Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH:9]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(Cl)(Cl)Cl>[CH:14]1([N:11]2[CH2:12][CH2:13][CH:9]([NH:8][C:6](=[O:7])[C:5]3[CH:20]=[CH:21][C:2]([NH:1][C:22](=[O:24])[CH3:23])=[CH:3][CH:4]=3)[CH2:10]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1ccc(C(=O)NC2CCN(C3CCCCC3)C2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(C(=O)NC2CCN(C3CCCCC3)C2)cc1
Yield: 50 %

Procedure:
To a suspension of 8.6 g. (0.3 mole) of p-amino-N-(1-cyclohexyl-3-pyrrolidinyl)benzamide in 50 ml. of chloroform was added dropwise with stirring, 3.37 g. (0.03 mole) of acetic anhydride. The mixture was stirred for 30 minutes and the solution extracted with dilute sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in hot ethyl acetate and an equivalent amount of isopropyl ether added to precipitate the product. After recrystallizing from the same solvent, 5.1 g. (50%) of product melting at 184°-186°C. was obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)[CH3:2].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:16])=[O:12])=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1ccc(CC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(CC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Ethylphenylacetic acid (3.0 g) (see Japanese Unexamined Patent Publication 63-233975) was dissolved in dichloromethane (15 ml), and thereto were added oxalyl chloride (6.0 ml) and N,N-dimethylformamide (one drop). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated under reduced pressure, and the residue was subjected to azeotropic distillation with toluene to give a crude 4-ethylphenylacetyl chloride, which was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[NH:14][CH:15]([CH3:19])[C:16](=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:14]([C:8]1[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:7]=1[CH3:6])[CH:15]([CH3:19])[C:16](=[O:18])[CH3:17])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(=O)C(C)Nc1c(C)cccc1C
Solvent: Cc1ccccc1
Product: CC(=O)C(C)N(C(=O)CCl)c1c(C)cccc1C

Procedure:
A 152.6-g (1.35-mol) sample of chloroacetyl chloride was added over 0.25 hour in small portions to a stirred solution of 170.8 g (0.89 mol) 3-(2,6-dimethylphenylamino)-2-butanone in 500 ml toluene. The reaction mixture was heated under reflux for 3 hours, cooled and filtered. The filtrate was concentrated and chromatographed on silica gel using dichlormethane eluant. The eluted material was recrystallized several times from ethyl ether/hexane to give the 3-(N-chloroacetyl-2,6-dimethylphenylamino)-2-butanone product, as a brown solid, m.p. 78°-82° C. The infrared spectrum of the product showed strong carbonyl absorption at 5.8 and 6.1 microns. This product is tabulated in Table I as Compound No. 5-A.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:11])[C:8]([CH3:10])=[CH2:9].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=C(C)C(=O)Cl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: C=C(C)C(=O)c1ccccc1

Procedure:
Benzene (1 mL), methacryloyl chloride (0.156 mg), and aluminium chloride (199 mg) were reacted in carbon disulfide (2 mL) at from 0° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (106 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][N:21]3[CH3:25])=[O:19])[CH2:14][CH2:13]2)[CH:4]=[C:3]1[C:26](O)=[O:27].[N:29]1([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>>[N:29]1([C:35]2[CH:36]=[C:37]([NH:41][C:26]([C:3]3[N:2]([CH3:1])[C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][C:9]=4[CH2:11][N:12]3[CH2:13][CH2:14][N:15]([C:18]([C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[CH3:25])=[O:19])[CH2:16][CH2:17]3)=[O:27])[CH:38]=[CH:39][CH:40]=2)[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: CN1CCCC1C(=O)N1CCN(Cc2cccc3cc(C(=O)O)n(C)c23)CC1
Reactant: Nc1cccc(N2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC[C@H]1C(=O)N1CCN(Cc2cccc3cc(C(=O)Nc4cccc(N5CCOCC5)c4)n(C)c23)CC1

Procedure:
1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid and 3-morpholin-4-yl-phenylamine are used as reactants. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (HATU) is used instead of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (TBTU).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][C:12]=3[CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.C1COCC1>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:22]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2cc(OC3CCCCC3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(OC3CCCCC3)ccc2CCC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 98.5 %

