Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[CH:7]=O.Cl.[CH2:17]([NH2:19])[CH3:18].C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>CO.C(O)(=O)C>[CH2:17]([NH:19][CH2:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:18]
Reactant: CCN
Reactant: O=Cc1cc(Cl)ccc1OC1CCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNCc1cc(Cl)ccc1OC1CCCC1
Temperature: 70 °C
Yield: 80.5 %

Procedure:
5-Chloro-2-cyclopentoxybenzaldehyde (9.35 g, 41.6 mmol) and ethylamine hydrochloride (18.6 g, 229 mmol) in methanol (100 ml) for 30 minutes at ambient temperatures, following which sodium cyanoborohydride (5.6 g, 88 mmol) was added and the reaction left to reflux at 70° C. for 70 hours with periodic acidification to pH 6 using glacial acetic acid. Normal hydrochloric acid (100 ml) was added in a dropwise fashion and the resultant mixture basified with 2 normal sodium hydroxide solution until a pH of 11 existed, whereupon the product was extracted into dichloromethane (250 ml×2) and ethyl acetate (250 ml×2). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and the solvent removed to yield the title compound (8.5 g, 80%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[N:27]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:25]=2)=[O:23])=[CH:17][CH:16]=1.C(O)C>CS(C)=O.CC(O)=O.CC(O)=O.C1CCC([N-]C2CCCCC2)CC1.C1CCC([N-]C2CCCCC2)CC1.[Pd+2]>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]3[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:35])[N:27]=[C:26]([C:36]([F:37])([F:38])[F:39])[CH:25]=3)=[O:23])=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(Nc1ccc(Br)cc1)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: C1CCC([N-]C2CCCCC2)CC1
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)Nc1ccc(-c2ccc(NC(=O)c3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2)cc1
Temperature: 60 °C
Yield: 34 %

Procedure:
In a 4 ml vial was added 22.3 mg (0.125 mmol) of (4-acetylaminophenyl)boronic acid, 11 mg (0.025 mmol) of N-(4-bromophenyl)-1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide, 200 μL of a saturated CsCO3 solution of ethanol and 10 μg of DAPCy. The vial was sealed and heated to 60° C. overnight. The crude product was dissolved up in 200 μL of DMSO and injected directly on a reverse phase LCMS preparative instrument. The relevant fraction was collected dried to afford 2-(2-Chloro-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (4′-acetylamino-biphenyl-4-yl)-amide (4.3 mg, 0.0086 mmol: 34% yield as an off white solid. MS (ESI) m/z 499 [M+H]+.
Reaction SMILES: Cl.FC1C=C(C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.[F:43][C:44]1[CH:70]=[C:69]([N+:71]([O-])=O)[CH:68]=[CH:67][C:45]=1[O:46][C:47]1[C:52]2=[C:53]([CH3:66])[C:54]([O:56][CH2:57][CH2:58][N:59]3[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]3)=[CH:55][N:51]2[N:50]=[CH:49][N:48]=1>>[F:43][C:44]1[CH:70]=[C:69]([NH2:71])[CH:68]=[CH:67][C:45]=1[O:46][C:47]1[C:52]2=[C:53]([CH3:66])[C:54]([O:56][CH2:57][CH2:58][N:59]3[CH2:60][CH2:61][N:62]([CH3:65])[CH2:63][CH2:64]3)=[CH:55][N:51]2[N:50]=[CH:49][N:48]=1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Yield: 51.1 %

