Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5](=[N:10][NH:11][C:12](=[O:34])[C:13]1[CH:18]=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])[C:16]([F:32])=[CH:15][C:14]=1[Cl:33])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3].CI.[C:37](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:4][C:2]([C:5](=[N:10][N:11]([CH3:37])[C:12](=[O:34])[C:13]1[CH:18]=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])[C:16]([F:32])=[CH:15][C:14]=1[Cl:33])[C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:1])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)NN=C(C(C)(C)C)C(C)(C)C)c(Cl)cc2F)c1=O
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN(N=C(C(C)(C)C)C(C)(C)C)C(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 20.3 %

Procedure:
A mixed solution of 2-chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl)-4-fluoro-benzoic acid, 2-[1-(1,1-dimethylethyl)-2,2-dimethylpropylidene]hydrazide (0.48 g), excess of methyl iodide and potassium carbonate (0.132 g) in acetonitrile (20 ml) was heated at reflux temperature overnight. The mixture was allowed to cool to ambient temperature and partitioned between ethyl acetate and brine. The organic phase was washed with brine (×3) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluted with a mixed solvent of ethyl acetate and hexane (1:4 to 1:2) to give the titled compound (0.25 g) along with its, 2-chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl)-4-fluoro-benzoic acid, 2-[1-(1,1-dimethylethyl)-2,2-dimethylpropylidene]-1-methylhydrazide (0.1 g, Compound No. 6-8)
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][O:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][N:14]1[C@@H:19]([CH2:20][CH2:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][O:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][C@@H:19]1[CH2:20][CH2:21][CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CCC(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CCC(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
Sodium borohydride (2 mg, 0.053 mmol), followed by MeOH (0.15 mL), was added to a solution of {(Z)-4-[(R)-2-oxo-6-(3-oxo-4-phenyl-butyl)-piperidin-1-yl]-but-2-enyloxy}-acetic acid methyl ester (11.5 mg, 0.030 mmol) in CH2Cl2 (0.5 mL) at 0° C. The mixture was allowed to warm to rt. After 30 min at rt, the reaction was quenched with aqueous HCl (0.5 M) and extracted with EtOAc (3×7 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford 10.1 mg (87%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:35])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C@@H:19]3[CH2:23]B(C(OC(C)(C)C)=O)[C@@H:21](C(OC)=O)[CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[Cl-].[NH4+:37]>C(OCC)C.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:35])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C@H:19]3[CH2:20][C@H:21]([C:5]([OH:35])([CH3:6])[CH3:4])[NH:37][CH2:23]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1
Reactant: COC(=O)[C@H]1C[C@H](Nc2nc(-c3cc(F)ccc3O)nc3ccccc23)CB1C(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)[C@H]1C[C@H](Nc2nc(-c3cc(F)ccc3O)nc3ccccc23)CN1
Reaction time: 1 h
Yield: 31 %

Procedure:
A Grignard solution of MeMgl (0.270 mL, 3M in diethyl ether, 0.810 mmol) was added to a solution of (2R,4R)-1-tert-butyl 2-methyl 4-(2-(5-fluoro-2-hydroxyphenyl)quinazolin-4-ylamino)borolane-1,2-dicarboxylate (0.039 g, 0.081 mmol, prepared as described in Synthesis 89-A) in THF (1 mL) and the solution refluxed for 10 h. Saturated aqueous ammonium chloride (20 mL) was added and the aqueous phase extracted with ethyl acetate (3×20 mL). Organic phases were combined, dried (MgSO4) and concentrated. The resulting crude Boc-protected amine was stirred with 4M HCl in dioxane (6 mL) for 1 h. The mixture was concentrated and the crude purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by silica column chromatography (3 cm plug of silica), eluting with 20% methanol in dichloromethane, gave the title compound as a solid (0.012 g, 31%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:22][CH2:23][C:24]([OH:26])=O)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.CN(C1C=CC=CN=1)C.C(N=C=NC(C)C)(C)C>C1COCC1.CCOC(C)=O>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:24](=[O:26])[CH2:23][CH2:22][N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]3[CH2:20][CH2:21][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][C:11]2=3)=[CH:31][CH:30]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCC(=O)O)c3ccccc23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)CCn2c3c(c4ccccc42)CCN(C(=O)OC(C)(C)C)CC3)cc1
Reaction time: 29 h
Yield: 83.5 %

