Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1)[S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][O:23][C@H:20]1[CH2:19][CH2:18][C@H:17]([N:3]([CH2:1][CH3:2])[S:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:22][CH2:21]1
Reactant: CCN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: BrCCCCBr
Product: CCN([C@H]1CC[C@H](OCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 11.11, trans-N-Ethyl-N-(4-hydroxy-cyclohexyl)-4-trifluoromethyl-benzenesulfonamide and 1,4-Dibromobutane were converted to yield trans-N-[4-(4-Bromo-butoxy)-cyclohexyl]-N-ethyl-4-trifluoromethyl-benzenesulfonamide as colorless oil, MS 470 (M−CH3, 1Br).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C@@H:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[C:29]2[C:28]([CH2:30]O)=[CH:27][S:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:19])[C@@H:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:30][C:28]2[C:29]3[C:21]([CH3:20])=[CH:22][CH:23]=[CH:24][C:25]=3[S:26][CH:27]=2)[C:10]1=[O:18])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc2scc(CO)c12
Reactant: C[C@@H](C(=O)OC(C)(C)C)n1c(=O)[nH]c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: Cc1cccc2scc(Cn3c(=O)n([C@@H](C)C(=O)OC(C)(C)C)c4ccccc43)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
To a solution of (S)-2-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid tert-butyl ester (0.3 g, 0.46 mmol), (4-Methyl-benzo[b]thiophen-3-yl)-methanol (0.12 g, 0.69 mmol), and triphenylphosphine (0.14 g, 0.55 mmol) was added dropwise DIAD (0.11 mL, 0.55 mmoL) at 0° C. The mixture was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with ethyl acetate and washed with water (×2). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 4:1 Hexanes:ethyl acetate as an eluent to afford 0.12 g (62%) of the desired product as a brownish oil. This product was not pure (˜70% pure by 1H-NMR), but was used for the next reaction without further purification.
Reaction SMILES: C1C(=O)N(Br)C(=O)C1.[Cl:9][C:10]1[N:15]=[C:14]([CH2:16][C:17]([C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)=O)[CH:13]=[CH:12][N:11]=1.[NH2:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1)=[S:40].O>CC(N(C)C)=O>[Cl:9][C:10]1[N:15]=[C:14]([C:16]2[S:40][C:39]([N:41]3[CH2:42][CH2:43][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:45][CH2:46]3)=[N:38][C:17]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[C:20]=2[F:37])[CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 0.25 h
Yield: 47.8 %

Procedure:
NBS (0.21 g, 1.2 mmol) was added to a stirring solution of N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (0.50 g, 1.13 mmol) in DMA (5.5 ml) at rt. The reaction was allowed to stir for 15 min, then 1,1-dimethylethyl 4-(aminocarbonothioyl)-1-piperazinecarboxylate (0.55 g, 2.26 mmol) was added and the reaction was allowed to stir for 1 h. LCMS analysis indicated the reaction had progressed sufficiently, the reaction was poured into water and the bright yellow precipitate was collected by filtration. The filter cake was dissolved in DCM, dried over MgSO4, filtered and the filtrate was concentrated onto silica gel. Purification by flash chromatography afforded the title compound of Step B (0.36 g, 45% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.79 (s, 1H), 8.32 (d, J=5.5 Hz, 1H), 7.25-7.64 (m, 6H), 6.47 (d, J=5.5 Hz, 1H), 3.53-3.58 (m, 4H), 3.43-3.51 (m, 4H), 1.42 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH-:12])(=[O:11])=[O:10].[O-:13][C:14]#[N:15].[K+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:14]([NH2:15])=[O:13])(=[O:10])=[O:11]
Reactant: N#C[O-]
Reactant: [NH-]S(=O)(=O)c1c(F)cccc1F
Agent: [K+]
Solvent: CCO
Product: NC(=O)NS(=O)(=O)c1c(F)cccc1F

Procedure:
2,6-Difluorophenylsulphonylamide in an amount of 9.65 g and 6.5 g of potassium cyanate in 100 ml of ethanol are refluxed for 3 hours. After dilution with water and filtration while hot the solution is acidified with 5 ml of conc. hydrochloric acid. The desired N-(2,6-difluorophenylsulphonyl)urea is obtained in a yield of 10.0 g; melting point 198° C. (decomp.)
