Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].Cl.[NH2:29][CH:30]1[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2>>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:29][CH:30]2[C:42]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:36]3[C:31]2=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1C
Reactant: NC1c2ccccc2-c2ccccc21
Agent: Cl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CNC2c3ccccc3-c3ccccc32)cc1-c1ccccc1C

Procedure:
The desired compound was prepared using the method described in Example 403H starting with N-[4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 403G, and 9-aminofluorene hydrochloride salt m/e (ESI) 551 (MH+)
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](O)[CH2:9][C@H:8]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:6])[CH:2]=[CH2:3].[C:20]([OH:28])(=[S:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:27][C:20](=[O:28])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][C@H:8]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: OC(=S)c1ccccc1
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1ccccn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1Cc1ccccn1
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-pyridylmethyl) pyrrolidine (1.0 g), thiobenzoic acid (973 μl) and triphenylphosphine (1.30 g) in tetrahydrofuran (20 ml) was added dropwise diethyl azodicarboxylate (1.2 ml) at 0° C. The reaction mixture was stirred for 30 minutes, and then diluted with water and ethyl acetate. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layer was washed with water (twice) and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel to give (2R,4S)-1-allyloxycarbonyl-4-benzoylthio-2-(2-pyridylmethyl)pyrrolidine (1.34 g).
Reaction SMILES: [CH3:1][C:2]1[Se:6][C:5]([C:7]([C:9]2[O:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=O)=[CH:4][CH:3]=1.[CH2:18]([NH:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N1C2C=C[Se]C=2C(C2OC(C(OC)=O)=CC=2)=N1)C1C=CC=CC=1>C(O)(=O)C>[CH2:18]([N:25]1[C:4]2[CH:3]=[C:2]([CH3:1])[Se:6][C:5]=2[C:7]([C:9]2[O:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNCc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(C)[se]2)o1
Agent: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc(C)[se]c23)o1

Procedure:
Compound 7 (5.94 g, 0.02 mole), benzylhydrazine 50 (4.88 g, 0.04 mole) and glacial acetic acid (1.5 ml) were allowed to react as in the preparation of compound 55 to afford compound 56. Yield: 1.56 g (19.5%); white crystals;
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9]([CH3:15])=[N:10][N:11]([CH3:14])[C:12]=2[CH3:13])=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([N:25]([CH:35]2[CH2:37][CH2:36]2)CC2C=CC(OC)=CC=2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]([C:8]2[C:9]([CH3:15])=[N:10][N:11]([CH3:14])[C:12]=2[CH3:13])=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([NH:25][CH:35]2[CH2:37][CH2:36]2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(-c4c(C)nn(C)c4C)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(C)c(C)c1-c1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.5 %

Procedure:
To a round bottom flask charged with 2-((2-chloro-5-cyano-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30 mg, 0.052 mmol) in dichloromethane (345 μl) was added anisole (22.64 μl, 0.207 mmol), followed by trifluoroacetic acid (200 μl, 2.59 mmol). The reaction mixture was stirred at room temperature 2 d. Excess TFA was removed by concentration in vacuo. The crude residue was taken up in methanol and free based using a Phenomenex Strata SCX 1 g column. The column was flushed with 3 column volumes MeOH and 1 column volume 7 N NH3/MeOH. The ammonia containing fraction was concentrated in vacuo. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. 2-((2-Chloro-5-cyano-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (8 mg) was isolated.
Reaction SMILES: BrC1C2C(=CC=CC=2)C(C2C=CC(Cl)=CC=2)=C(C(OC(C)(C)C)C(O)=O)C=1C.[C:29]([O:33][CH:34]([C:40]1[C:49]([CH3:50])=[CH:48][C:47]2[C:42](=[CH:43][C:44]([Cl:51])=[CH:45][CH:46]=2)[C:41]=1[C:52]1[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=1)[C:35]([O:37]CC)=[O:36])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][CH:34]([C:40]1[C:49]([CH3:50])=[CH:48][C:47]2[C:42](=[CH:43][C:44]([Cl:51])=[CH:45][CH:46]=2)[C:41]=1[C:52]1[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=1)[C:35]([OH:37])=[O:36])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Cl)cc2c1-c1ccc(Cl)cc1
Agent: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1Br
Product: Cc1cc2ccc(Cl)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)acetic acid (149) was prepared in a similar manner to 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid of Example 124, except using ethyl 2-tert-butoxy-2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)acetate, giving the title compound (parent form) 1H-NMR: (400 MHz, DMSO-d6): δ 12.86 (s, broad, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.83 (s, 1H), 7.73-7.67 (m, 2H), 7.56-7.49 (m, 2H), 7.40 (d, J=8.2 Hz, 1H), 7.11 (d, J=1.6 Hz, 1H), 5.00 (s, 1H), 2.57 (s, 3H), 0.93 (s, 9H). LCMS-ESI− (m/z): [M−H]− calcd for C23H21Cl2O3: 415.1; Found: 415.3.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=[O:11]>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc2ccccc2o1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)C1Cc2ccccc2O1
Temperature: 60 °C
Yield: 96.2 %

