Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Cl.[N:12]([O-])=O.[Na+]>>[C:1]([N:9]=[N+:10]=[N-:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=N[O-]
Reactant: NNC(=O)c1cccnc1
Agent: Cl
Agent: [Na+]
Product: [N-]=[N+]=NC(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
Nicotinic acid hydrazide (18 g) was added in small portions with ice cooling to 22 ml concentrated hydrochloric acid, and 30 ml of aqueous solution of 18 g sodium nitrite was then added dropwise while maintaining the temperature at 0° C. or lower. The mixture was stirred at 0° C. for 15 minutes and extracted with ether, the extract was washed with an aqueous solution of sodium bicarbonate and dried over anhydrous sodium sulfate, and the solvent was distilled off from the dried solution, giving 16 g of nicotinic acid azide.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:14]([O:16][C:17](=[O:28])[CH:18]([NH2:27])/[CH:19]=[C:20](\[CH3:26])/[CH2:21][P:22]([OH:25])([OH:24])=[O:23])[CH3:15].[BH4-].[Na+].Cl>O.C(O)C.C(O)(=O)C>[CH2:14]([O:16][C:17](=[O:28])[CH:18]([NH:27][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)/[CH:19]=[C:20](\[CH3:26])/[CH2:21][P:22]([OH:24])([OH:25])=[O:23])[CH3:15]
Reactant: CCOC(=O)C(N)/C=C(\C)CP(=O)(O)O
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(/C=C(\C)CP(=O)(O)O)NCc1ccccc1
Reaction time: 0.5 h

Procedure:
16 ml of glacial acetic acid, 5.90 g of sodium acetate (anhydrous) and 12.2 ml of benzaldehyde are added to a solution of 5.69 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester in 48 ml of water and 48 ml of ethanol. 15.70 g of sodium borohydride are added in approximately 70 portions within a period of one hour with intensive cooling with ice/sodium chloride, 4 ml of benzaldehyde being added after half the addition has taken place, after approximately 30 minutes. The temperature of the reaction mixture is kept at from 0 to 10°. When the addition is complete, the mixture is stirred at 0° for one hour to complete the reaction, and then 1 N hydrochloric acid is added dropwise until an acidic reaction to Congo red takes place. The undissolved salts are filtered off and washed with water. The filtrate is concentrated to dryness by evaporation in vacuo, and the residue is concentrated by evaporation twice more after the addition of ethanol. The residue is then stirred with 150 ml of ethanol, and the undissolved material is filtered off with suction and washed with ethanol. 25 ml of propylene oxide are added to the filtrate, and the mixture is then stirred for 2 hours. The material which crystallises out (mainly educt) is filtered off. The mother liquor is concentrated to dryness by evaporation and stirred with 350 ml of ethyl acetate. The crystalline crude product obtained after filtration with suction is recrystallised from ethanol. In this manner there is obtained E-2-benzylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, m.p. 192 ° (decomp.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C:10](=[CH:11][C:12]3[C:17]2=[N:16][C:15]([Br:22])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([Br:22])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)Cc2cc3ccc(Br)nc3n21
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21

Procedure:
This compound was prepared in analogy to example 2, intermediate, from (4R)-6-bromo-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and sodium cyanoborohydride.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:15][CH3:16].[CH3:17][N:18](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:15][CH3:16])#[N:18]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(C)c1ccc(I)c(OC)c1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)c1ccc(C#N)c(OC)c1
Temperature: 120 °C
Reaction time: 36 h
Yield: 51 %

