Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:26]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]2)=[CH:4][CH:3]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCCC(c2cccc3ccc(N)cc23)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCCC(c2cccc3ccc(NC(=O)c4ccccc4)cc23)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
A mixture of 7-amino-1-(1-methyl-3-piperidinyl)-naphthalene (0.203 g, 0.845 mmol, product of example 61) and triethylamine (0.141 mL, 1.01 mmol) in tetrahydrofuran (5 mL) was chilled to 0° C. and benzoyl chloride (0.118 mL, 1.01 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The reaction was concentrated at reduced pressure and the residue was taken up in methylene chloride. The organic phase was extracted with 0.5N sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1×2 inches). Elution proceeded as follows: 50% ethyl acetate/hexane (225 mL), 75% ethyl acetate/hexane (150 mL) nil; 75% ethyl acetate/hexane (400 mL) and ethyl acetate (200 mL) 0.198 g of pink foam. This product was converted to an HCl salt in methanol, treated with activated carbon, and filtered. The filtrate was concentrated and triturated with ether to give 0.091 g (31%) of the title compound as an amorphous solid with a melting range of 140°-170° C. 1H NMR (DMSO d6) δ 10.59 (s, 1 H), 10.34 (br s, 1 H), 8.73 (s, 1H), 8.06 (d, J=7 Hz, 2 H), 7.94 (distorted t, J=10 Hz, 2 H), 7.82 (d, J=7 Hz, 1H), 7.63-7.53 (m, 3 H), 7.47-7.39 (m, 2 H), 3.78 (br t, J=12 Hz, 1 H), 3.56 (br t, J=11 Hz, 2 H), 3.05 (br s, 1 H), 2.83 (br s, 3 H), 2.15-1.97 (m0 2 H), 1.71 (br s, 1 H). HRMS m/e calculated for C23H24N2O; m/e 344.1883. Observed m/e 344.1886.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[Cl:21])[CH:7]=1)[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:16][C:15]=2[Cl:21])=[O:22])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)cc2Cl)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3)cc2Cl)c1
Temperature: 80 °C

Procedure:
[3-(4-Bromo-2-chloro-benzoylamino)-phenyl]-acetic acid ethyl ester (198 mg, 0.50 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated at 80° C. The crude residue was purified by column chromatography using 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][CH2:14][OH:15])=[CH:9][CH:10]=2)[C:5](=[O:16])[C:4]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:18])=[CH:3]1.C(O)(=O)C>CO.CN(C=O)C.[Pt]>[NH2:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH2:13][CH2:14][OH:15])=[CH:9][CH:10]=2)[C:5](=[O:16])[C:4]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:18])=[CH:3]1
Reactant: Nn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Agent: [Pt]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCO)ccc21
Reaction time: 4.5 h
Yield: 47.1 %

Procedure:
1-Amino-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.21 g) from Example No. 118 is dissolved in a 1:1 mixture of methanol/DMF. To the solution is added 5% platinum on carbon (0.11 g) and acetic acid (0.5 mL). The reaction is shaken under a hydrogen atmosphere (35 psi) for 4.5 hours. The catalyst is removed by filtration through Celite. The filtrate is concentrated in vacuo, and the resulting white solid is triturated with dichloromethane. The crude product is then purified by column chromatography (MeOH/CH2Cl2: 3%, 5%) yielding 0.10 g of the title compound as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][C@H:14]([OH:21])[C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:22])[CH2:3]1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1>CN(C)C1C=CN=CC=1.CN(C)C=O.CCOCC>[Si:23]([O:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][C@H:14]([OH:21])[C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:22])[CH2:3]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)C(=O)CC[C@@H]12
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2C[C@H](O)[C@]2(C)C(=O)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3α, 12α-dihydroxy-5β-androstan-17-one (4.29 g), tert-butyldimethylsilyl chloride (3.26 g), 4-dimethylaminopyridine (0.17 g) and imidazole (1.9 g) in dimethylformamide (38 ml) is stirred at room temperature for about 1 hour, diluted with ether and washed with water. The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product which is used, without further treatment, for the next step.
Reaction SMILES: Br[CH2:2][C:3]([Br:5])=[O:4].[C:6]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[O:12]([C:13]1[CH:14]=[CH:15][C:16]([CH2:2][C:3]([Br:5])=[O:4])=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Br)Cc1ccc(Oc2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 37.9 %