Procedure:
To methyl 2-cyclohexyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (412 mg, 1.37 mmol) dissolved in a mixed solvent of methanol (5 ml) and THF (5 ml) was added a 1N aqueous solution of sodium hydroxide (4.0 ml), and the resulting mixture was stirred at 50° C. for 6 hours. The reaction mixture was mixed with 1 N hydrochloric acid (4.0 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water and was dried under reduced pressure to obtain 2-cyclohexyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (388 mg, 1.35 mmol, 99%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:37])=[C:23]([N:25]4[CH2:34][CH2:33][C:32]5[C:27](=[C:28]([F:36])[CH:29]=[CH:30][C:31]=5[F:35])[CH2:26]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.CCOCC>[F:35][C:31]1[CH:30]=[CH:29][C:28]([F:36])=[C:27]2[C:32]=1[CH2:33][CH2:34][N:25]([C:23]1[C:22]([NH2:37])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[CH:24]=1)[CH2:26]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5c(F)ccc(F)c5C4)c3)cn2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1N1CCc2c(F)ccc(F)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{4-[6-Amino-5-(5,8-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (26 mg, 0.051 mmol) was dissolved in MeOH (20 mL), 1.0 M of HCl in Et2O (20 mL) was added, and the mixture was stirred at rt overnight. The solvent was removed in vacuo to give the title compound as a brown solid. 1H NMR (400 MHz, CD3OD): δ=2.33-2.42 (m, 4H), 3.08 (t, J=5.2 Hz, 2H), 3.23-3.36 (m, 2H), 3.39 (t, J=5.6 Hz, 2H), 3.59 (d, J=12.8 Hz, 2H), 4.24 (s, 2H), 4.62-4.72 (m, 1H), 6.99-7.04 (m, 2H), 7.97 (s, 1H), 8.01 (s, 1H), 8.07 (s, 1H), 8.39 (s, 1H). MS(ES+): m/z=411.08 (42) [MH+]. HPLC: tR=2.10 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]#[N:12])[CH:5]=1.CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21])=[C:6]([C:11]#[N:12])[CH:5]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3-cyano-4-hydroxybenzoic acid methyl ester from example 51, step 1 (2 g, 11.3 mmol) was dissolved in CH2Cl2 (57 ml) and cooled to 0° C. in an ice bath. The mixture was treated with Et3N (3 ml, 22.6 mol) followed by the addition of Tf2O (1.9 ml, 11.3 mmol). The reaction mixture was warmed to room temp. and stirred for 4 hours. Saturated NaHCO3 (10 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The organic layers were combined and dried (MgSO4), filtered, and concentrated. The residue was then purified by flash chromatography (15% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: Cl[CH2:2][C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][C@H:3]2[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]2)=[CH:13][C:12]=1[C:18]([F:19])([F:20])[F:21]
Reactant: Oc1ccc(Br)c(C(F)(F)F)c1
Reactant: CC1(C)OC[C@H](CCl)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@H](COc2ccc(Br)c(C(F)(F)F)c2)O1
Temperature: 60 °C
Reaction time: 6 h
Yield: 56.3 %

Procedure:
(S)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (63; 3.3 g, 20.5 mmol) was added to a mixture containing 4-bromo-3-(trifluoromethyl)phenol (126; 5 g, 20 mmol) and K2CO3 (8.30 g, 60 mmol) in 20 mL of DMF. The resulting reaction mixture was stirred at 60° C. for 6 h. Upon cooling to room temperature, the mixture was poured into water and extracted by EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:EtOAc=50:1) to afford (S)-4-((4-bromo-3-(trifluoromethyl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxolane (4 g, 56%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[C:20]([C:38]([NH2:40])=[O:39])=[N:21][CH:22]=[C:23]([N:25]5[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](N(CC)C)=[O:33])[CH2:26]5)[N:24]=4)=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:51][C:52]1[CH:61]=[CH:60][CH:59]=[CH:58][C:53]=1C(OC)=O>CN(C=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[C:20]([C:38]([NH2:40])=[O:39])=[N:21][CH:22]=[C:23]([N:25]5[CH2:30][CH2:29][CH2:28][C@@H:27]([N:31]6[CH2:51][C:52]7[C:53](=[CH:58][CH:59]=[CH:60][CH:61]=7)[C:32]6=[O:33])[CH2:26]5)[N:24]=4)=[CH:14][CH:13]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(C)C(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3ccc(C4CCN(C5CCCC5)CC4)cc3)n2)C1
Reactant: COC(=O)c1ccccc1CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ncc(N2CCC[C@@H](N3Cc4ccccc4C3=O)C2)nc1Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
(R)-5-(3-Aminopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (436) (50 mg, 0.1 mmol) was dissolved in 4 mL DMF. To it were added DIEA (180 μL, 1.0 mmol) and then methyl 2-bromomethylbenzoate (46 mg, 0.2 mmol) at RT. The reaction temperature was raised to 60° C. and the mixture was stirred for overnight. It was cooled to RT, quenched with 0.5 mL TFA, and directly subjected to reverse phase preparative HPLC using 5 mM HCl (aq) and nest MeCN to isolate the title compound, (R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(1-oxoisoindolin-2-yl)piperidin-1-yl)pyrazine-2-carboxamide (450), as HCl salt (19 mg). LC-MS (ESI): m/z (M+1) 580.8. UV: λ=269, 275, 304, 335, 372 nm. Proton NMR (CD3OD): δ 7.84 (1H, d, J=7.5 Hz), 7.69 (1H, s), 7.66-7.58 (2H, m), 7.56-7.52 (3H, m), 7.12 (2H, d, J=8.5 Hz), 4.67-4.57 (3H, m), 4.40-4.30 (2H, m), 3.64 (2H, m), 3.55 (1H, m), 3.27-3.06 (4H, m), 2.76 (1H, m), 2.24-1.72 (18H, m) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@@H:15]([CH2:17][O:18]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@H:14]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][O:45][CH2:46][C@@H:47]([CH3:51])[CH2:48][O:49][CH3:50])=[CH:40][CH:39]=2)[C@@H:13]([O:52][CH2:53][C:54]2[CH:55]=[CH:56][C:57]3[O:62][CH2:61][C:60](=[O:63])[N:59]([CH2:64][CH2:65][CH2:66][O:67][CH3:68])[C:58]=3[CH:69]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C@H:13]([O:52][CH2:53][C:54]2[CH:55]=[CH:56][C:57]3[O:62][CH2:61][C:60](=[O:63])[N:59]([CH2:64][CH2:65][CH2:66][O:67][CH3:68])[C:58]=3[CH:69]=2)[C@@H:14]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][O:45][CH2:46][C@@H:47]([CH3:51])[CH2:48][O:49][CH3:50])=[CH:40][CH:39]=2)[C@H:15]([CH2:17][OH:18])[CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1C(=O)COc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COCCCN1C(=O)COc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CO)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reaction time: 15 h

