Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27](O)=[O:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[OH:30][CH2:31][C:32]([NH:35][S:36]([C:39]1[S:40][C:41]([Cl:45])=[C:42]([NH2:44])[CH:43]=1)(=[O:38])=[O:37])([CH3:34])[CH3:33]>>[Cl:45][C:41]1[S:40][C:39]([S:36](=[O:38])(=[O:37])[NH:35][C:32]([CH3:34])([CH3:33])[CH2:31][OH:30])=[CH:43][C:42]=1[NH:44][C:27]([C:26]1[CH:25]=[N:24][N:17]2[C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]([C:6]3[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:12])[F:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[N:15][C:16]=12)=[O:28]
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: CC(C)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cc(S(=O)(=O)NC(C)(C)CO)sc4Cl)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to general procedure II. Yellow solid. MS (ISP) 684.3 [(M−H)−]; mp 234° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[BH4-].[Na+].C(OCC)(=O)C>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[CH:15]([OH:17])[CH3:16]
Reactant: CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)c1cc(-c2cccc(Cl)c2)ccc1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.6 %

Procedure:
To a solution of 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone (see example 35, 0.15 g, 0.61 mmol) in anhydrous methanol was added sodium borohydride (0.07 g, 1.03 mmol) at room temperature (rt) under nitrogen. After 15 minutes, the reaction mixture was treated with ice-water. Ethyl acetate (30 mL) was added, organic layer was separated, and aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (10 mL) and dried over MgSO4. After removal of solvent, the residue obtained was crystallized from toluene to afford 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanol as white solid (0.087 g, 58%): 1H-NMR (DMSO-d6) δ7.55 (t, 1H, J=1.4 Hz), 7.50 (d, 1H, J=7.8 Hz), 7.44 (d, 1H, J=2,1 Hz), 7.39 (t, 1H, J=8.2 Hz), 7.31-7.21 (m, 2H), 6.68 (d, 1H, J=8.1 Hz), 5.25 (s, 2H), 5.20 (m, 1H), 4.83 (m, 1H), 1.35 (d, 3H, J=8.8 Hz); MS (EI) m/z 247 (M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[N:13]1([CH2:18][C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:17]=[CH:16][N:15]=[CH:14]1.CCOC(C)=O>O1CCOCC1>[N:13]1([CH2:18][C:19]2[CH:20]=[C:21]([NH:22][C:2]3[CH:7]=[CH:6][N:5]4[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]4[N:3]=3)[CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: Nc1cccc(Cn2ccnc2)c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=Cc1cnn2ccc(Nc3cccc(Cn4ccnc4)c3)nc12
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (40 mg, 0.221 mmol) in dioxane was added 3-((1H-imidazol-1-yl)methyl)aniline (115 mg, 0.663 mmol). The mixture was heated in microwave for 120 minutes at 120° C. EtOAc was added to the mixture, and washed with water. The organic layer was then dried over Na2SO4 and solvent was removed under reduced pressure to yield 5-(3-((1H-imidazol-1-yl)methyl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. The resulting solid was used in the next step without further purification. LCMS (M+1=319)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Br:23])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16]>>[Br:11][C:12]1[CH:13]=[C:14]([C:15]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[CH:7]=[N:8][CH:9]=[CH:10][C:2]2=3)=[O:16])[CH:18]=[C:19]([Br:23])[C:20]=1[O:21][CH3:22]
Reactant: c1cc2c(cn1)OCCN2
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Product: COc1c(Br)cc(C(=O)N2CCOc3cnccc32)cc1Br

Procedure:
By the same method as in the step d) of Example 2, 2,3-dihydro-1H-pyrido[3,4-b][1,4]-oxazine (180 mg, 0.587 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (193 mg, 0.587 mmol) were reacted to obtain the target compound 5, (3,5-dibromo-4-methoxy-phenyl)-(2,3-dihydro-pyrido[3,4-b][1,4]oxazin-1-yl)-methanone, as white solid (85 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[CH2:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH2:15]Cl)[C:8](=[O:17])[CH2:7]1.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:15][CH2:14][CH2:13][N:9]2[C:10](=[O:12])[CH2:11][N:6]([CH2:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[O:2][CH3:1])[CH2:7][C:8]2=[O:17])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccccc1CN1CC(=O)N(CCCCl)C(=O)C1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Product: COc1ccccc1CN1CC(=O)N(CCCN2CCN(C(=O)OCc3ccccc3)CC2)C(=O)C1