Procedure:
A mixture of 3.31 g (0.038 mol) of bromoacetyl bromide, 50 ml of methylene chloride and 5 g (0.029 mol) of diphenyl ether is cooled to 0-5° C. and 4.42 ml (0.033 mol) of aluminum chloride are added. The mixture is stirred at room temperature for 4 hours. It is poured into a-water/ice mixture, the two phases are separated and the organic phase is washed with 1 N hydrochloric acid and with water. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a silica gel column using a 7/3 cyclohexane/ethyl acetate mixture as the eluent. The fraction of the medium corresponding to 3.2 g of 2-(4-phenoxyphenyl)acetyl bromide is isolated. The resulting oil is mixed with 5.9 ml (0.077 mol) of trifluoroacetic acid and 7.7 ml (0.048 mol) of triethylsilane. The mixture is heated at 80° C. for 4 hours and the residue is taken up with an ethyl ether/sodium bicarbonate mixture. The two phases are separated, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 7 g of the title compound.
Reaction SMILES: N#N.[C:3]([Si:7]([CH3:26])([CH3:25])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].[NH4+].[Cl-]>CCO.O.[Fe]>[C:3]([Si:7]([CH3:26])([CH3:25])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH2:22])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc([N+](=O)[O-])n2)o1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc(N)n2)o1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-4-nitro-2H-[1,2,3]triazole (100 mg, 0.28 mmol), iron powder (48 mg, 0.85 mmol) and NH4Cl (76 mg, 1.42 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 85° C. for 20 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by water (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions O2: tR=0.98 min; [M+H]+=324.42.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[N:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)C(C)C)(C)C.O>CN1C(=O)CCC1>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[N:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: Fc1cc(F)c(F)nc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(F)c(F)cc2F)CC1
Temperature: 150 °C

Procedure:
A mixture of 2,3,5,6-tetrafluoropyridine (755 mg, 5 mmol, Aldrich), 1-Boc-piperazine (558 mg, 3 mmol, Aldrich) and N,N-diisopropylethylamine (1 mL, 5.8 mmol, Aldrich) in NMP (5 mL) was heated at 150° C. for 16 h. The reaction mixture was cooled to room temperature, water (25 mL) was added, and the mixture was extracted with EtOAc (2×40 mL). The combined organic phases were washed with brine (50 mL), then dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with 20% EtOAc/hexane to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 318 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4].[CH3:16][O:17][CH2:18][CH2:19]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([O:5][CH2:19][CH2:18][O:17][CH3:16])=[O:4]
Reactant: COCCO
Reactant: CCCCCCCCCCC(O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC(O)C(=O)OCCOC

Procedure:
The alpha-hydroxylauric acid prepared in the foregoing manner was converted to the 2-methoxyethyl ester by refluxing a 5:1 molar ratio of 2-methoxyethanol with the acid in toluene solvent in the presence of a catalytic amount (0.3%) of p-toluenesulfonic acid. The reaction vessel was fitted with a moisture trap to remove H2O as it forms during the esterification. After water evolution was complete, the reaction mixture was water-washed and refined with 5% KOH/70:30 water:alcohol. The product was water-washed a second time, and the solvent was evaporated to yield 2-methoxyethyl alpha-hydroxylaurate.
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH3:4].[CH2:11]([O:18][CH2:19][CH2:20][NH:21][C:22]1[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]=[C:24]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]=1[NH2:37])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>[CH2:11]([O:18][CH2:19][CH2:20][N:21]1[C:22]2[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]=[C:24]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:23]=2[N:37]=[C:1]1[CH2:2][CH2:3][CH3:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCOCc2ccccc2)c1C
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCOCc1ccccc1
Yield: 83.5 %