Procedure:
A mixture of 1-benzofuran-2-carboxylic acid (40.0 g, 250.0 mmol) and palladium hydroxide (20 wt. % on carbon, 2.0 g) in acetic acid (400 ml) was heated at 60° C. under a hydrogen atmosphere (80 psi) for 2 h. The mixture was filtered to give a solution of the title compound (39.5 g) in acetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17]Cl)[CH3:14]>>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH2:13][N:15]([CH2:19][CH3:20])[CH2:16][CH3:17])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCN(CC)CCCl
Reactant: CCOC(=O)c1ccc(O)cc1
Product: CCOC(=O)c1ccc(OCCN(CC)CC)cc1

Procedure:
The title compound was prepared by alkylation of ethyl-4-hydroxybenzoate with diethylchloroethylamine using methods analogous to those described in Example 2(i).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10](NC3C=CC(S(N4CCC(O)CC4)(=O)=O)=CC=3)[N:11]=2)[CH2:4][CH2:3]C1.[CH2:32]([O:39][CH2:40][C:41]([N:43]([CH3:51])[C:44]1[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=1)=[O:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:39][CH2:40][C:41]([N:43]([C:44]1[CH:45]=[CH:46][C:47]([NH:50][C:10]2[N:11]=[C:6]([NH:5][CH:1]3[CH2:4][CH2:3]3)[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=2)=[CH:48][CH:49]=1)[CH3:51])=[O:42])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=S(=O)(c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1)N1CCC(O)CC1
Reactant: CN(C(=O)COCc1ccccc1)c1ccc(N)cc1
Product: CN(C(=O)COCc1ccccc1)c1ccc(Nc2nc(NC3CC3)c3cc[nH]c3n2)cc1

Procedure:
According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, 2-benzoxy-N-methyl-N-(4-aminophenyl)acetamide and 2-Chloro-N-cylclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave 2-benzyloxy N-(4-(4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide (MS calcd for C25H26N6O2 442.2, found [MH] 443.5).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C.[CH:27]([C:29]1[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32])=O.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>C(O)C>[CH2:9]([NH:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:27][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([O:33][CH3:34])=[O:32])=[CH:22][CH:21]=1)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: COC(=O)c1ccccc1C=O
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCCCCCCCCCNC(=O)c1ccc(NCc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of 4-amino-N-dodecylbenzamide (0.304 g, 1.0 mmol), acetic acid (0.060 g, 1.0 mmol) and methyl 2-formylbenzoate (0.164 g, 1.0 mmol) in ethanol (2 mL) was added at once NaBH3CN (0.075 g, 1.20 mmol). The resulting mixture was stirred overnight at rt. A saturated solution of NaHCO3 (10 mL) was added to the reaction mixture, the aqueous layer was separated and extracted with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated to give a colorless oil. This crude product was purified by column chromatography over silica gel to give the title compound as a colorless oil (0.212 g, 47%). M+(LC/MS(ESI)): 453.6. HPLC (Condition A), Rt: 6.64 min (HPLC purity: 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[O:26])=[CH:21][C:20]=4[Cl:34])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:35]=1.O1CCOCC1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[C:84]([NH2:87])(=[O:86])[CH3:85].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:84]([NH:87][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[O:26])=[CH:21][C:20]=4[Cl:34])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:35]=1)(=[O:86])[CH3:85]
Reactant: CN1CCN(C(=O)c2ccc(N(C)C(=O)c3cc4c(s3)-c3ccc(Br)cc3OCC4)c(Cl)c2)CC1
Reactant: CC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccc(C(=O)N4CCN(C)CC4)cc3Cl)sc1-2
Temperature: 100 °C
Yield: 5.5 %