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][NH:3]1.Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1.C(N(CC)CC)C>CN1CCCC1=O>[CH3:1][C@@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][N:3]1[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN[C@@H](C)CN1c1ccc(C#N)cn1
Yield: 9 %

Procedure:
Combine (2S,5R)-2,5-dimethyl-piperazine (200 mg, 1.75 mmol), 6-chloro-nicotinonitrile (1.75 mmol) and triethylamine (5.25 mmol) in a 0.875 M solution of 1-methyl-2-pyrrolidinone. Microwave reaction mixture for 30 min at 150° C. Partition between ethyl acetate and water, collecting organic phase. Wash aqueous layer again with ethyl acetate and combine organics. Dry with sodium sulfate, filter and concentrate. Purify on preparative HPLC to give the title compound. (9% yield)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[CH2:13][N:14]1[C:15](=[O:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]1=[O:23]
Reactant: O=C1c2ccccc2C(=O)N1Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2[nH]nc(CN3C(=O)c4ccccc4C3=O)c2c1
Yield: 95.3 %

Procedure:
2-(5-Nitro-1H-indazol-3-ylmethyl)-isoindole-1,3-dione (0.71 gm) was dissolved in methanol and hydrogenated at 1 atm. using 10% Pd/C (catalytic) for 18 hrs. The catalyst was filtered and the mixture evaporated to obtain 614 mg of title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.Cl[C:17]([O:19][CH3:20])=[O:18]>CN(C1C=CN=CC=1)C.ClCl>[C:17](=[O:18])([O:19][CH3:20])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC1(c2cc(F)ccc2O)CCCCC1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: ClCl
Product: COC(=O)Oc1ccc(F)cc1C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of 4-fluoro-2-(1-methylcyclohexyl)phenol (23.5 g, 113 mmol), TEA (31 mL, 226 mmol) and DMAP (700 mg, 5.7 mmol) in CH2 Cl2(250 mL) was added methyl chloroformate dropwise at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured onto crushed ice and extracted with CH2Cl2(100 mL×3). The organic layer was washed with brine, dried over MgSO4, evaporated under vacuum. The crude product was purified by chromatography on silica gel diluted with (hexane:ethyl acetate=100:1) to give 4-fluoro-2-(1-methylcyclohexyl)phenyl methyl carbonate as red brown oil (43.9 g, 72.1% yield). 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, J=3.2, 11.2 Hz, 1 H), 7.05-7.02 (m, 1H), 6.93-6.88 (m, 1H), 3.91 (s, 3H), 2.02-1.96 (m, 2H), 1.66-1.36 (m, 8H), 1.23 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=[C:33]=[S:34])[CH:27]=1>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:33]([NH:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[S:34])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: S=C=Nc1cccnc1
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)Nc5cccnc5)c4c(c23)C1=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 8 ml of acetonitrile. 67 μl (2 molar equivalents) of 3-pyridyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 132 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=94%) which was characterized as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[K+].I[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[Cl:23].CCOC(C)=O>CN1CCCC1=O>[Cl:19][C:18]1[CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=[C:14]([Cl:23])[C:13]=1[O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(I)c(Cl)c1
Reactant: Cc1cc(O)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1F
Temperature: 130 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A mixture of 3-methyl-4-fluorophenol (99 mg, 0.79 mmol), potassium hydroxide (53 mg, 0.94 mmol), 4-iodo-3,5-dichloro-nitrobenzene (250 mg, 0.79 mmol) and 4A° molecular sieves (75 mg) in N-methylpyrolidinone (3 mL) was stirred at 130° C. for 2 h. The reaction mixture was poured into ice cold 1 N HCI (20 mL) and EtOAc (25 mL) was added. The EtOAc phase was separated and washed with 1 N HCI (3×25 mL) and brine (25 mL). The EtOAc solution was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (Hexanes: CH2CI2=7:3) to afford 3,5-dichloro-4-(4-fluoro-3-methyl-phenoxy)-nitrobenzene (207 mg). MS Calc.: 315.0 Found: 315.0 (M).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN(C)C=O>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 3,4-dihydroxybenzaldehyde (21.6 g), potassium carbonate (21.56 g) and N,N-dimethylformamide (200 mL) was added dropwise benzyl bromide (18.5 mL) under ice-cooling, and the resulting mixture was stirred at room temperature for 16 hours. Two mol/L hydrochloric acid (40 mL) was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give the title compound (19.0 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(Cl)Cl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:34])=[CH:23][CH:24]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1ccc(C2CCNCC2OCc2ccc3ccccc3c2)cc1)c1ccccc1

Procedure:
In an analogous manner to that described in Example 22(l), starting from tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(3-oxo-3-phenyl-propyl)-phenyl]-piperidine-1-carboxylate by cleavage of the BOC group using trifluoroacetic acid in methylene chloride there was obtained (3RS,4RS)-3-[4-(3-naphthalen-2-ylmethoxy-piperidin-4-yl)-phenyl]-1-phenyl-propan-1-one trifluoroacetate as a white powder; MS: 450 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]2)[NH:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:11]=[C:10]3[N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc(N3CCCC3)c3cc(N4CCCCC4)ccc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI/CI): predicted mass O21H24N6O2, 392.2.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][Mg]Cl.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:11]