Procedure:
3-(3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)propanoic acid (0.105 g, 0.292 mmol), p-anisidine (0.0377 g, 0.306 mmol, 1.05 equiv.) and dimethylaminopyridine (0.0357 g, 0.292 mmol, 1.00 equiv.) were dissolved in THF at rt under N2. Diisopropylcarbodiimide (0.0503 mL, 0.0405 g, 0.321 mmol, 1.00 equiv.) was added, then the reaction mixture was stirred for 29 h. The reaction mixture was taken up in EtOAc and washed with 10% aq. citric acid (2×), saturated aq. NaHCO3 (2×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product (0.1686 g) was chromatographed (SiO2 25 g, eluted with 9:1 toluene: acetone) to give tert-butyl 6-[3-(4-methoxyanilino)-3-oxopropyl]-1,4, 5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.113 g) in 84% yield. 1H NMR (300 MHz, CDCl3) δ 1.47, 2.68-2.76, 2.95-3.08, 3.56-3.70, 3.79, 4.53, 6.83, 7.12-7.54; MS (ESI+) for C27H33N3O4 m/z 464.0 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][C:10]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:7])[CH3:6])C.[H][H]>C(O)C.[Pd]>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:29])=[O:3])=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(Oc1ccc(O)cc1-c1ccccc1)C(=O)O

