was crystallized from EtOAc-hexane to give 1.10 g of the title compound as an off-white solid, mp 138°-140° C. (estimated purity 87%; contains minor unbrominated and dibrominated contaminants by TLC); mass spectrum (FAB) m/e 400, 402 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.I[C:30]1[C:38]2[C:33](=[N:34][CH:35]=[N:36][C:37]=2[NH2:39])[N:32]([C@H:40]2[CH2:45][CH2:44][C@@H:43]([N:46]3[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]3)[CH2:42][CH2:41]2)[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:39][C:37]1[N:36]=[CH:35][N:34]=[C:33]2[N:32]([C@H:40]3[CH2:45][CH2:44][C@@H:43]([N:46]4[CH2:47][CH2:48][N:49]([CH3:52])[CH2:50][CH2:51]4)[CH2:42][CH2:41]3)[N:31]=[C:30]([C:7]3[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[C:3]([O:2][CH3:1])[CH:8]=3)[C:38]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OCc1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of benzyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]carbamate (2.00 g, 0.0052 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.92 g, 0.0044 mol), tetrakis-(triphenylphosphine)palladium (0.300 g, 0.00026 mol) and sodium carbonate (1.35 g, 0.0109 mol) was heated in a mixture of ethylene glycol dimethyl ether (70 mL) and water (35 mL) at 80° C. for sixteen hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (180 mL), the organic layer separated and the aqueous layer further extracted twice with ethyl acetate (250 mL each). The combined organic extracts were dried over magnesium sulfate. The solvents were evaporated under reduced pressure to leave a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (96:3:1) as a mobile phase to give cis-benzyl N-{4-{4-amino-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl}carbamate as a white solid (1.88 g, 0.0023 mol). Cis-benzyl N-{4-{4-amino-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl}carbamate (0.206 g, 0.00036 mol) was dissolved in refluxing ethanol (17 mL) and a preheated solution of maleic acid (0.126 g, 0.00108 mol) in ethanol (8 mL) was added. The mixture was refluxed for 10 min, cooled to ambient temperature and the precipitate collected by filtration, washed with ethyl acetate and dried to give cis-benzyl N-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl}-carbamate dimaleate as a white solid (0.224 g, 0.00028 mol):
Reaction SMILES: [OH-:1].[Na+].[CH:3]([C:5]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:26][CH3:27])[CH:11]=2)[N:6]=1)=[O:4]>O1CCOCC1.[Ag-]=O>[C:3]([C:5]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:26][CH3:27])[CH:11]=2)[N:6]=1)([OH:1])=[O:4]
Reactant: COc1ccc2nc(C=O)nc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: [OH-]
Agent: O=[Ag-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2nc(C(=O)O)nc(NCc3ccc4c(c3)OCO4)c2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
1.00 g of silver (I) oxide and 15 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 0.59 g (1.8 mmol) of the 2-formyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline prepared in Example 141 in 20 ml of 1,4-dioxane. The obtained mixture was stirred at 60° C. After 30 minutes, the reaction mixture was filtered through Celite and the filter cake was washed with a small amount of dioxane and water. The filtrate and washings were neutralized with 1N hydrochloric acid and extracted with chloroform/ethanol. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under a reduced pressure to remove the solvent. The crystal thus formed was recovered by filtration and washed with chloroform to give 0.34 g of the title compound as a pale-yellow crystal.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:11][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2cc[nH]c2c1

Procedure:
A solution of 1H-indole-6-carboxylic acid (10 g) in methanol (300 mL) was treated with concentrated sulfuric acid (0.5 mL) then heated on a steam bath for 10 hours. The solvent was removed under reduced pressure and the residue partitioned between saturated sodium bicarbonate solution (150 mL) and dichloromethane (150 mL). The aqueous layer was further extracted twice with dichloromethane (150 mL). The combined organics were dried over sodium sulfate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (7:3, v/v) to give the title compound (7.4 g) as a white solid, m.p. 79-81° C. MS: 176(MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[N:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[N:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnn2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-oxo-3-(3-pyridazin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K27) (224 mg, 0.75 mmol) according to the general procedure M. Obtained as a white solid (250 mg, 67%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].N1C=CN=C1.[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>>[Si:28]([O:14][CH2:13][C@H:12]1[O:15][C@@H:7]([N:6]2[CH:16]=[C:2]([CH3:1])[C:3](=[O:18])[NH:4][C:5]2=[O:17])[C@H:8]([OH:9])[C@@H:10]1[OH:11])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29]