Procedure:
Following the procedure of Example 91, to a solution containing 8-bromo-N-(2-chloro-4-(4-methylpiperazine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (0.095 g, 0.16 mmol) in 1,4-dioxane (2.00 mL, 25.6 mmol;) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos, 9.6 mg, 0.016 mmol;), acetamide (15 mg, 0.25 mmol;), and cesium carbonate (120 mg, 0.36 mmol) then degassed with nitrogen gas for 15 min. To the reaction mixture was added tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 7.6 mg, 0.0083 mmol;). The reaction mixture was heat at 100° C. for 18 h. The crude product was submitted for rHPLC to give 147 (5.5%). MS: (ESI+) 553.2
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:13][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>ClCCl.CO>[CH3:13][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([I:12])[C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1cc(I)c(Cl)cc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(I)c(Cl)cc1Cl

Procedure:
Sodium iodate (4.4 g) and iodine (11.1 g) were added to 90% sulfuric acid (330 mL), and stirred at room temperature for 8 hours. 2,4-Dichlorobenzoic acid (21 g) commercially available was added and stirred at the same temperature for 24 hours. The reaction solution was poured into ice water (3 L), and the precipitated solid material was collected by filtration. Further, the solid material was washed with water, and dried under reduced pressure. 2,4-Dichloro-5-iodobenzoic acid (16.8 g) was obtained by recrystallization (acetic acid-water). The resulting 2,4-dichloro-5-iodobenzoic acid (2 g) was dissolved in a mixture of dichloromethane (20 mL) and methanol (20 mL). Trimethylsilyldiazomethane (hexane solution, 2 M) was added dropwise until the solution became yellow. A small amount of acetic acid was added, and then the resulting mixture was concentrated under reduced pressure. The resulting residue was recrystallized using hexane to give the title compound 2,4-dichloro-5-iodobenzoic acid methyl ester as white solid (2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][OH:23])=[N:12][C:11]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])N.[C:31]([N:34]=[C:35]=[O:36])(=[O:33])[CH3:32]>>[C:31]([NH:34][C:35](=[O:36])[O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:24]([CH3:26])[CH3:25])[N:12]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)N=C=O
Reactant: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: NC(=O)[O-]
Product: CC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Yield: 76 %

Procedure:
5-(3,5-Dichlorophenylthio)-4-isoproyl-1-(4-pyridylmethyl)-2-hydroxymethyl-1H-imidazole (89) (245 mg, 0.6 mmol) prepared in accordance with the method as described in WO 96/10019 was converted to the carbamate with acetyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 90 (225 mg, 76%) as crystals. Mp. 135-137° C. Rf 0.32 (10:1 EtOAc - CH3OH).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:21]1([C:27](C2C=CC=CC=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC1CC2C3C(=CC=CC=3)C(=O)CC=2CC1>>[CH3:34][C:33]1[CH:32]=[CH:31][C:30]2[CH:29]=[CH:27][C:21]3[C:26]([C:2]=2[C:3]=1[OH:5])=[CH:25][CH:24]=[CH:23][CH:22]=3
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: CC1CCC2=C(C1)c1ccccc1C(=O)C2
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc2ccc3ccccc3c2c1O