Procedure:
This compound was prepared according to the process described in Example 5 by condensing 4-(2-methoxybenzyl)-1-(3-chloropropyl)piperazine-2,6-dione with 4benzyloxycarbonylpiperazine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]([OH:14])=O)[C:8]([OH:11])=[N:9][CH:10]=1)=[O:4].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:6]=[C:7]([C:12](=[O:14])[NH:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:8]([OH:11])=[N:9][CH:10]=1
Reactant: COC(=O)c1cnc(O)c(C(=O)O)c1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(O)c(C(=O)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a mixture of 2-hydroxy-pyridine-3,5-dicarboxylic acid 5-methyl ester, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC. HCl 0.49 g, 2.6 mmol), 1-hydroxybenzotriazole hydrate (HOBT 0.35 g, 2.6 mmol), in dimethylformamide (10 ml) was added benzylamine 0.27 g (2.6 mmol). The mixture was stirred overnight at room temperature. Water was added (20 ml), and the mixture was filtered. The solid product was slurried in hot ethyl acetate to give 0.17 g (28% yield) of the title compound. MS: m/z (APCI, AP+) 287 [M.]+. CHN Analysis: C15H14N2O4.0.47 H2O; Calcd: C, 61.12; H, 5.11; N, 9.50. Found: C, 61.17; H, 4.81; N, 9.71.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:49])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH2:40][O:41]C3CCCCO3)[CH:35]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:41][CH2:40][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:27]3[CH2:26][C:25](=[O:49])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:23])[F:21])[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:39]=[CH:38][N:37]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M262) (0.48 g, 0.67 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[C:14]([S:15](Cl)(=[O:17])=[O:16])=[CH:13][C:12]([N+:19]([O-:21])=[O:20])=[CH:11][CH:10]=1>O>[C:1]1([O:7][S:15]([C:14]2[C:9]([Cl:8])=[CH:10][CH:11]=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=2)(=[O:16])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Oc2ccccc2)c1
Reaction time: 3.5 h

Procedure:
To 37.6 parts of phenol stirring in 780 parts water at pH 9.0 and at 5°-10° C. was added 100 parts 6-chloro-3-nitrobenzenesulphonyl chloride. A few drops of Calsolene oil wetting agent were added and the mixture was stirred at pH 9.5°-10° and 5°-10° C. for 3.5 hours, cooled and filtered. The solid was washed with cold water, and dried to give 116 parts of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28]CN(CC)CC.COS(OC)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH3:28])=[CH:15][CH:14]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Product: CNc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 46 %

Procedure:
A solution of (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-aminobenzyl)amino]-4-methyl-pentanoic acid amide (Example 48, 400 mg, 1 mmol), Et3N (0.16 mL, 1.1 mmol), dimethylsulfate (139 mg, 1.1 mmol) in 25 mL of toluene was stirred at rt for 18 h. The reaction was concentrated, then taken into EtOAc and washed with H2O, brine, dried over K2CO3 and concentrated to give a crude mixture of starting material and product. The material was further purified by flash chromatography (SiO2, 35% EtOAc/hexanes) to afford the title compound, 195 mg, in 46% yield. MS (ESI), (M+H)+424.1; 1H NMR (CDCl3) δ7.65 (d, 2H, J=8.0), 7.58 (d, 2H, J=8.2), 7.47 (d, 2H, J=8.0), 7.31 (d, 2H, J=8.5), 6.24 (br s, 1H), 5.16 (br s, 1H), 4.50(dd, 2H, J=50, 17), 4.27 (t, 1H, J=10), 2.44 (s, 3H), 1.74-1.83 (m, 1H), 1.25-1.33 (m, 1H), 0.93-1.01 (m, 1H), 0.74 (d, 3H, J=7.0), 0.63 (d, 3H, J=7.0).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>C(Cl)Cl>[C:16]([O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: COC(=O)C(C)(C)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(C)(C)COC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
Under an argon atmosphere a stirred solution of 10.0 grams (0.076 mole) of methyl 3-hydroxy-2,2-dimethylpropionate and 6.6 grams (0.083 mole) of pyridine in 40 ml of dry methylene chloride was cooled to 0°. To this 6.0 grams (0.076 mole) of acetyl chloride was added dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it was stirred for 18 hours. The reaction mixture was washed with 50 ml of water, two portions of 50 ml each of an aqueous solution of 5% hydrochloric acid, and finally, 50 ml of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oil residue. The oil was distilled under reduced pressure to give 8.0 grams of methyl 3-acetoxy-2,2-dimethylpropionate; bp 85°-90°/33 Pa.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=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.[CH2:36]1[CH:38]([CH:39]([OH:42])C#N)[CH2:37]1>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([CH:39]([CH:38]2[CH2:36][CH2:37]2)[OH:42])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CC(O)C1CC1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)C3CC3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and cylopropyl carboxaldehyde.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:27][CH:28]([CH3:33])[CH2:29]B(O)O.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:27][CH:28]([CH3:33])[CH3:29])[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)CB(O)O
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1OCc1ccccc1
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: [K+]
Solvent: C1COCCO1
Product: CCCCOC(=O)c1nc(CC(C)C)c2ccccc2c1OCc1ccccc1
Reaction time: 48 h