Procedure:
Following a procedure similar to that for the synthesis of Compound C of Example 36, 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazine (2.90 g, 6.74 mmol) was converted to the title compound (1.38 g, 51%). MS(ESI+) m/z 401.3 (M+H)+.
Reaction SMILES: F[C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.C[O-].[Na+].[C:16](OCC)(=[O:18])C.O>CO>[F:8][C:5]1[N:4]=[C:3]([C:9]([O:11][CH3:12])=[O:10])[C:2]([O:18][CH3:16])=[N:7][CH:6]=1
Reactant: COC(=O)c1nc(F)cnc1F
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(F)cnc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In 4 mL of methanol was dissolved 0.2 g of methyl 3,6-difluoro-2-pyrazinecarboxylate. Then, a 28% methanol solution of sodium methoxide was added at −25° C., and the mixture thus obtained was stirred at 0° C. for 10 minutes. The reaction mixture was poured into a mixture of 30 mL of ethyl acetate and 30 mL of water, and the organic layer was separated. The organic layer thus obtained was washed successively with 15 ml of water and 15 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel chromatography [eluent: n-hexane:ethyl acetate=5:1] to obtain 0.09 g of methyl 6-fluoro-3-methoxy-2-pyrazinecarboxylate as a colorless solid product.
Reaction SMILES: C([N:4]1[CH2:27][CH2:26][C:7]2[N:8]([CH:16]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[CH3:18])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1)C=C>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH:16]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[CH3:18])[C:7]3[CH2:26][CH2:27][NH:4][CH2:5][C:6]=3[C:14]=2[CH:13]=1
Reactant: C=CCN1CCc2c(c3cc(C)ccc3n2C=C(C)c2ccc(C)nc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=Cn1c2c(c3cc(C)ccc31)CNCC2)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
To a de-aerated solution of 2-allyl-8-methyl-5-[2-(6-methyl-pyridin-3-yl)-propenyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (750 mg, 2.1 mmol) in DCM (7.5 mL) were added 1,3-dimethylbarbutaric acid (984 mg, 6.302 mmol) and Pd(PPh3)4 (48 mg, 0.042 mmol), and the reaction mixture stirred for 1 h at RT. The reaction mixture was concentrated and the residue diluted with 25% saturated potassium carbonate and extracted with EtOAc (3×30 mL). The combined organic layer was washed with water (2×25 mL), dried over anhydrous sodium sulfate and concentrated to afford crude material, which was purified by column chromatography using neutral alumina and 2% MeOH-DCM followed by reverse phase HPLC to yield 8-methyl-5-[2-(6-methyl-pyridin-3-yl)-propenyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (180 mg). 1H NMR (CD3OD, TFA salt) δ (ppm): 8.92 (s, 1H), 8.65 (d, 1H), 7.90 (d, 1H), 7.36 (d, 2H), 7.18 (d, 1H), 7.16 (d, 1H), 4.50 (s, 2H), 3.65 (t, 2H), 3.10 (t, 2H), 2.80 (s, 3H), 2.42 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36](Br)=[CH:37][CH:38]=1)(=[O:33])=[O:32]>>[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36]([C:2]#[C:1][C:3]2[N:4]=[CH:5][N:6]3[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:37][CH:38]=1)(=[O:33])=[O:32]
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2ncn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.18) (130 mg, 0.37 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (115 mg, 0.37 mmol) according to general procedure II. Obtained as a red solid (150 mg, 70%). MS (ISN) 586.0 [(M−H)−]; mp 178° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[NH2:16][C:17]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].O>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:17]2[N:16]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:20][C:19](=[O:21])[C:18]=2[CH:22]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1oc(-c2ccccc2)nc2ccc(Cl)cc12
Reaction time: 16 h
Yield: 92.7 %