Procedure:
Pyridine hydrochloride (0.04 g, 0.380 mmol), and trimethyl orthobutyrate (4.6 mL, 28.48 mmol) were added to a stirred solution of N4-[2-(benzyloxy)ethyl]-5,6-dimethyl-2-phenoxypyridine-3,4-diamine (6.9 g, 18.984 mmol) prepared as in Part E of Example 4 in toluene (65 mL). After the resulting solution was heated to reflux for 2 hours, the reaction was complete as determined by TLC (using 1/1 hexane/ethyl acetate), HPLC, and LC/MS. The reaction solution was then concentrated under reduced pressure, and the resulting oil was dissolved in ethyl acetate. The ethyl acetate solution was washed with brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting tan solids were triturated with diethyl ether, filtered off, and dried to provide 6.5862 g of pure product (by NMR and LC/MS), which was used in the next step.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=2)[N:19]([CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:18]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=2)[N:19]([CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:18]=1)=[O:10]
Reactant: COCCOCCOCCn1cc(CC2CCCN2C(=O)C(NC(=O)OC(C)(C)C)C2CCCCC2)c2ccc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOCCOCCn1cc(CC2CCCN2C(=O)C(N)C2CCCCC2)c2ccc(F)cc21
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of 82 (250 mg, 0.43 mmol) in DCM (5 mL) was treated with TFA (1 mL) at room temperature. After 2 h, the reaction mixture was concentrated, diluted with EtOAc, washed with 1N aqueous NaOH and brine, dried over Na2SO4, filtered and concentrated to afford 210 mg (100%) of 83 as a light yellow wax. The product was used without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][C:13]([O:15]CC)=O)[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C@H:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][C@@H:20]([OH:32])[CH2:19][NH:18][C:13](=[O:15])[CH2:12][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: CCOC(=O)COc1cccc2cccnc12
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Solvent: CCO
Product: O=C(COc1cccc2cccnc12)NC[C@H](O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a stirred mixture of ethyl 2-(quinolin-8-yloxy)acetate (250 mg, 1.08 mmol) in EtOH (2 mL) was added (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (222 mg, 1.08 mmol). The mixture was stirred at 120° C. for 0.5 hour under microwave heating. After evaporation of the solvent, the residue was purified first by prep-TLC and then prep-SFC to afford (140 mg, Yield 36%). 1H NMR (400 MHz, MeOD) 6=8.91 (d, J=4.3 Hz, 1H), 8.42 (d, J=8.3 Hz, 1H), 7.69-7.54 (m, 3H), 7.30 (d, J=7.3 Hz, 1H), 7.12-6.96 (m, 4H), 4.78 (s, 2H), 4.18-4.07 (m, 1H), 3.71 (s, 2H), 3.60-3.49 (m, 1H), 3.48-3.40 (m, 1H), 2.89 (d, J=5.8 Hz, 2H), 2.84 (d, J=4.8 Hz, 2H), 2.69-2.55 (m, 2H). LCMS (m/z): 392.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[O:12]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[CH:22]=[N+:23]([CH3:25])[CH3:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O(C1C=C(C=CC=1)C=O)C1C=CC=CC=1.CNC>>[CH3:24][N:23]([CH3:25])[CH:22]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1])[C:21]1[CH:26]=[CH:27][CH:28]=[C:19]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:20]=1
Reactant: C[N+](C)=Cc1cccc(Oc2ccccc2)c1
Reactant: Cc1cc2ccccc2[nH]1
Agent: CNC
Agent: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Product: Cc1[nH]c2ccccc2c1C(c1cccc(Oc2ccccc2)c1)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and (3-phenoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3-phenoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.[C:18](O)(=O)[CH3:19].Cl>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[C:5]2[C:4]1[CH2:5][CH2:6][NH:7][CH2:18][CH:19]=1
Reactant: CC(=O)O
Reactant: Fc1ccc(-n2ccc3cc(Cl)ccc32)cc1
Agent: Cl
Solvent: CC(C)=O
Product: Fc1ccc(-n2cc(C3=CCNCC3)c3cc(Cl)ccc32)cc1
Temperature: 60 °C

Procedure:
5-chloro-1-(4-fluorophenyl)indole (6.70 kg) and 4-piperidone-mono-hydrate,hydrochloride (8.38 kg) were transferred to a 200 L reactor under N2 cover. Acetic acid (67 L) was added and the reaction mixture was heated to 60° C. Concentrated HCl (37%, 33.5 L) was added during ½ hour and then the mixture was heated to the reflux temperature (85° C.) and refluxed for 1 hour (final temperature 95° C.). After cooling to 30° C., 33.5 L acetone was added followed by further cooling to 25° C. Filtration, wash (acetone 20 L) and drying in vacuum at 60° C. gave the title product as a white powder, yield 8.94 kg.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11]2)[O:6][N:5]=1)([CH3:3])[CH3:2].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:27]=3[F:36])[N:24]=[CH:25][C:18]=12.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1>[F:36][C:27]1[CH:28]=[C:29]([S:32]([CH3:35])(=[O:33])=[O:34])[CH:30]=[CH:31][C:26]=1[N:23]1[C:19]2=[N:20][CH:21]=[N:22][C:17]([NH:15][CH:12]3[CH2:13][CH2:14][N:10]([CH2:9][C:7]4[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=4)[CH2:11]3)=[C:18]2[CH:25]=[N:24]1
Reactant: CC(C)c1noc(CN2CCC(N)C2)n1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1noc(CN2CCC(Nc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3F)C2)n1
Yield: 91.4 %