Procedure:
To a stirred solution of ethyl 2-(4-iodo-3-methoxyphenyl)propanoate (626 mg, 1.873 mmol) in dimethylformamide were added zinc cyanide (227 mg, 1.929 mmol) and tetrakis(triphenylphosphine) palladium (216 mg, 0.1873 mmol). The reaction mixture was stirred for 36 h at 120° C., then cooled to room temperature, diluted with ethyl acetate. The mixture was filtered using celite pad. The filtrate dissolved in ethyl acetate and extracted with NaHCO3. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. Ethyl 2-(4-cyano-3-methoxyphenyl)propanoate (222 mg) was obtained as 51% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([CH2:29]O)[CH2:13]N1CC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C1)=[N:9][C:8]([O:31]C)=[CH:7][CH:6]=2.C(N(C(C)C)CC)(C)C.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:31])[N:9]3[CH2:13][C:12](=[CH2:29])[C:11]=1[C:10]=23
Reactant: COc1ccc2ncc(Cl)c(C(CO)CN3CC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C3)c2n1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C1Cn2c(=O)ccc3ncc(Cl)c1c32

Procedure:
A solution of 1,1-dimethylethyl ((3R,45)-1-{(2R/S)-2-[3-chloro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-hydroxypropyl}-3-hydroxy-4-piperidinyl)carbamate (8.75 g, 18.7 mmol) and diisopropylethylamine (4.9 ml) in dichloromethane (90 ml) was treated at 0° C. under argon with para-toluenesulphonic anhydride (6.7 g, 20.6 mmol). After 3 hours at room temperature more para-toluenesulphonic anhydride (0.7 g) was added. After 2.5 days the mixture was washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (2×) and the combined organic extracts dried and evaporated. The residue was chromatographed, eluting with methanol/dichloromethane to give firstly the partially purified title compound (0.84 g, 21%) then 1,1-dimethylethyl {(3R,4S)-1-[(3-chloro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-3-hydroxy-4-piperidinyl}carbamate (3.93 g, 48%). The partially purified title compound (0.84 g) was further purified by chromatography eluting with methanol/dichloromethane affording pure product (0.57 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:20]([O:22][CH2:23][C:24](Cl)=O)[CH3:21].C(N(CC)CC)C.C(O)C>ClCCl>[CH2:20]([O:22][CH2:23][C:24]1[N:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:21]
Reactant: CCOCC(=O)Cl
Reactant: CCOC(=O)CCNc1c(N)cnc2ccccc12
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
Ethyl N-(3-aminoquinolin-4-yl)-β-alaninate (20.0 g, 77.3 mmol, prepared in Parts A and B of Example 22) was treated with ethoxyacetyl chloride (11.29 g, 92.5 mmol) according to a modification the method described in Part A of Example 12. The reaction in dichloromethane (300 mL) was stirred for 1.5 hours, and after the addition of triethylamine (43.08 mL, 309.1 mmol) and ethanol (300 mL), the reaction was heated at reflux for four hours and then subjected to the work-up procedure to provide 25.0 g of ethyl 3-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:13]([Cl:21])=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].O>O1CCCC1>[Cl:21][C:13]1[C:12]([N:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[CH:17][C:16]([CH:18]2[CH2:20][CH2:19]2)=[CH:15][N:14]=1