Procedure:
Benzoyl chloride (5.3 mL, 45 mmol) was added dropwise to a suspension of Na2CO3 (3.8 g, 36 mmol) and 2-amino-5-chloro-benzoic acid (3.1 g, 18 mmol) in THF (60 mL). The mixture was allowed to stir for 16 h and then H2O (200 mL) was added. The resulting precipitate was collected by filtration, washed with MeOH/H2O (1/1, 100 mL) and then dried in vacuo to provide 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one (4.3 g, 92%). To a suspension of the benzoxazinone (5.0 g, 19 mmol) in CH2Cl2 (100 mL) at −78° C. was added o-tolylmagnesium chloride (2 M in THF, 48 mmol) dropwise. The mixture was allowed to warm to −30° C. and stir for 1 h. 1N HCl (100 mL) was then added. The organic phase was collected and the aqueous phase was washed with CH2Cl2 (2×50 mL). The combined organic portions were washed with 0.1N NaOH (2×50 mL), dried over MgSO4, filtered and concentrated in vacuo to provide N-[4-chloro-2-(2-methyl-benzoyl)-phenyl]-benzamide (6.3 g, 93%). The acylated amino-benzophenone (3.5 g, 10 mmol) was dissolved in MeOH (50 mL) containing KOH (3 M, 30 mmol) and was refluxed for 16 h. The solution was then cooled to room temperature and diluted with H2O (50 mL) and EtOAc (100 mL). The organic phase was collected, washed with H2O (3×50 mL), dried over MgSO4, filtered and evaporated to dryness in vacuo to provide 1m (2.4 g, 98%) MS m/z=246 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](OCC)=O)=[CH:11][C:10]=1[O:20][CH3:21])#[N:2].[BH4-].[Li+].[C:24]([O:27][CH2:28][CH3:29])(=[O:26])[CH3:25].[Cl-].[NH4+]>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:25]([C:10](=[O:20])[CH2:9][CH2:4][CH3:3])[C:24]([O:27][CH2:28][CH3:29])=[O:26])=[CH:11][C:10]=1[O:20][CH3:21])#[N:2]
Reactant: CCOC(=O)c1ccc(-c2ccccc2C#N)c(OC)c1
Reactant: CCOC(C)=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(OC)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
To a solution of ethyl 2′-cyano-2-methoxybiphenyl-4-carboxylate (0.28 g) in tetrahydrofuran (10 mL) was added lithium borohydride (0.22 g), and the mixture was stirred at room temperature for 15 hr. To the reaction mixture were added ethyl acetate and saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in toluene (5 mL), phosphorus tribromide (0.050 mL) was added, and the mixture was stirred for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. This was dissolved in tetrahydrofuran (2 mL), the mixture was added dropwise to a solution of ethyl 3-oxohexanoate (0.25 g) and 60% sodium hydride (0.047 g) in tetrahydrofuran (2 mL) at 0° C., and the mixture was stirred at room temperature for 15 hr. To the reaction mixture were added ethyl acetate and saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.26 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH:7]=[C:6]2[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C[O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]Br)[CH:29]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH:7]=[C:6]2[CH:19]1[CH2:24][CH2:23][N:22]([CH2:34][C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:27]([OH:36])=[O:26])[CH2:21][CH2:20]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2CCc1ccsc1
Product: COc1ccc2c(c1)c(C1CCN(Cc3cccc(C(=O)O)c3)CC1)cn2CCc1ccsc1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 1.7 g (5 mmol) of 5-methoxy-3-piperidin-4-yl-1-(2-thiophen-3-yl-ethyl)-1H-indole and 1.3 g (5.5 mmol) of 3-bromomethyl-benzoic acid methyl ester. After standard work-up, 0.8 g (34% of yield) of the expected acid were obtained.
Reaction SMILES: [CH:1]1([CH:11]2[CH2:13][CH2:12]2)[CH2:3][CH:2]1[C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[H][H]>O1CCCC1.[Ru]>[CH:1]1([CH:11]2[CH2:13][CH2:12]2)[CH2:3][CH:2]1[CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:5]1[NH2:6]
Reactant: Nc1ccccc1C1CC1C1CC1
Reactant: [H][H]
Agent: [Ru]
Solvent: C1CCOC1
Product: NC1CCCCC1C1CC1C1CC1
Temperature: 25 °C

Procedure:
0.289 g of Ru/C (5%) are added to a solution comprising 3.00 g (17.31 mmol) 2-[1,1′-Bi(cyclopropyl)-2-yl]anilin in 20 ml of tetrahydrofuran, and the mixture is hydrogenated with 100 bar of hydrogen at 120° C. for 20 hours. After cooling to room temperature, the catalyst is filtered off through Celite 545 and the product is concentrated under reduced pressure. This gives 3.01 g (96%) of 2-[1,1′-Bi(cyclopropyl)-2-yl]cyclohexanamine having a purity of 96% according to MSD-HPLC.
Reaction SMILES: CO[C:3](=[O:14])[CH:4]=[C:5]1[CH2:11][CH:10]2[N:12]([CH3:13])[CH:7]([CH2:8][CH2:9]2)[CH2:6]1.[C:15]1([Mg]Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:12]1[CH:7]2[CH2:8][CH2:9][CH:10]1[CH2:11][C:5](=[CH:4][C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14])[CH2:6]2
Reactant: COC(=O)C=C1CC2CCC(C1)N2C
Reactant: Cl[Mg]c1ccccc1
Product: CN1C2CCC1CC(=CC(O)(c1ccccc1)c1ccccc1)C2

