Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[C:9]=1[C:29]#[N:30]>N1C=CC=CC=1>[C:29]([C:9]1[C:10]([C:25]([F:28])([F:26])[F:27])=[N:11][N:12]([C:13]2[C:14]([Cl:24])=[CH:15][C:16]([C:20]([F:22])([F:21])[F:23])=[CH:17][C:18]=2[Cl:19])[C:8]=1[NH:7][C:2]([O:4][CH2:5][CH3:6])=[O:3])#[N:30]
Reactant: CCOC(=O)Cl
Reactant: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Solvent: c1ccncc1
Product: CCOC(=O)Nc1c(C#N)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 8 h

Procedure:
Ethyl chloroformate (1.6 g) was added to a stirred solution of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.9 g) in pyridine (15 ml). After stirring overnight another addition of ethyl chloroformate (1.0 ml) was made, and the mixture was left for a further 12 hours. The solvent was evaporated in vacuo and the residue was acidified with dilute hydrochloric acid, and extracted with dichloromethane. This extract was washed with water (3×), dried over anhydrous magnesium sulphate, filtered, and evaporated in vacuo. Purification by chromatography on silica (Merck, 40-230 mesh, 0.7 kg cm−2) eluting with ethyl acetate-petroleum ether (1:1) gave a white solid, which was recrystallized from a mixture of dichloromethane and hexane to furnish white crystals of 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxycarbonylamino-3-trifluoromethylpyrazole, m.p. 177-179° C.
Reaction SMILES: C([NH:5][CH2:6][P:7](=[O:20])([CH2:14][NH:15]C(OC)=O)[CH2:8][NH:9]C(OC)=O)(OC)=O.[BrH:21]>>[BrH:21].[BrH:21].[BrH:21].[NH2:5][CH2:6][P:7](=[O:20])([CH2:14][NH2:15])[CH2:8][NH2:9]
Reactant: COC(=O)NCP(=O)(CNC(=O)OC)CNC(=O)OC
Agent: Br
Product: NCP(=O)(CN)CN
Yield: 49.9 %

Procedure:
A solution of 31.12 g (0.1 mol) of tris(N-carbomethoxyaminomethyl)phosphine oxide in 100 ml of constant-boiling (47-49%) hydrobromic acid was heated to reflux with constant stirring. Within a few minutes, solids started to separate. The mixture was heated at reflux for one hour, cooled, and filtered. The filter cake, rinsed with ethanol and air-dried, afforded 18.95 g (49.9% yield) of tris(aminomethyl)phosphine oxide trihydrobromide as a white, crystalline solid, dec. 233° C. with reddening. Another 2.60 g (6.8% yield) was recovered from the filtrate after heating at reflux an additional hour.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:22][CH3:23])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([NH2:21])=[O:20])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO.C(#N)C>[NH2:30][CH:1]([C:4]1[C:5]([O:22][CH3:23])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([NH2:21])=[O:20])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:2]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(F)c(C(N)=O)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1ccc(F)c(C(N)=O)c1
Temperature: 65 °C

Procedure:
A mixture of 3′-acetyl-5′-chloro-4-fluoro-2′-methoxy-6′-methylbiphenyl-3-carboxamide (50 mg, 0.1 mmol), ammonium acetate (115 mg, 1.49 mmol) and sodium cyanoborohydride (19 mg, 0.30 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness. The resulting crude product was used directly in next step (36 mg, 70%). LCMS calculated for C17H16ClFNO2 (M−NH2)+: m/z=320.1. found: 320.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[C:18]([OH:19])[C:13]3=[CH:12][N:11]=2)=[O:9])=[CH:4][C:3]=1[O:20][CH3:21].I[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39]I>>[CH2:23]([O:19][C:18]1[C:13]2[N:14]([C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([O:20][CH3:21])[CH:4]=3)=[O:9])=[N:11][CH:12]=2)[CH:15]=[CH:16][CH:17]=1)[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:19][C:18]1[C:13]2[N:14]([C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([O:20][CH3:21])[CH:4]=3)=[O:9])=[N:11][CH:12]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc(C(=O)c2ncc3c(O)cccn23)ccc1N
Reactant: ICCOCCOCCOCCOCCOCCI
Product: COc1cc(C(=O)c2ncc3c(OCCOCCOCCOCCOCCOCCOc4cccn5c(C(=O)c6ccc(N)c(OC)c6)ncc45)cccn23)ccc1N
Yield: 27 %