Reactant: C[Mg]Cl
Reactant: O=Cc1ccc(I)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 2-fluoro-4-iodo-benzaldehyde (17.40 g, 69.60 mmol) in anhydrous tetrahydrofuran (300 mL) at −10° C. under an atmosphere of nitrogen was added 3.0 M methylmagnesium chloride in tetrahydrofuran (27.84 mL, 83.52 mmol) via syringe at such a rate as to maintain the temperature of the reaction mixture below 0° C. The reaction was stirred for 30 minutes while warming to room temperature. Saturated aqueous ammonium chloride solution was added and the mixture was diluted with ethyl acetate (200 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic extracts were combined, washed with water (1×50 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 15 to 40% v/v ethyl acetate/hexanes to give 1-(2-fluoro-4-iodo-phenyl)-ethanol (15.50 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH:20]=[CH:21][CH:22]=1.[Br:31]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:31])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[CH:20]=[CH:21][CH:22]=1
Reactant: CCOP(=O)(OCC)c1cccc(Cn2cnc3c(N)nc(OCCOC)nc32)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOP(=O)(OCC)c1cccc(Cn2c(Br)nc3c(N)nc(OCCOC)nc32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethyl 3-((6-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonate (30) (400 mg, 0.92 mmol) was dissolved in acetonitrile and N-bromosuccinimide (500 mg, 2.8 mmol) was added in one portion. After stirring at room temperature for 2 h, the reaction mixture was diluted with ethyl acetate (150 mL) and washed with water, 0.2 M sodium thiosulfate solution and brine. The organic phase was dried with sodium sulfate and the solvent was removed under vacuum. The crude diethyl 3-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonate (450 mg, 95%) was used in the next step without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[C:28]([NH:41][C:42]2[N:47]=[CH:46][N:45]=[C:44]3[NH:48][N:49]=[C:50]([O:51][CH2:52][CH2:53][NH:54][CH3:55])[C:43]=23)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=1.[C:56]([OH:60])(=O)[CH2:57][OH:58].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:25][C:26]1[CH:27]=[C:28]([NH:41][C:42]2[N:47]=[CH:46][N:45]=[C:44]3[NH:48][N:49]=[C:50]([O:51][CH2:52][CH2:53][N:54]([CH3:55])[C:56](=[O:60])[CH2:57][OH:58])[C:43]=23)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=1
Reactant: CNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCOc1n[nH]c2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12)C(=O)CO
Reaction time: 8 h
Yield: 99.8 %

Procedure:
HATU (52 mg) was added to a stirred solution of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-3-[2-(methylamino)ethoxy]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 60/47 mg, 0.10 mmol), glycolic acid (10 mg, 0.13 mmol) and DIPEA (60 μl) in DMF (4 ml) and the solution was stirred overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between water and DCM. Organic extracts were dried and concentrated and the residue triturated with ether to give the title compound as a white solid (50 mg, 94%); Mass Spectrum 500.8 (M+/retention time 2.18 minutes).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][OH:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl:14][C:15]1[N:20]=[C:19]([C:21]2[C:22](F)=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=2)[C:18]2[N:29]([CH2:41][C@H:42]3[CH2:47][CH2:46][C@H:45]([CH3:48])[CH2:44][CH2:43]3)[C:30]([N:32]3[CH2:37][CH2:36][O:35][C@@H:34]4[CH2:38][CH2:39][CH2:40][C@@H:33]34)=[N:31][C:17]=2[CH:16]=1>CN(C=O)C>[Si:3]([O:10][CH2:11][CH2:12][O:13][C:22]1[C:21]([C:19]2[C:18]3[N:29]([CH2:41][C@H:42]4[CH2:47][CH2:46][C@H:45]([CH3:48])[CH2:44][CH2:43]4)[C:30]([N:32]4[CH2:37][CH2:36][O:35][C@@H:34]5[CH2:38][CH2:39][CH2:40][C@@H:33]45)=[N:31][C:17]=3[CH:16]=[C:15]([Cl:14])[N:20]=2)=[CH:26][C:25]([Cl:27])=[CH:24][N:23]=1)([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:5])[CH3:4]
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(-c4cc(Cl)cnc4F)c32)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ncc(Cl)cc1-c1nc(Cl)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
NaH (24 mg, 0.6 mmol) was added to solution of 2-((tert-butyldimethylsilyl)oxy)ethanol (70 mg, 0.4 mmol) in DMF (1.0 mL) at 0° C., and the reaction was stirred at 0° C. for 30 minutes. A solution of 6-chloro-4-(5-chloro-2-fluoropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic, Example 18.1, Step 1; 100 mg, 0.2 mmol) was added, and the reaction was stirred at 0° C. for 30 minutes. The reaction was quenched by adding saturated aqueous NH4Cl solution and extracted using EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Purification of the residue on a silica gel column with 0 to 50% EtOAc/hexane afforded 4-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-5-chloropyridin-3-yl]-6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic). MS APCl calc'd. for C34H49Cl2N5O3Si [M+H]+ 674. found 674.