Procedure:
A solution of 2-(5-benzyloxy-biphenyl-2-yloxy)-2-methyl-propionic acid ethyl ester (3.58 g, 7.63 mmol maximum) in ethanol (75 mL) was treated with 5% Pd/C (3.0 g) and hydrogen (balloon, room temperature, 16 h). The mixture was filtered and concentrated to a viscous colorless oil (2.44 g, 107%): 1H NMR (400 MHz, CDCl3) δ 1.25 (t, 3H, J=7.1 Hz), 1.27 (s, 6H), 4.20 (q, 2H, J=7.3 Hz), 4.95 (brs, 1H), 6.67 (dd, 1H, J=3.4, 8.8 Hz), 6.81 (d, 1H, J=3.4 Hz), 6.88 (d, 1H, J=8.8 Hz), 7.30 (dt, 1H, J=1.5, 7.3 Hz), 7.37 (dt, 2H, J=1.5, 7.3 Hz), 7.52 (dd, 2H, J=1.5, 6.8 Hz).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([CH3:8])[C:5](Br)=[O:6].[CH3:9][OH:10]>C(Cl)(Cl)Cl>[CH3:9][O:10][C:5](=[O:6])[CH:4]([CH3:8])[CH2:3][CH2:2][Br:1]
Reactant: CO
Reactant: CC(CCBr)C(=O)Br
Solvent: ClC(Cl)Cl
Product: COC(=O)C(C)CCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
A solution of 4-bromo-2-methyl-butyryl bromide (6.2 g, 43.0 mmol, 1.0 eq) in CHCl3 (10 mL) was cooled at 0° C. MeOH (10 mL) was slowly added and the resulting mixture stirred at room temperature for 16 hours. The solvent was evaporated and the residue dissolved in CHCl3 and washed with water and brine. The organic layer was collected and dried with Na2SO4. Evaporation of the solvent gave 4-bromo-2-methyl-butyric acid methyl ester as thick oil (4.3 g, yield 51%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]([N:15]1[CH2:20][C@@H:19]([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[C@H:18]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][O:40][CH2:41][C@@H:42]([CH3:46])[CH2:43][O:44][CH3:45])=[CH:35][CH:34]=2)[C@@H:17]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][C:52]3[O:57][CH2:56][CH2:55][N:54]([CH2:58][CH2:59][CH2:60][O:61][CH3:62])[C:53]=3[CH:63]=2)[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN1CCCN(C)C1=O.COC(C)(C)C>[CH2:5]([O:12][C:13]([N:15]1[CH2:16][C@H:17]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][C:52]3[O:57][CH2:56][CH2:55][N:54]([CH2:58][CH2:59][CH2:60][O:61][CH3:62])[C:53]=3[CH:63]=2)[C@@H:18]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][O:40][CH2:41][C@@H:42]([CH3:46])[CH2:43][O:44][CH3:45])=[CH:35][CH:34]=2)[C@H:19]([CH2:21][N:1]=[N+:2]=[N-:3])[CH2:20]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](COS(=O)(=O)c4ccc(C)cc4)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN1CCCN(C)C1=O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CN=[N+]=[N-])[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
31.265 mmol of sodium azide are added to a solution of 6.253 mmol of (3R,4R,5S)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-3-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(toluene-4-sulfonyloxymethyl) -piperidine-1-carboxylic acid benzyl ester in 50 ml of 1,3-dimethyl-tetrahydro -pyrimidin-2-one (DMPU) under argon at 45° C. After 5 hours, the reaction mixture is cooled to room temperature, diluted with tert-butyl methyl ether, washed with water and brine, dried with sodium sulfate and evaporated. The crude title compound is obtained as a yellow oil. Rf=0.58 (EtOAc-heptane 2:1); Rt=5.96 (gradient I).
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:28][C:29]1[CH:43]=[CH:42][C:32]([C:33]2[CH:38]=[C:37]([CH2:39][CH3:40])[C:36]([Pb+3])=[CH:35][CH:34]=2)=[CH:31][CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]2[CH:34]=[CH:35][C:36]([CH:4]3[C:5](=[O:10])[C@H:6]4[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]4)[C:3]3=[O:11])=[C:37]([CH2:39][CH3:40])[CH:38]=2)=[CH:42][CH:43]=1
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Reactant: CCc1cc(-c2ccc(Cl)cc2)ccc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cc(-c2ccc(Cl)cc2)ccc1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 33.4 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (0.20 g, 1.30 mmol) and 4-dimethylaminopyridine (0.792 g, 6.49 mmol) are added to a mixture of chloroform (4 ml) and toluene (1 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4′-Chloro-3-ethylbiphen-4-yllead triacetate (0.856 g, 1.43 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×5 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(4′-chloro-3-ethylbiphenyl-4-yl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (0.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Reactant: CN1CCN(C2CCN(c3ccc(N)cc3C#N)CC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 17.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.7 g) and 5-amino-2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]benzonitrile (2.0 g), the title compound (0.6 g) was obtained, melting point: 240° C. (decomposition).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C(Cl)Cl>[CH2:17]([O:16][C:14](=[O:15])[NH:3][CH2:1][CH3:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethylamine (1.3 mL, 20.0 mmol) and diisopropylethylamine (7 mL, 40.0 mmol) were combined in CH2Cl2 (200 mL) and cooled to 0° C. Benzyl chloroformate (2.86 mL, 20.0 mmol) was added dropwise, and the reaction was stirred at 0° C. for 30 minutes. Once no starting material was seen by analytical tlc, the mixture was warmed to room temperature and washed with H2O, 0.1N aqueous HCl, and H2O, and then dried and concentrated to give the title compound.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:8]2[NH:9][CH:10]=[C:11]([CH2:12][CH2:13][OH:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.O=[C:17]([CH2:23][CH3:24])[CH2:18][C:19]([O:21][CH3:22])=[O:20]>C1(C)C=CC=CC=1>[CH2:23]([C:17]1([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:10]2[NH:9][C:8]3[C:7]([C:11]=2[CH2:12][CH2:13][O:14]1)=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:2][CH3:1])[CH3:24]
Reactant: CCC(=O)CC(=O)OC
Reactant: CCc1cccc2c(CCO)c[nH]c12
Agent: Cl
Solvent: Cc1ccccc1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Reaction time: 7 h
Yield: 82.7 %

Procedure:
To a solution of 7-ethyltryptophol (12.0 g) in a mixture of methanolic hydrogen chloride (10% w/v, 50.0 ml) and toluene (50 ml), methyl 3-oxopentanoate (9.1 g, 0.07 mole) was added in one lot, at 25° C. The reaction mixture was stirred at 25-30° c for 7 hours. The reaction mixture concentrated to about 20 ml under reduced pressure. Methanol (50 ml) was added to the concentrate and the solution was extracted with hexane (100 ml). Hexane was concentrated to about 20 ml and methanol (10 ml) was added. The product was filtered, washed with methanol and dried to afford the title compound (15.8 g, 84%), m.p. 128-130° C., purity: 97.8%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[N:14]=1)[CH:7]=[C:6]2[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[Br:31][C:32]1[C:40]2[C:35](=[N:36][CH:37]=[N:38][C:39]=2Cl)[NH:34][N:33]=1>>[Br:31][C:32]1[C:40]2[C:35](=[N:36][CH:37]=[N:38][C:39]=2[N:28]2[CH2:27][CH2:26][N:25]([C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=[C:8]([C:13]4[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[N:14]=4)[CH:7]=3)[CH2:30][CH2:29]2)[NH:34][N:33]=1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Reactant: COCCCNc1nccc(-c2cc(N3CCNCC3)c3cc(OC)ccc3c2)n1
Product: COCCCNc1nccc(-c2cc(N3CCN(c4ncnc5[nH]nc(Br)c45)CC3)c3cc(OC)ccc3c2)n1