Procedure:
By following the process described in Stage A of Example 8, Example 10 is prepared from (4-amino-3-methoxyphenyl)(8-hydroxyimidazo[1,5-a]pyridin-3-yl)-methanone (described in Patent Application WO2006097625) with 1,17-diiodo-3,6,9,12,15-pentaoxaheptadecane (Example R2). After purification by flash chromatography on silica gel (dichloromethane/acetone gradient=90/10 to 70/30), 0.93 g (27%) of a yellow powder is obtained.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[CH2:5]([O:12][C:13](=[O:28])[NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH2:25]Br)=[CH:20][CH:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:5]([O:12][C:13](=[O:28])[NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:4]=[C:1]([CH3:2])[O:3][CH:25]=2)=[CH:22][CH:23]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(NCCOc1ccc(C(=O)CBr)cc1)OCc1ccccc1
Reactant: CC(N)=O
Product: Cc1nc(-c2ccc(OCCNC(=O)OCc3ccccc3)cc2)co1
Temperature: 130 °C
Yield: 57.6 %

Procedure:
Acetamide (2.95 g, 50.0 mmol) and benzyl-[2-(4-bromoacetylphenoxy)-ethyl]-carbamate (1.20 g, 3.06 mmol) were combined in a round-bottomed flask and heated to about 130° C. for about ninety minutes. The reaction mixture was then allowed to cool to room temperature, and the resulting orange solid was partitioned between ethyl acetate and water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude solid was purified by column chromatography (silica gel; methylene chloride to 10% ethyl acetate/methylene chloride) to afford 621 mg (58% yield) of the product as a white solid. LRMS ([M+H]+)=353.3.
Reaction SMILES: Cl.C(OCC)(=O)C.[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27]C(C)(C)C)=O)[CH2:21][C@H:20]2[O:32][CH3:33])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15].ClC1O[C:37]2[C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CO>[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([C:25]3[O:27][C:37]4[C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=[CH:40][C:38]=4[N:39]=3)[CH2:21][C@H:20]2[O:32][CH3:33])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Reactant: COC(=O)c1cccc2nc(Cl)oc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc4cccc(C(=O)OC)c4o3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
Methanol (2 ml) and a 4 N hydrochloric acid/ethyl acetate solution (2 mL) were added to tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (1g) (60 mg, 0.16 mmol), and the mixture was stirred at room temperature for two hours. Following concentration under reduced pressure, the residue was dissolved in DMF (4 mL). Methyl 2-chloro-1,3-benzooxazole-7-carboxylate (34 mg, 0.16 mmol) (reference: U.S. Pat. No. 6,166,011 A1) and diisopropylethylamine (1 ml) were added, and the mixture was stirred at 80° C. for six hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with water and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was recrystallized from an ethyl acetate/hexane solvent to obtain 75 mg of the title compound as crystals.
Reaction SMILES: C([Li])CCC.Cl[C:7]1[CH:8]=[N:9][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)[O:15][N:14]=2)=[N:11][CH:12]=1.C1C[O:31][CH2:30]C1>CN(C=O)C>[CH2:24]([C:21]1[CH:22]=[CH:23][C:18]([C:16]2[O:15][N:14]=[C:13]([C:10]3[N:9]=[CH:8][C:7]([CH:30]=[O:31])=[CH:12][N:11]=3)[N:17]=2)=[CH:19][CH:20]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: C1CCOC1
Reactant: CC(C)Cc1ccc(-c2nc(-c3ncc(Cl)cn3)no2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(-c2nc(-c3ncc(C=O)cn3)no2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
n-Butyllithium (4.77 mL, 7.16 mmol) was added to a solution of 5-chloro-2-[5-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrimidine (1.5 g, 4.77 mmol) and THF (50 mL) at −78° C. and stirred for 7 hours DMF (3 mL) was added to the reaction mixture, warmed to 0° C. and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (25 mL) and the organic layer was separated and washed with water (3×25 mL) and brine (1×25 mL) and concentrated in vacuo to provide the title compound (1.13 g, 76% yield) as an orange solid.
Reaction SMILES: Cl[CH:2]([C:6](=[O:8])[CH3:7])[C:3](=[O:5])[CH3:4].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)#[N:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:3]([CH:2]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=1)[C:6](=[O:8])[CH3:7])(=[O:5])[CH3:4]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(=O)C(Oc1ccc(C#N)cc1)C(C)=O