Procedure:
In a 500 ml 3-neck flask equipped with magnetic stirrer and reflux condenser with nitrogen inlet, 66 ml of trifluoroacetic acid and 88 ml of trifluoroacetic anhydride were mixed together cautiously. The mixture was stirred under nitrogen and 54.6 g (0.21 mole) of 97% triphenylmethanol was added in increments over a 30 minute period giving an intense yellow-green solution. Heat was liberated. The reaction mixture was refluxed for one hour, cooled and 22.0 g (0.105 mole) of 3-methyl-1,2,3,4-tetrahydrophenanthrone as prepared above was added all at once, followed by refluxing under nitrogen for 21 hours. The amber mixture was cooled in an ice water bath and filtered to remove the solids. The filtrate was poured on crushed ice and the light tan precipitate was collected, washed with water and air-dried overnight. The solids were extracted with several portions of hexanes at room temperature to take up the 4-phenanthrol trifluoroacetate. The hexanes were concentrated to 400 ml, cooled in a freezer, then filtered. The filtrate was concentrated under vacuum to an oil. 40 ml of degassed 10% aqueous sodium hydroxide (containing a trace amount of sodium hydrosulfite) was added to the oil, followed by 110 ml of methanol. Nitrogen was passed through the mixture with stirring for one hour at room temperature. The mixture was filtered, and while cooling in an ice water bath, the filtrate was acidified with dilute hydrochloric acid to give a light tan precipitate. The precipitate was collected by filtration, washed with water and dried under vacuum to give 17.9 g (79.13% by weight) of 3-methyl-4-phenanthrol as a tan solid. M/e 208; M.P. 88°-92° C.; λmax 275 (16,200) methanol.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=1[O:22][CH3:23].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[NH:4][N:3]=2)=[CH:15][C:14]=1[O:22][CH3:23]
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: COc1cc(B(O)O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: COc1cc(-c2n[nH]c3ncnc(N)c23)ccc1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 48.5 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.500 g, 1.91 mmoles) in DMF (8 ml), ethanol (4 ml) and water (4 ml), 4-Fluoro-3-methoxyphenyl boronic acid (0.423 g, 2.49 mmoles) and sodium carbonate (1.01 g, 9.57 mmoles) were added and the system is degassed for 30 min Tetrakis triphenylphosphine Palladium (0.436 g, 0.377 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.240 g, 48% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.64(s, 1H), 8.20(s, 1H), 8.08(s, 1H), 7.54(d, J=9.3Hz, 1H), 7.34(d, J=8.3Hz, 1H),3.82(s, 3H).
Reaction SMILES: CS(O[CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1)(=O)=O.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>C(#N)C>[N:22]1([CH2:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:8][CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Solvent: CC#N
Product: Clc1ccc(C(CC2OCCO2)Cn2ccnc2)cc1Cl
Yield: 77.7 %

Procedure:
1-Methanesulphonyloxy-2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propane (15.5 g) (see Preparation 16) and imidazole (9 g) were dissolved in anhydrous acetonitrile (100 ml) and the mixture heated at reflux for 90 hours. The solvent was removed under reduced pressure, the residue dissolved in dichloromethane (100 ml) and the solvent again removed under reduced pressure. The residue was dissolved in dichloromethane (300 ml) and washed with sufficient aqueous sodium carbonate solution to ensure that the aqueous phase reached pH14. The two phases were separated and the aqueous phase extracted with dichloromethane (100 ml). The organic phases were then combined and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel, eluting with a solvent gradient of 99:1 changing to 95:5, by volume, dichloromethane:methanol to give 1-(imidazol-1-yl)-2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propane (11.1 g) as an orange oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:11])[NH:6]2.[C:12]([O:16][C:17](=[O:25])[NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:25])[NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[NH:4][C:5](=[O:11])[NH:6]3)[CH2:21][CH2:20]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=c1[nH]c2ncnc(Cl)c2[nH]1
Product: CC(C)(C)OC(=O)NC1CCN(c2ncnc3[nH]c(=O)[nH]c23)CC1

Procedure:
By reacting 6-chloro-7,9-dihydro-purin-8-one with piperidin-4-yl-carbamic acid tert-butyl ester according to the method of Example 4A, the title compound was obtained. LC/MS: (LCT) Rt 5.68 [M+H]+ 335.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[CH:25]=[C:24]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH:23]=[C:22]([O:38][CH3:39])[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:37][C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[N:28]([C:26]([C:24]1[CH:23]=[C:22]([O:38][CH3:39])[N:21]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:25]=1)=[O:27])[CH2:29][CH2:30]2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: COc1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)N2CCc3cc(F)ccc32)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 0.361 g (1.24 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride, 0.380 mg (1.24 mmol) (2-chloro-6-methoxypyridin-4-yl)-(5-fluoro-2,3-dihydroindol-1-yl)-methanone and 514 mg (3.72 mmol) potassium carbonate in 3.0 mL NMP was stirred for 8 h at 130° C. After cooling the reaction mixture to RT the precipitate formed was filtered off and purified by preparative HPLC. The fractions containing the product were combined and evaporated down i. vac.