Procedure:
A mixture of 1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-pyrrolidin-3-ylamine (354 mg, 1.68 mmol), 4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 1.53 mmol), and potassium carbonate (3.18 g, 23 mmol) in THF (20 mL) was refluxed for 2 hours. Water was added to the reaction mixture and the product was extracted with ethylacetate. The ethylacetate layer was dried over MgSO4. The organic layer was concentrated in vacuo to afford compound A133 as a white solid (700 mg, 91%). Exact mass calculated for C22H25FN8O3S 500.18, found 501.1 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: Nc1cccnc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Nc3cccnc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and pyridin-3-ylamine to give N3-(5-methyl-1H-pyrazol-3-yl)-N1-pyridin-3-yl-isoquinoline-1,3-diamine. LC-MS m/e 317(MH+).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]1(O)[CH2:23][CH2:22][CH2:21][CH2:20]1.C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]1[CH2:23][CH2:22][CH2:21][CH:20]=1
Reactant: OC1(c2ccncc2Br)CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1cnccc1C1=CCCC1
Temperature: 120 °C
Yield: 72.6 %

Procedure:
PTSA (819 mg, 4.315 mmol) was added portionwise to a stirred mixture of 1-(3-bromo-pyridin-4-yl)-cyclopentanol (I-34a: 520 mg, 2.15 mmol) in 25 mL of toluene. The resulting mixture was heated to reflux at 120° C. for 4 hours. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was concentrated, basified with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated to afford the crude product. Purification by column chromatography on silica gel (8% ethyl acetate in hexane) afforded 350 mg of the product (73% yield).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:14]=1[C:15]#[N:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(F)(F)F.CCOCC>C(OCC)C.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[F:21][C:18]1[CH:19]=[CH:20][C:13]([O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[C:14]([C:15]2([NH2:16])[CH2:2][CH2:1]2)[CH:17]=1
Reactant: CC[Mg]Br
Reactant: N#Cc1cc(F)ccc1OCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2cc(F)ccc2OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Ethylmagnesium bromide, (35.2 ml of a 3M solution in diethyl ether) was added as a slow stream to a mechanically stirred mixture of tetraisopropyl orthotitanate (16.37 mL) and 2-(benzyloxy)-5-fluorobenzonitrile (12 g) in diethyl ether (400 mL) cooled to −78° C. The resulting solution was stirred at −78° C. for 15 min and then warmed to room temperature over 1.5 h. Boron trifluoride etherate (13.38 mL) was added and the mixture was stirred for 30 min. The reaction was quenched with 1 M HCl (400 ml) and the aqueous layer was separated. The diethyl ether layer was further extracted into 1M HCl (2×200 mL). The combined aqueous layers were cooled in an ice bath and basified with 1M aqueous NaOH solution. The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) then dichloromethane/MeOH (90:10, 300 mL). The combined filtrates were separated and the aqueous layer further extracted into dichloromethane (2×200 mL). The combined organics were dried (MgSO4) and evaporated and residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol). The basic fractions were evaporated to give the subtitle compound (3.4 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][CH2:7][C:8]1[C:9]([NH2:15])=[N:10][CH:11]=[C:12]([Br:14])[CH:13]=1)C.[H-].[Na+]>CS(C)=O>[Br:14][C:12]1[CH:11]=[N:10][C:9]2[NH:15][C:4](=[O:3])[CH2:5][O:6][CH2:7][C:8]=2[CH:13]=1
Reactant: CCOC(=O)COCc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1COCc2cc(Br)cnc2N1
Temperature: 0 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
(2-Amino-5-bromo-pyridin-3-ylmethoxy)-acetic acid ethyl ester (381 mg, 1.3 mmol) is dissolved in 15 mL of DMSO and 60% sodium hydride (53 mg, 1.3 mmol) is added. The mixture is stirred for 4 hrs and then ice-cold water (100 mL) is added into reaction. The solid formed is filtered and rinsed with more water (2×50 mL) and 50% EtOAc in heptane (30 mL). Then it is dried to give 205 mg of 3-bromo-5,9-dihydro-6-oxa-1,9-diaza-benzocyclohepten-8-one which is used without purification.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:4]=1)=[O:2].[BH4-].[Na+]>CO>[O:9]([C:5]1[N:4]=[C:3]([CH2:1][OH:2])[CH:8]=[CH:7][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1cccc(Oc2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(Oc2ccccc2)n1

Procedure:
The 6-phenoxy-2-pyridinylmethanol may be prepared by first reacting phenol with 2,6-dibromopyridine in dimethyl sulfoxide under basic conditions to give 2-bromo-6-phenoxypyridine. This compound is then reacted at -70° C. with n-butyllithium in diethyl ether and then with dimethylformamide at -30° C. to give 2-formyl-6-phenoxypyridine. This aldehyde is in turn reacted with sodium borohydride in methanol, yielding the corresponding 6-phenoxy-2-pyridinylmethanol.