Procedure:
A mixture of commercially available 3-chloro-2,4-pentanedione (14.01 ml, 92 mmol), 4-cyanophenol (10 g, 84 mmol), caesium carbonate (29.9 g, 92 mmol) and acetone (160 ml) was heated under reflux for 5 hours. After cooling, a solid was removed by filtration and it was washed with dichloromethane (100 ml). The combined filtrates were concentrated under reduced pressure. The remaining oil was diluted with dichloromethane (150 ml), washed with 1M hydrochloric acid (100 ml), then brine (50 ml), dried over magnesium sulphate, filtered and finally concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (15:1, by volume then 10:1) to provide the title compound, which crystallised on standing, as pale yellow crystals (7.27 g, 39.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[CH3:23])[CH3:22]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C)c(C)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
3,4-Dimethylphenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:17]=1.[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH2:22]>C(O)CCC>[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH:22][C:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH:11][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:17][C:6]=2[N:7]=1
Reactant: COC(CN)OC
Reactant: Cc1ccc2c(c1)NC(=S)c1ccccc1N2
Solvent: CCCCO
Product: COC(CNC1=Nc2cc(C)ccc2Nc2ccccc21)OC

Procedure:
In the manner given in Example 4, 8-methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione is treated with amino acetaldehyde dimethyl acetal in n-butanol to give 8-methyl-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]-acetaldehyde dimethyl acetal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:25]([F:26])=[C:24]2[C:20](/[C:21](=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=3[F:36])/[C:22](=[O:27])[NH:23]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[NH:8][CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:21]2([C:20]3[C:24](=[C:25]([F:26])[C:17]([Cl:16])=[CH:18][CH:19]=3)[NH:23][C:22]2=[O:27])[CH:28]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[F:36])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1Nc2c(ccc(Cl)c2F)/C1=C/c1cccc(Cl)c1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CC(C)(C)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1c2ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (2 g, 9.4 mmol) prepared in Example 1 and E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-7-fluoro-1,3-dihydro-indol-2-one (1.1 g, 3.4 mmol) prepared in Example 172 in dichloromethane (60 mL) were added triethylamine (1.4 mL, 10 mmol) and AgF (0.43 g, 3.4 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. The residue was dissolved into tert-butanol (20 mL), and DBU (1.5 g, 10 mmol) was added. The reaction mixture was heated at 120° C. for 2 h. The mixture was then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (20-40% EtOAc in hexanes) to give as rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester a white solid (0.91 g, 50%)
Reaction SMILES: [OH:1][C@@H:2]([CH:23]([CH3:28])[CH2:24][CH2:25][CH2:26][CH3:27])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1>[C:29]([O:1][C@@H:2]([CH:23]([CH3:28])[CH2:24][CH2:25][CH2:26][CH3:27])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCCC(C)[C@H](O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCCCC(C)[C@@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)OC(=O)c1ccccc1

Procedure:
In analogy to Example 1(a), 1.7 g of (1S,5R,6R,7R)-6-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octenyl]-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one, 8 ml of pyridine, and 1 ml of benzoyl chloride yield 2.06 g of the dibenzoate as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=C(C=C[CH:11]=1)C(OO)=O.[CH2:12]([NH:14][C:15]([CH:17]1[CH2:21][CH:20]([N:22]2[C:26]3[N:27]=[C:28]([S:41]CCC)[N:29]=[C:30]([NH:31][CH:32]4[CH2:34][CH:33]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:25]=3[N:24]=[N:23]2)[CH:19]([OH:45])[CH:18]1[OH:46])=[O:16])[CH3:13].ClCCl>C(O)C>[CH2:12]([NH:14][C:15]([CH:17]1[CH2:21][CH:20]([N:22]2[C:26]3[N:27]=[C:28]([S:41][CH:2]([CH3:3])[CH3:11])[N:29]=[C:30]([NH:31][CH:32]4[CH2:34][CH:33]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:25]=3[N:24]=[N:23]2)[CH:19]([OH:45])[CH:18]1[OH:46])=[O:16])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Solvent: ClCCl
Solvent: CCO
Product: CCNC(=O)C1CC(n2nnc3c(NC4CC4c4ccccc4)nc(SC(C)C)nc32)C(O)C1O