Reactant: CCOC(=O)c1cnn(-c2cc(C3CC3)cnc2Cl)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)cnn1-c1cc(C2CC2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of 1-(2-chloro-5-cyclopropylpyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.13 g) in tetrahydrofuran (30 ml) were added 4 N aqueous solution of sodium hydroxide (30 ml) and water (20 ml), and stirred at room temperature overnight. After completion of the reaction, the organic solvent was evaporated in vacuo, then water and diethyl ether were added thereto, and the aqueous layer was separated. To the aqueous layer was added concentrated hydrochloric acid under ice-cooling to adjust the layer to pH 5, the precipitated solid was collected by filtration, washed, and then dried at 60° C. under air blow to give the titled compound (922 mg) as a white solid. MS (ESI) m/z: 278 (M+H)+.
Reaction SMILES: Cl.Br[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.C(OCC)(=O)C>C1COCC1.O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)=[CH:19][CH:18]=1
Reactant: BrCc1ccncc1
Reactant: Sc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc(SCc2ccncc2)cc1
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
A suspension of 4-bromomethylpyridine hydrochloride (1.59 g, 6.3 mmol) in THF (10 mL) was treated dropwise with a solution of potassium carbonate (3.33 g, 24.0 mmol) in H2O (6 mL) at 0–5° C., and the resulting mixture was stirred at 0–5° C. for 10 min before being treated dropwise with a solution of 4-bromo-benzenethiol (1.14 g, 6.0 mmol) in THF (5.0 mL) at 0–5° C. under N2. The resulting reaction mixture was subsequently stirred at 0–5° C. for an additional 20 min. When TLC and LCMS showed that the reaction was complete, the reaction mixture was treated with water (15 mL) and ethyl acetate (25 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with water (2×15 mL) and saturated aqueous NaCl solution (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (5–25% EtOAc-hexane gradient elution) to afford the desired 4-(4-bromo-phenylsulfanylmethyl) pyridine 301 (1.374 g; 82%) as a pale-yellow solid, which was directly used in subsequent reactions.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:14]([C@@:15]4([CH3:23])[CH2:16][CH2:17][C:18](=O)[C:19]([CH3:21])([CH3:20])[C@:2]124)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[OH:24].[ClH:25].Cl.[NH:27]1[CH2:31][CH2:30][C@@H:29]([O:32][NH2:33])[CH2:28]1>>[ClH:25].[NH:27]1[CH2:31][CH2:30][C@@H:29]([O:32]/[N:33]=[C:18]2/[C:19]([CH3:21])([CH3:20])[C@:2]34[O:1][C@H:3]3[CH2:4][C@@H:5]3[C@@H:14]([C@@:15]4([CH3:23])[CH2:16][CH2:17]/2)[CH2:13][CH2:12][C@@:10]2([CH3:11])[C@H:6]3[CH2:7][CH2:8][C@@H:9]2[OH:24])[CH2:28]1
Reactant: NO[C@@H]1CCNC1
Reactant: CC1(C)C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]3O[C@]312
Agent: Cl
Product: CC1(C)/C(=N/O[C@@H]2CCNC2)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]3O[C@]312
Yield: 75 %