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: Cc1cn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Yield: 72.9 %

Procedure:
A solution of 5-methyluridine (1.42 g, 5.49 mmol), imidazole (0,816 g, 11.26 mmol) and tertbutyldimethylsilyl chloride (0.9 g, 6.01 mmol) was stirred at room temperature for 24 hours and then concentrated in vacuo. The residue obtained was purified by chromatography on a silica gel column using CHCl3 -methanol (30:1) as the eluent to give 1.49 g (73%) of 5'-O-tert-butyldimethylsilyl-5-methyluridine as a colorless solid: mp 209°-211° C. (ethyl acetate); 1H NMR (DMSO-d6) δ 0.0 (6H, s, (CH3)2Si), 0.81 (9H, s, (CH3)3CSi), 3.60-3.90 (5H, m, 2, 3, 4' and 5'-H), 4.97 (1H, d, J=4.39 Hz, 3'-OH, exchangeable), 5.25 (1H, d, J=5.57 Hz, 2'-OH, exchangeable), 5.71 (1H, d, J=5.57 Hz, 1'-H), 7.32 (1H, s, 6-H), 11.21 (1H, s, NH, exchangeable).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[N:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:12]12[CH:11]([N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:10]1[CH2:9][NH:8][CH2:13]2
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2N(Cc1ccccc1)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CN(Cc2ccccc2)C2C3CNCC32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 6-dibenzylamino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.800 g, 2.10 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (2.5 mL). The resulting mixture was stirred at ambient temperature for 3 hours and then quenched with saturated aqueous solution of Na2CO3 (10 mL). The organic phase was separated, washed with water, saturated NaCl, dried over MgSO4 and then concentrated in vacuo. The obtained crude product, (3-azabicyclo[3.1.0]hex-6-yl)dibenzylamine, was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[C:8]=1[CH3:24].ClC1C=CC=C(C(OO)=[O:33])C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:33])[C:8]=1[CH3:24]
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3s2)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3s2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
0.6 g of 2-{4-(3-methoxypropoxy)-3-methylpyridine-2-yl}methylthiobenzothiazole was dissolved in 20 ml of dichloromethane to obtain a solution. 0.36 g of 80% m-chloroperbenzoic acid was added to the solution at -45° C. After one hour, 0.34 g of triethylamine and 30 ml of a saturated aqueous solution of sodium hydrogencarbonate were added to the obtained mixture. The resulting mixture was stirred at a room temperature for 30 minutes. The dichloromethane layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate twice, dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain a residue. This residue was purified by silica gel column chromatography to obtain 0.17 g of the title compound as a white crystal.
Reaction SMILES: [CH3:1][C:2]12[C:14]3[C:6](=[CH:7][CH:8]=[C:9]([NH:15][C:16]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([O:26]C)=[O:25])=[N:22][CH:23]=4)=[O:17])[C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]12[C:14]3[C:6](=[CH:7][CH:8]=[C:9]([NH:15][C:16]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([OH:26])=[O:25])=[N:22][CH:23]=4)=[O:17])[C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc3c4c2CCCC4(C)CCC3)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC12CCCc3ccc(NC(=O)c4ccc(C(=O)O)nc4)c(c31)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
A solution of methyl 5-[(6a-methyl-5,6,6a,7,8,9-hexahydro-4H-phenalenyl)carbamoyl]pyridine-2-carboxylate (0.161 g) in ethanol (10 ml) was added with 2 N aqueous sodium hydroxide (1 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethanol-chloroform to obtain the title compound (0.149 g, yield: 96%) as pale yellow powdery crystals (melting point: 199-200° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.Cl[C:41]1C=CC([C@@H](O)C(F)(F)F)=C(N2C=CC(C3CC3)=N2)[CH:42]=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:42][CH2:41]3)=[N:35]2)[C:23]([F:25])([F:24])[F:26])[N:3]=1
Reactant: O[C@H](c1ccc(Cl)cc1-n1ccc(C2CC2)n1)C(F)(F)F
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Product: Nc1nc(O[C@H](c2ccc(Cl)cc2-n2ccc(C3CC3)n2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(4-chloro-2-(3-cyclopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (Intermediate 42).