Procedure:
The title compound was prepared from (8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-acetic acid methyl ester and phenylmagnesium chloride by following the experimental procedures in Example 1 (44% yield): LCMS (ES) m/z 320 (M+H)+; 1H-NMR(CDCl3) δ 1.20 (m, 1H), 1.54 (m, 1H), 1.70 (m, 1H), 1.77 (m, 1H), 1.93 (m, 1H), 2.04 (m, 1H), 2.26 (s, 3H), 2.35 (m, 1H), 2.71 (m, 1H), 2.97 (m, 1H), 3.19 (m, 1H), 6.14 (s, 1H), 7.21 (m, 2H), 7.30 (m, 4H), 7.45 (m, 2H), 7.53 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:44]=[CH:43][C:39]3=[N:40][O:41][N:42]=[C:38]3[CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.CS(C)=O>[N:40]1[O:41][N:42]=[C:38]2[CH:37]=[C:36]([C:2]3[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]4[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=4[CH3:25])=[O:16])[C:5]4[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=4[N:7]=3)[CH:44]=[CH:43][C:39]=12
Reactant: CC1(C)OB(c2ccc3nonc3c2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4nonc4c3)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.180 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,1,3-benzoxadiazole (57.7 mg, 0.235 mmol), DMSO (2 mL), sodium carbonate (0.271 mL, 0.541 mmol), and bis(triphenylphosphine)palladium(II) chloride (12.67 mg, 0.018 mmol) wherein the reaction time was 8 h. The final product was collected as 17 mg (20%). LCMS LCMS E-S (M+H)=472.4 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (d, J=6.8 Hz, 6H), 2.12 (s, 3H), 2.27 (s, 3H) 4.42 (d, J=4.8 Hz, 2H) 5.32 (quin, J=6.6 Hz, 1H), 5.90 (s, 1H), 8.00 (s, 1H), 8.23 (d, J=9.4 Hz, 1H), 8.54-8.64 (m, 1H), 8.79 (t, J=4.7 Hz, 1H), 8.91 (s, 1H), 11.54 (br. s., 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[N:7][C:6]=1[CH3:14])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[N:7][C:6]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cnc1C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cc(N)cnc1C
Reaction time: 3 h