Procedure:
3-Chloroperoxybenzoic acid (50%, 9.0 g) was added to a suspension of the product of example 1, step e) (4.1 g) in ethanol (200 ml) and dichloromethane (50 ml) and the resulting solution stirred at room temperature for 18 hours. The reaction mixture was concentrated and the residue taken up in ethyl acetate (500 ml) , washed with 10% aqueous sodium metabisulfite solution (2×100 ml) and 10% aqueous sodium bicarbonate solution (2×100 ml) then dried and concentrated. Purification (SiO2, ethyl acetate as eluant) gave the subtitle compound (2.4 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]([C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[F:24])[N:14]=[C:13]2[N:25]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:26]=[C:27]([CH3:28])[C:12]=12)=[O:10].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH:41]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=2)[C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]([C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[F:24])[N:14]=[C:13]2[N:25]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:26]=[C:27]([CH3:28])[C:12]=12)=[O:10]
Reactant: O=Cc1ccccn1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3F)cc(C(=O)N3C[C@@H](C)NC[C@@H]3C)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: O
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3F)cc(C(=O)N3C[C@@H](C)N(Cc4ccccn4)C[C@@H]3C)c12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a mixture of ((2S,5R)-2,5-Dimethyl-piperazin-1-yl)-[6-(2-fluoro-4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone (200 mg, precursor of example 543) and pyridine-2-carboxaldehyde (46 mg) in dichloroethane (5 mL) containing acetic acid (7.4 μL) was added sodium triacetoxy borohydride (136 mg) at r.t., then the mixture was stirred at 40° C. overnight. Water was added carefully and the mixture was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated to dryness giving ((2S,5R)-2,5-Dimethyl-4-pyridin-2-ylmethyl-piperazin-1-yl)-[6-(2-fluoro-4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone. This was dissolved in THF (7 mL) containing conc. hydrochloric acid (1.5 mL) and stirred r.t. overnight. The precipitate formed was filtered off and dried in air. ((2S,5R)-2,5-Dimethyl-4-pyridin-2-ylmethyl-piperazin-1-yl)-[6-(2-fluoro-4-hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone was obtained as a hydrochloride salt (263 mg, 100%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.CS(O[CH2:11][CH:12]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])[CH2:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)(=O)=O>>[CH:15]1([CH2:14][CH2:13][CH:12]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[CH2:11][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CS(=O)(=O)OCC(CCC1CCCC1)c1ccc(Cl)cc1Cl
Reactant: c1nc[nH]n1
Product: Clc1ccc(C(CCC2CCCC2)Cn2cncn2)c(Cl)c1

Procedure:
mp. 71° C., by the reaction of 1H-1,2,4-triazole with 4-cyclopentyl-2-(2,4-dichlorophenyl)butyl methanesulfonate; and
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([CH2:35][O:36]C(=O)C)=[O:34]>>[OH:36][CH2:35][C:33]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:34]
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Reactant: CC(=O)OCC(=O)Cl
Product: O=C(CO)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A156) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][S:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccc(S(C)(=O)=O)cc3)s2)c(C)[nH]c1=O

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 4-methanesulfonyl-benzyl amine as described in Step 5, Example 24 to give the title compound. MS: m/e 467 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=Cc1cc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F

Procedure:
Prepared according to Procedure A using 2,8-dichloroquinoline 3-carbaldehyde (1.0 g, 4.42 mmol), 2-trifluoromethylphenyl boronic acid (0.924 g, 4.87 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (0.256 g, 0.221 mmol, 0.05 eq), and sodium carbonate (2.34 g, 22.1 mmol, 5 eq) in acetonitrile (30 mL) and water (10 mL). After purification, 2-(2-trifluoromethylphenyl)-8-chloroquinoline-3-carbaldehyde was obtained as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.95 (1 H, s), 9.19 (1 H, s), 8.33 (1 H, dd, J=8.5, 1.2 Hz), 8.20 (1 H, dd, J=7.3, 1.2 Hz), 7.95 (1 H, d, J=7.3 Hz), 7.74-7.87 (2 H, m), 7.63 (1 H, d, J=7.3 Hz) Mass Spectrum (ESI) m/e=336.1 and 338.0 (M+1)
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[F:34][CH:35]([F:48])[O:36][CH2:37][CH:38]([CH3:47])[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:40]>O1CCCC1>[Br:1][C:38]([CH3:47])([CH2:37][O:36][CH:35]([F:48])[F:34])[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:40]
Reactant: [Br-]
Reactant: CC(COC(F)F)C(=O)c1ccccc1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(Br)(COC(F)F)C(=O)c1ccccc1
Yield: 172.4 %

Procedure:
3.58 g of phenyltrimethylammonium tribromide was added to a mixture comprising 2.04 g of 3-difluoromethoxyisobutyrophenone and 30 ml of tetrahydrofuran, followed by a reaction for two hours at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 2.79 g of oily α-bromo-3-difluoromethoxyisobutyrophenone.