Procedure:
A mixture of 4-Benzyloxy-1-bromo-isoquinoline-3-carboxylic acid butyl ester (207 mg, 0.5 mmol, see example D-86a), Pd(PPh3)4 (58 mg, 0.05 mmol), 2-methylpropylboronic acid (78 mg, 0.75 mmol), K2CO3 (207 mg, 1.5 mmol), and 1,4-dioxane (4 ml) was refluxed with stirring for 48 h. Subsequently, the mixture was concentrated in vacuo. To the residue was added water (5 ml) and the mixture was extracted with EtOAc (2×20 ml). The organic phase was dried over MgsO4 and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes EtOAc=88 12 as the eluent gave the title compound as a yellowish oil (136 mg); MS-(+)-ion M+1=392.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:26]\[OH:27])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(Br)cc2)C2CCCC2)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(Br)cc2)C2CCCC2)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-cyclopentyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=403.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16].[OH-].[Na+]>C1C=CC=CC=1.O>[C:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)(=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(C)C)cc1
Reaction time: 3 h
Yield: 88.4 %

Procedure:
10 g of ethyl 4-aminophenylacetate was dissolved in 100 ml of benzene and to this was added 25 ml of water. To the solution were added dropwise a solution of 6 g of isobutyryl chloride in 20 ml of benzene and a solution of 2.4 g of 93% NaOH in 25 ml of water simultaneously under stirring over 15 minutes. After completion of the dropwise addition, the reaction mixture was stirred for 3 hours and allowed to stand at room temperature overnight. After separating the benzene layer, washing it with 1N-HCl solution and further washing with a saturated solution of sodium chloride, the benzene layer was dried over anhydrous sodium sulfate. After separating sodium sulfate by filteration, the solvent was distilled off under reduced pressure and the residue was dissolved in 30 ml of benzene and crystallized from 90 ml of n-hexane. The formed crystals were separated by filteration and were dried at a temperature below 60° C. under reduced pressure to give 12.3 g of ethyl 4-(isobutyrylamino)phenylacetate (Yield: 88.3%). M.P. 92.5°-93.5° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1(=[O:12])[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:11][C:7]1[CH2:8][CH2:9][CH2:10][C:5](=[O:12])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCCC(=O)C1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC1=CC(=O)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
According to Scheme 4 Step 1: Acetyl chloride (19.6 mmol, 1.39 mL) was added to a solution of cyclohexane-1,3-dione (17.8 mmol, 2.00 g) and pyridine (17.8 mmol, 1.28 mL) in CHCl3 (60 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with the addition of water and the organic phase was washed with a solution of HCl (0.1 M, 30 mL), a saturated solution of NaHCO3 (30 mL) and water (30 mL). The organic phase was dried over Na2SO4 and concentrated to yield 3-oxocyclohex-1-enyl acetate (13.2 mmol, 2.04 g, 74%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[N:17]=[C:16]([C@@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]4)[NH:15][N:14]=3)[CH:11]=2)[NH:6][N:5]=1.[C:31](Cl)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[N:17]=[C:16]([C@@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]4)[NH:15][N:14]=3)[CH:11]=2)[N:6]([C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc(-c3ccc4[nH]nc(Br)c4c3)n[nH]2)C1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc(-c3ccc4c(c3)c(Br)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]2)C1
Reaction time: 0.5 h

Procedure:
Added Sodium Hydride (100 mg; 2.5 mmol) to a solution of (R)-tert-butyl 3-(3-(3-bromo-1H-indazol-5-yl)-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate (530 mg, 0.988 mmol) in DMF (5 ml) at 0° C., then stirred for 30 minutes. Trityl Chloride (570 mg, 2.05 mmol) was added, and stirred at room temperature overnight. Added water (100 ml), filtered precipitated solid, washed with water, dried, then chromatographed on silica gel eluting with 30% v/v EtOAc/Hexanes to yield a mixture of mono and dialkylated products (560 mg, 8:2 mono/dialkylation).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10](=[CH2:12])[CH3:11]>>[C:10]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[OH:8])([CH3:12])([CH3:11])[CH3:9]
Reactant: Oc1ccc(Br)cc1
Reactant: C=C(C)C
Product: CC(C)(C)c1cc(Br)ccc1O
Temperature: 80 °C