Procedure:
Prepared in 75% yield (51 mg) as described in Example 2 starting from 5α,6α-epoxy-17β-hydroxy-4,4-dimethylandrostan-3-one, (Preparation 8, 50 mg) and 3-(R)-pyrrolidinyloxyamine dihydrochloride (Preparation 12, 105 mg).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([CH3:50])[CH2:46][CH2:45]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]2[CH2:49][CH2:48][CH:47]([CH3:50])[CH2:46][CH2:45]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1CCN(C(=O)CCl)CC1
Product: CCN(Cc1ccc(OCCN2CCC(C)CC2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 41 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (9.5 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.9 mg) was obtained.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]([OH:8])[CH2:4][N+:5]([O-:7])=[O:6].[C:13](OCC)(=[O:15])[CH3:14]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:13]([O:8][CH:3]([CH:2]([CH3:1])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:4][N+:5]([O-:7])=[O:6])(=[O:15])[CH3:14]
Reactant: CC(C)CC(C)C(O)C[N+](=O)[O-]
Reactant: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C[N+](=O)[O-])C(C)CC(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.3 %

Procedure:
After dissolving 7.8 g of 3,5-dimethyl-1-nitro-2-hexanol in 30 ml of pyridine, 10 ml of acetic anhydride were added thereto, and the solution was stirred at room temperature for 2.5 hours. Ethyl acetate was added to the solution, and the organic layer was washed with 1 mol/l of aqueous hydrochloric acid and saturated saline. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 8.4 g of 3,5-dimethyl-1-nitrohex-2-yl acetate (yield: 87.3%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:9])([CH3:6])([CH3:5])[CH3:4].IC.[C:30](O)(=O)C>C1COCC1>[C:3]([O:7][C:8]([N:10]([CH3:30])[CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NCCOCCOCCOCCOCCC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(CCOCCOCCOCCOCCC(=O)O)C(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
85.4 mg of NaH are added portionwise to a solution, cooled to 0° C., of 520 mg of 3-[2-(2-{2-[2-((tert-butoxycarbonyl)amino)ethoxy]ethoxy}ethoxy)ethoxy]propanoic acid in 14 ml of THF. After stirring for 5 min, 150 μl of iodomethane are added. The mixture is then stirred at AT for 2 h and then an additional 150 μl of iodomethane are added. After 12 h at AT, the mixture is hydrolysed and then brought to acidic pH by addition of aqueous acetic acid at 0° C. The aqueous phase is extracted 3× with AcOEt, the combined organic phases are dried over MgSO4 and concentrated under RP, and the crude product obtained is reacted again according to the same protocol with 85 mg of NaH and 176 μl of iodomethane for an additional 2 h. 500 mg of 3-[2-(2-{2-[2-((tert-butoxycarbonyl)(methyl)amino)ethoxy]ethoxy}ethoxy)ethoxy]propanoic acid are thus obtained.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH2:15]([NH2:18])[CH2:16][CH3:17].[CH:19]1([CH2:25][NH:26][C:27]2[CH:28]=[C:29]([CH:42]=[CH:43][CH:44]=2)[O:30][C:31]2[CH:32]=[CH:33][C:34]([N+:39]([O-:41])=[O:40])=[C:35]([CH:38]=2)[CH:36]=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCCl>[CH:19]1([CH2:25][NH:26][C:27]2[CH:44]=[CH:43][CH:42]=[C:29]([O:30][C:31]3[CH:32]=[CH:33][C:34]([N+:39]([O-:41])=[O:40])=[C:35]([CH2:36][NH:18][CH2:15][CH2:16][CH3:17])[CH:38]=3)[CH:28]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1cc(Oc2cccc(NCC3CCCCC3)c2)ccc1[N+](=O)[O-]
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNCc1cc(Oc2cccc(NCC3CCCCC3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaBH(OAc)3 (0.0080 mol) was added to a mixture of propylamine (0.0054 mol) and 5-[3-(cyclohexylmethyl-amino)-phenoxy]-2-nitro-benzaldehyde (0.00054 mol) in DCE (100 mL). Then the reaction mixture was stirred overnight at room temperature and washed with a saturated NaHCO3 solution. The organic layer was separated, dried (MgSO4), and filtered, and the solvent was evaporated. The residue was purified by column chromatography (eluent: 100% CH2Cl2). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[CH:13](OCC)(OCC)OCC.[BH4-].[Na+]>>[CH3:12][O:11][C:7]1[C:6]2[C:2]([NH:1][CH3:13])=[N:3][O:4][C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2onc(N)c12
Reactant: CCOC(OCC)OCC
Agent: [BH4-]
Agent: [Na+]
Product: CNc1noc2cccc(OC)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.8 g [11 mmol] of 3-amino-4-methoxy-1,2-benzisoxazole and 22.5 g [151.8 mmol] of triethyl orthoformate are boiled under reflux with exclusion of moisture for 18 hours. After concentrating by rotary evaporation under reduced pressure, the remaining residue is taken up in 50 ml of ethanol and, after the addition of 3.05 g [80.6 mmol] of sodium borohydride, the mixture is stirred first at room temperature for 3 hours and then at 50° C. for 12 hours. The mixture is concentrated, and the residue is dissolved in dichloromethane and washed with water. After drying and concentrating the organic phase, 1.5 g of the compound (XIIa-1) are obtained as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:34]([NH:41][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:4][CH:3]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCc1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cnc(NCCN3CCCCC3)nc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccccc3)n2)c2cnc(NCCN3CCCCC3)nc21
Temperature: 105 °C
Reaction time: 16 h