Procedure:
4-{4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-6-methoxy-2-naphthyl}-N-(3-methoxypropyl)pyrimidin-2-amine was synthesized according to General Procedure E except 4-(6-methoxy-4-(piperazin-1-yl)naphthalen-2-yl)-N-(3-methoxypropyl)pyrimidin-2-amine and 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine were used. 4-{4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-6-methoxy-2-naphthyl}-N-(3-methoxypropyl)pyrimidin-2-amine (177) was isolated as a yellow solid. M.p.=225-227° C. LCMS (m/z): 605 [M+H].
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:36])[C:5]([NH:7][C:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]1[C:17](=[O:35])[C:18]([O:26]C(C3C=CC=CC=3)=O)=[C:19]([C:21]([O:23]CC)=O)[N:20]=[C:9]21)=[O:6])[CH3:3].CNC.Cl.[CH:41]1([C:44]2[CH:45]=[C:46]([CH2:51][NH2:52])[CH:47]=[CH:48][C:49]=2[F:50])[CH2:43][CH2:42]1.C(N(CC)CC)C>C(O)C>[CH:41]1([C:44]2[CH:45]=[C:46]([CH:47]=[CH:48][C:49]=2[F:50])[CH2:51][NH:52][C:21]([C:19]2[N:20]=[C:9]3[C:8]4([NH:7][C:5](=[O:6])[C:4]([N:2]([CH3:1])[CH3:3])=[O:36])[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]4)[CH2:11][N:10]3[C:17](=[O:35])[C:18]=2[OH:26])=[O:23])[CH2:42][CH2:43]1
Reactant: NCc1ccc(F)c(C2CC2)c1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)c(C3CC3)c2)c(O)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
A suspension of ethyl 10-(((dimethylamino)(oxo)acetyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (0.025 g, 0.050 mmol) and dimethylamine (0.050 mL, 0.101 mmol) (2 M in methanol) in ethanol (1 mL) was stirred at 50° C. for 1 h. Added to the mixture were (3-cyclopropyl-4-fluorophenyl)methanamine hydrochloride salt (0.025 g, 0.126 mmol) and triethylamine (0.070 mL, 0.504 mmol) and the mixture stirred at 90° C. for 5 h. The mixture was cooled to room temperature and concentrated. The brown residue was purified by preparative HPLC: Solvent A=10% ACN/90% H2O/0.1% trifluoroacetic acid; Solvent B=90% ACN/10% H2O/0.1% trifluoroacetic acid; Start % B=0; Final % B=100; Gradient time=20 min; Stop time=23 min; Column=Sunfire 19×100 mm, C18, 5 μm. The resulting purple solid was triturated with hot methanol to give the title compound as a white solid (6.0 mg, 21% yield). 1H NMR (500 MHz, CDCl3) δ: 12.03 (1 H, s), 8.56 (1 H, t, J=5.49 Hz), 8.15 (1 H, s), 7.11-7.20 (1 H, m), 6.85-7.01 (2 H, m),4.49 (2 H, d, J=6.10 Hz), 4.16 (2 H, d, J=3.97 Hz), 3.28 (3 H, s), 2.91 (3 H, s), 2.42-2.65 (3 H, m), 2.01-2.18 (3 H, m), 1.86-2.00 (2 H, m), 1.71 (2 H, ddd, J=13.28, 6.56, 6.41 Hz), 0.90-1.02 (2 H, m), 0.67-0.80 (2 H, m). LCMS (M+H) calcd for C26H31FN5O5: 512.23; found: 512.24.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([N:11]=[C:12]=[S:13])[CH2:4][CH2:3]1.C(Cl)Cl.[CH3:17][NH2:18]>C(O)C>[CH3:17][NH:18][C:12]([NH:11][CH:5]1[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:2](=[O:1])[CH2:3][CH2:4]1)=[S:13]
Reactant: O=C1CCC(N=C=S)c2ccsc21
Reactant: CN
Solvent: CCO
Solvent: ClCCl
Product: CNC(=S)NC1CCC(=O)c2sccc21