Procedure:
To a solution of 2-methyl-5-nitro-nicotinic acid ethyl ester 7 (1.43 mmol) in MeOH (15 mL) is added Pd (5% on carbon, 50% wet; 10% weight). After purging, the reaction mixture is stirred under hydrogen atmosphere for 3 h. The solvent is filtered through celite and the celite cake is washed with MeOH. The solvent is removed under vacuum to afford 5-amino-2-methyl-nicotinic acid ethyl ester 8 as yellow solid, which is used without further purification. 1H NMR (400 MHz, d6-DMSO) δ 7.19 (d, J=4.0 Hz, 1H), 6.78 (d, J=4.0 Hz, 2H), 4.10 (s, 2H), 3.56 (q, J=8.0 Hz, 2H), 1.80 (s, 3H), 0.59 (t, J=8.0 Hz, 3H). MS (m/z) (M+1)+: 182.0.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[C:29](P(=O)(OC)OC)C(=O)C)=[N-].C(=O)([O-])[O-].[K+].[K+]>CO>[C:14]([Si:1]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]#[CH:29])[CH2:21][CH2:20]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)[Si](OC1CCC(C=O)CC1)(c1ccccc1)c1ccccc1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A suspension of 4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexanecarbaldehyde (4.74 g), dimethyl (1-diazo-2-oxopropyl)phosphonate (2.98 g) and potassium carbonate (3.57 g) in methanol (40 mL) was stirred at room temperature for 2 hr. The reaction mixture was extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (4.15 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=S)[NH:9]2)[CH:7]=1.[NH3:22].C(OO)(C)(C)C>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10]([NH2:22])=[N:9]2)[CH:7]=1
Reactant: N
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(Br)ccc2F)C1(F)F
Agent: CC(C)(C)OO
Solvent: CO
Product: CC1(C)OCC(N)=N[C@](C)(c2cc(Br)ccc2F)C1(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepane-3-thione (intermediate B7.1) (959 mg, 2.51 mmol) in methanol (27 ml) was treated consecutively with ammonia in methanol (7M; 21.5 ml, 151 mmol) and dropwise with tert-butylhydroperoxide (70% in water; 2.07 ml, 15.1 mmol). The reaction mixture was stirred at room temperature overnight. For the workup, the methanol was evaporated at reduced pressure, and the residue partitioned between dichloromethane and water. The organic layer was washed with brine, then the 2 aqueous layers extracted with dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated at reduced pressure. The first purification of the crude product by chromatography on silica-amine phase using a gradient of heptane/ethyl acetate=100:0 to 72:28 was followed by a filtration through a SCX-2 cartridge. The cartridge was washed with a mixture of heptane and ethyl acetate and the product was recovered eluting with a solution of ammonia in methanol (7M). The (R)-5-(5-bromo-2-fluoro-phenyl)-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine was obtained as a light yellow foam (463 mg, 51% yield). MS (ISP): m/z=365.2 [(M+H)+] and 367.1 [(M+2+H)+].
Reaction SMILES: [F:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Br[C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:22][C:20]1[CH:21]=[CH:14][C:15]([C:16]#[N:17])=[C:18]([C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=2)[CH:19]=1
Reactant: COc1cc(B(O)O)c(F)cn1
Reactant: N#Cc1ccc(Cl)cc1Br
Product: COc1cc(-c2cc(Cl)ccc2C#N)c(F)cn1

Procedure:
256 mg (1.5 mmol) of 5-fluoro-2-methoxypyridin-4-ylboronic acid and 295 mg (1.34 mmol) of 2-bromo-4-chlorobenzonitrile were reacted according to General Method 2A. The product was precipitated with water. Yield: 146 mg (37% of theory)
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[C:13]2[SH:17])=[CH:8][CH:7]=1)([O:3]CC)=[O:2].[OH-].[Na+]>O>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[N:15][N:14]=[C:13]2[SH:17])=[CH:10][CH:11]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1ccc(-n2cnnc2S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(-n2cnnc2S)cc1
Yield: 82.4 %

Procedure:
To 8.2 g of 1-(4-carboethoxyphenyl)-2-mercapto-1,3,4-triazole was added 50 ml of an aqueous solution of 2 mol/liter of sodium hydroxide and the mixture was refluxed for 1 hour. Then, 100 ml of water was added to the reaction mixture and after filtering away insoluble matter, the pH of the filtrate was adjusted to about 1 by the addition of hydrochloric acid. Crystals thus formed were collected by filtration, dissolved in 500 ml of N,N-dimethylformamide and ethyl acetate and hexane were added to the solution, whereby 6.0 g of 1-(4-carboxyphenyl)-2-mercapto-1,3,4-triazole was obtained. The yield was 82.2% and the melting point was above 300° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][CH2:11][NH:12][C:13](=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]#[C:10][CH2:11][NH:12][C:13](=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCC#CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC#CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{4-[6,6-bis-(4-fluoro-phenyl)-hexanoylamino]-but-2-ynyl}-carbamic acid tert-butyl ester (1.6 g, 3.4 mmol) was dissolved in dry CH2Cl2 (50 ml) followed by addition of TFA (20 ml). The resulting solution was stirred at room temperature for 2 hrs. The solution was concentrated under reduced pressure. The resulting residue was dissolved in water (20 ml) and pH of the solution was adjusted to 10. The water phase was extracted with CH2Cl2 (100 ml), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the desired product in almost quantitative yield.