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22]C#N)[CH2:17][CH2:16]1>>[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:13]2[NH:2][C:3](=[O:12])[C:4]3[C:5]([CH:11]=2)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=3)[CH2:17][CH2:16]1
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Reactant: N#CCCN1CCC(O)CC1
Product: Cc1cccc2c(=O)[nH]c(CCN3CCC(O)CC3)cc12
Yield: 9.2 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (5.6095 g) and 3-(4-hydroxypiperidin-1-yl)propionitrile (2.44 g), 3-[2-(4-hydroxypiperidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (418.2 mg) was obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:47]([C:49]1[S:53][CH:52]=[C:51]([C:54](O)=[O:55])[CH:50]=1)[CH3:48].C(N(CC)CC)C>CN(C=O)C>[CH2:47]([C:49]1[S:53][CH:52]=[C:51]([C:54]([N:28]2[CH2:29][C:30]3([CH2:35][CH2:34][N:33]([CH2:36][C:37]4[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=4)[CH2:32][CH2:31]3)[O:25][CH2:26][CH2:27]2)=[O:55])[CH:50]=1)[CH3:48]
Reactant: CCc1cc(C(=O)O)cs1
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)N2CCOC3(CCN(Cc4cc(F)cc(CCO)c4)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
HATU (0.449 g) was added in one portion to a solution at 0° C. of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.28 g) and 5-ethylthiophene-3-carboxylic acid (0.142 g) and triethylamine (0.506 mL) in DMF (10 mL). The mixture was then stirred at 20° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 2% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.21 g.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH2:10])=[O:4].[C:15]1([CH3:24])[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH:10][C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([CH3:24])=[CH:16][CH:17]=1)=[O:23])=[O:4]
Reactant: CNC(=O)c1[nH]c(C(C)(C)C)cc1N
Reactant: Cc1ccc(N=C=O)cc1
Solvent: ClCCl
Product: CNC(=O)c1[nH]c(C(C)(C)C)cc1NC(=O)Nc1ccc(C)cc1
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To a solution of 2-(N-methylcarbamoyl)-3-amino-5-tert-butylpyrrole (0.14 g, 0.70 mmol) in CH2Cl2 (5 mL) at room temp. was annd p-tolyl isocyanate (0.088 mL, 0.70 mmol, 1.0 equiv) and the resulting mixture was allowed to stir at room temp. overnight. The resulting precipitate was separated and washed with CH2Cl2 to give N-(2-methylcarbamoyl-5-tert-butyl-3-pyrrolyl)-N′-(4-methylphenyl)urea (0.17 g, 74%): mp 164-166° C.; 1H-NMR (DMSO-d6) δ1.23 (s, 9H), 2.19 (s, 3H), 2.75 (d, J=4.41 Hz, 3H), 6.49 (d, J=2.57 Hz, 1H), 7.01 (d, J=8.46 Hz, 2H), 7.33 (d, J=8.46 Hz, 2H), 7.60-7.63 (m, 1H), 9.45 (s, 1H), 9.50 (s, 1H), 10.17 (br s, 1H); FAB-LRMS m/z 329 (M+H).