Procedure:
80.00 g (426.0 mmol) of 4-bromophenol and 8.00 g of Dowex 50WX8 sulphonic acid resin are mixed in a 250 ml three-necked flask. The mixture is heated to 80° C. and a stream of isobutylene is passed through for 30 hours. The reaction mixture is cooled and the residue is purified by passing through a silica column eluted with a mixture composed of 95% dichloromethane and of 5% heptane. 88.00 g (90%) of the expected compound are collected in the form of a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[C:9]3[N:10]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:11]([C@@H:13]([NH:15][C:16]4[N:24]=[CH:23][N:22]=[C:21]5[C:17]=4[N:18]=[CH:19][N:20]5C4CCCCO4)[CH3:14])=[N:12][C:8]=3[CH:7]=[CH:6][C:5]=2[F:37])[CH2:3][CH2:2]1.Cl>CO.O1CCOCC1>[CH:1]1([C:4]2[C:9]3[N:10]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:11]([CH:13]([NH:15][C:16]4[N:24]=[CH:23][N:22]=[C:21]5[C:17]=4[N:18]=[CH:19][NH:20]5)[CH3:14])=[N:12][C:8]=3[CH:7]=[CH:6][C:5]=2[F:37])[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C3CC3)c2n1-c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(C3CC3)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To a mixture of [(S)-1-(7-cyclopropyl-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (20 mg, 0.04 mmol) in MeOH (2 mL) was added 4N HCl in dioxane (0.25 mL) and the reaction mixture stirred at RT for 30 min. The volatiles were removed under reduced pressure and the resulting residue purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 10-90%, 0.1% HCO2H in acetonitrile/water) to afford 198 (8 mg, 48%). LCMS (Method K): RT 3.74 and 3.81 min [M+H]+ 414.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.89 (1H, br s), 8.19-7.97 (2H, m), 7.90-7.30 (7H, m), 7.04-6.95 (1H, dd, J=11.67, 8.76 Hz), 5.29 (1H, br s), 1.52 (3H, d, J=6.81 Hz), 1.28-1.18 (1H, m), 0.43-0.29 (2H, m), 0.25-0.08 (2H, m)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[N:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[N:28]=1)[C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH3:35][CH:36]([CH3:41])[CH2:37][C:38](Cl)=[O:39]>N1C=CC=CC=1>[CH3:35][CH:36]([CH3:41])[CH2:37][C:38]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[N:28]=[C:29]([CH3:34])[CH:30]=[C:31]([CH3:33])[N:32]=1)[C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:39]
Reactant: CCCCCCCCCCCCCC(=O)N(CCCN)CCCCCNc1nc(C)cc(C)n1
Reactant: CC(C)CC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCC(=O)N(CCCCCNc1nc(C)cc(C)n1)CCCNC(=O)CC(C)C

Procedure:
The primary amine XV was treated with 3-methylbutanoyl chloride in pyridine in the manner described above (C). The crude product was chromatographed on a 24 g silica gel column (BioSil A) of dimensions 1 cm (id)×30 cm, developed with 30% acetone/CHCl3. Five ml fractions were collected. The pure product was found in tubes 14-22, 128 mg.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O[CH2:13][CH:14]1[CH2:22][CH:21]2[CH:17]([CH2:18][N:19]([C:23](=[O:33])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[CH2:20]2)[C:16]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])([OH:34])[CH2:15]1.C(N(CC)CC)C>ClCCl>[CH3:42][O:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:16]1([OH:34])[CH2:15][CH:14]([CH2:13][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:22][CH:21]2[CH:17]1[CH2:18][N:19]([C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])[CH2:20]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1CC(=O)N1CC2CC(CO)CC(O)(c3ccccc3OC)C2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)N1CC2CC(CS(=O)(=O)c3ccc(C)cc3)CC(O)(c3ccccc3OC)C2C1
Temperature: 20 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
3.05 g of p-toluenesulphonyl chloride are added to a solution of 3.4 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]perhydroisoindol-4-ol and 2.24 cm3 of triethylamine in 150 cm3 of dichloromethane. The mixture is stirred at 20° C. for 20 hours, washed with 100 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). 4.1 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-6-tosylmethylperhydroisoindol-4-ol are obtained in the form of a thick white foam.