Procedure:
A mixture of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylisothiocyanate (5.0 g) and methylene chloride (100 ml) is stirred and a saturated solution of methylamine in ethanol (15 ml ethanol saturated with methylamine) added. The mixture is stirred for 15 hours then heated at reflux for 2 hours, cooled and evaporated to dryness in vacuo. The residue is triturated with water, the title thiourea collected and dried.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[Br:11][C:12](Br)([F:14])[F:13]>CN(C)C=O>[Br:11][C:12]([F:14])([F:13])[O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: FC(F)(Br)Br
Reactant: N#Cc1ccc(O)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OC(F)(F)Br)cc1
Temperature: 25 °C

Procedure:
According to this reference, 1 mole of sodium salt of p-hydroxybenzo-nitrile and 1.7 moles of dibromodifluoromethane are dissolved in dimethylformamide, stirred at the room temperature for a day and distilled to obtain desired p-(bromodifluoromethoxy)-benzonitrile. However, the yield is only about 31.8%.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[CH3:14][S:15]([NH:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)(=[O:17])=[O:16]>C(O)C>[CH3:14][S:15]([NH:18][CH2:19][CH2:20][CH2:21][S:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)NCCCOS(C)(=O)=O
Reactant: Sc1cccc2nccn12
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)NCCCSc1cccc2nccn12
Yield: 47 %

Procedure:
To a solution of 5-mercaptoimidazo[1,2-a]pyridine (1.50 g, 10 mmoles) and 4M sodium methylate (2.93 ml, 12 mmoles) in ethanol (50 ml) was added 3-methylsulfonylamino-1-methylsulfonyloxypropane (2.77 g, 12 mmoles) at room temperature and the mixture was heated under reflux for 16 hours. After cooling, the solvent was distilled off. The residue was dissolved in chloroform, washed with an aqueous saturated sodium bicarbonate solution and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent: ethyl acetate/ethanol (50:1)] to obtain 1.34 g of the desired product (47.5%, pale yellow crystals).
Reaction SMILES: [Na].CO.Cl.[NH2:5][C:6]([NH2:8])=[NH:7].[Cl:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=2)[N:14]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:13]=1)=[O:11]>COCCOC>[ClH:9].[NH:7]([C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=2)[N:14]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:13]=1)=[O:11])[C:6]([NH2:8])=[NH:5]
Reactant: Cc1ccc2c(c1)c(C(=O)Cl)cn2-c1ccnc2ccccc12
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: COCCOC
Solvent: CO
Product: Cc1ccc2c(c1)c(C(=O)NC(=N)N)cn2-c1ccnc2ccccc12
Temperature: 22 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
0.365 g (15.9 mmol) of sodium is added at 22° C. under an argon atmosphere to 45 cm3 of methanol. After complete dissolution, 1.4 g (15 mmol) of guanidine hydrochloride are added. After stirring at 22° C. for 2 hours, the reaction mixture is filtered under an argon atmosphere. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is dissolved in 25 cm3 of 1,2-dimethoxyethane. 1 g of 3-chlorocarbonyl-5-methyl-1-(quinol-4-yl)-1H-indole, suspended in 20 cm3 of 1,2-dimethoxyethane, is subsequently added at 22° C. under an argon atmosphere. After stirring at 22° C. for 19 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 20 cm3 of water. After stirring at 22° C. for 1 hour, the suspension is filtered and dried to give a beige-coloured powder which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (7/3 by volume) and then dichloromethane/methanol/20% aqueous ammonia (18/3/0.5 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 1.1 g of a beige-coloured solid are obtained, which solid is triturated in 10 cm3 of N hydrochloric acid for 1 hour. After filtering off, the residue is recrystallised under hot conditions from 180 cm3 of methanol to give 0.66 g of 3-guanidinocarbonyl-5-methyl-1-(quinol-4-yl)-1H-indole hydrochloride in the form of pale yellow crystals melting at 268° C. (Analysis C20H17N5O.HCl; % calculated C, 63.24, H: 4.78, Cl: 9.33, N: 18.44, O: 4.21, % found C: 63.26, H: 4.72, Cl: 9.47, N: 18.57).