Procedure:
A sealed tube was charged with [3-(6-bromo-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-piperidin-1-yl-ethyl)-amine (from Example 41 supra) (285 mg, 0.54 mmol), benzylamine (69 mg, 0.65 mmol), Pd2(dba)3 (20 mg), DavePhos (30 mg), tBuONa (61 mg, 0.65 mmol) and dioxane (10 mL). This mixture was stirred at 105° C. under an atmosphere of N2 for 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was partitioned between water and dichloromethane. The water layer was extracted with dichloromethane twice. The combined organics was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by a column chromatography (silica gel, 8 g, 200-300 mesh, eluting with MeOH:dichloromethane, 1:100 to 1:50 to give [3-(6-benzylamino-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-piperidin-1-yl-ethyl)-amine as a light-yellow oil. (Yield 131 mg, 43.4%).
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[C:8]([O:19]C)[C:7]=2[C:21](=[O:32])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.B(Br)(Br)Br>O>[CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:16])([CH3:17])[O:13]3)=[C:8]([OH:19])[C:7]=2[C:21](=[O:32])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1c2c(cc(C3CCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)OC(C)(C)CC2=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(=O)c2c(cc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2O)O1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Under argon, 3.10 g (6.94 mmol) of 7-cyclopentyl-5-methoxy-2,2-dimethyl-6-[4-(trifluoro-methyl)benzoyl]-2,3-dihydro-4H-chromen-4-one (Example 8A) are dissolved in 30 ml of abs. dichloromethane. The mixture is cooled to −78° C., 6.25 ml (6.25 mmol) of boron tribromide (1 M in dichloromethane) are added and the yellowish solution is stirred at −78° C. After 1.5 h, another 6.25 ml (6.25 mmol) of boron tribromide (1 M in dichloromethane) are added, and stirring of the mixture is continued at −78° C. After 30 min, another 1.39 ml (1.39 mmol) of boron tribromide (1 M in dichloromethane) are added. After 30 min, 100 ml of water are added and the mixture is stirred for 30 min and allowed to warm to room temperature. The mixture is then extracted repeatedly with ethyl acetate. The combined organic phases are washed once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 25:1). This gives 1.85 g (62% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.I[CH2:16][CH3:17]>>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:16][CH3:17]
Reactant: CCI
Reactant: COC(=O)c1cc(Br)c2cn[nH]c2c1
Product: CCn1ncc2c(Br)cc(C(=O)OC)cc21

Procedure:
In accordance with Example 4 (Steps 1 and 2), methyl 4-bromo-1H-indazole-6-carboxylate was used instead of 5-nitro-1H-indazole, and 2-iodoethane was used instead of ethyl bromide-d5 to obtain methyl 4-bromo-1-ethyl-1H-indazole-6-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH:23][C@H:24]([C:30](O)=[O:31])[CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1.[NH2:33][C@H:34]([C:45]#[N:46])[CH2:35][C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=1[F:44]>>[C:45]([CH:34]([NH:33][C:30](=[O:31])[C@@H:24]([NH:23][C@@H:18]([C:15]1[CH:16]=[CH:17][C:12]([C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[Cl:1])=[CH:13][CH:14]=1)[C:19]([F:22])([F:21])[F:20])[CH2:25][C:26]([F:29])([CH3:27])[CH3:28])[CH2:35][C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=1[F:44])#[N:46]
Reactant: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2Cl)cc1)C(F)(F)F)C(=O)O
Reactant: N#Cc1ccc(C[C@H](N)C#N)c(F)c1
Product: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2Cl)cc1)C(F)(F)F)C(=O)NC(C#N)Cc1ccc(C#N)cc1F

Procedure:
(S)-2-[(S)-1-(2′-Chloro-4′-methanesulfonyl-biphenyl-4-yl)-2,2,2-trifluoro-ethylamino]-4-fluoro-4-methyl-pentanoic acid [1-cyano-2-(4-cyano-2-fluoro-phenyl)-ethyl]-amide was prepared from N-{(1S)-1-[2′-chloro-4′-(methylsulfonyl)biphenyl-4-yl]-2,2,2-trifluoroethyl}-4-fluoro-L-leucine and 4-[(2S)-(2-amino-2-cyanoethyl)]-3-fluorobenzonitrile using procedure described in Example 6.