Procedure:
A solution of 8.526 mmol of (3R,4R,5S)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl) -phenyl]-3-[4-(3-methoxy-propyl)-3-oxo-3,4-dihydro-2H-benzo [1,4]oxazin-6-ylmethoxy]-5-trityloxymethyl-piperidine-1-carboxylic acid benzyl ester in 20 ml of tetrahydrofuran and 80 ml of methanol is treated with 12.789 mmol of toluene-4-sulfonic acid.monohydrate. After stirring for 15 hours, the reaction mixture is basified with saturated aqueous sodium bicarbonate solution and concentrated under reduced pressure to remove most of the methanol and tetrahydrofuran. The residue is extracted with dichloromethane (3×)—the combined organic layers are washed successively with water and brine, dried with sodium sulfate and evaporated. The title compound is obtained as a yellow oil from the residue by flash chromatography (SiO2 60F). Rt=4.86 (gradient I).
Reaction SMILES: [Si:1]([OH:5])([OH:4])([OH:3])[OH:2].[OH-].[CH3:7][N+:8]([CH3:11])([CH3:10])[CH3:9]>>[Si:1]([O-:5])([O-:4])([O-:3])[O-:2].[CH3:7][N+:8]([CH3:11])([CH3:10])[CH3:9].[CH3:7][N+:8]([CH3:11])([CH3:10])[CH3:9].[CH3:7][N+:8]([CH3:11])([CH3:10])[CH3:9].[CH3:7][N+:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: O[Si](O)(O)O
Agent: C[N+](C)(C)C
Agent: [OH-]
Product: [O-][Si]([O-])([O-])[O-]
Temperature: 50 °C
Reaction time: 8 h

Procedure:
About 1250 ml of 10 percent aqueous tetramethylammonium hydroxide solution were added to 82.2 g of precipitated silicic acid. After the mixture had been stirred at 25° C. for 16 hours and at 50° C. for 8 hours, a clear solution was obtained. The solution was concentrated to two-thirds of its original volume and the tetramethylammonium silicate contained therein was crystallized at 4° C. About 359.5 g of tetramethylammonium silicate which still contained water were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[OH:10].C(OC([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:25]([O:30][CH2:31][CH2:32]O)=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:20][CH2:19]1)=O)(C)(C)C>>[N:21]1([C:24]2[C:25]([O:30][CH2:31][CH2:32][O:10][C:3]3[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]1
Reactant: COc1cccc(F)c1O
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Product: COc1cccc(F)c1OCCOc1nccnc1N1CCNCC1

Procedure:
The title compound was prepared starting from 2-fluoro-6-methoxyphenol (178 mg, 1.25 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.17 mmol; prepared in Example 52, Step 2) to give 230 mg (66%) of a yellow oil. HRMS m/z calcd for C17H21FN4O3(M)+348.1598, found 348.1602.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([O:17][CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:9]=3[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]([N:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([O:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH:15]=[CH:16][C:9]=3[CH2:8][CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCN(C(=O)C2CC2)CC3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CC1)N1CCc2ccc(OC3CCNCC3)cc2CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
70 mg tert-butyl 4-(3-cyclopropanecarbonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylate are placed in 1.4 ml dichloromethane and combined with 224 l trifluoroacetic acid. The reaction mixture is stirred for 3 hours at ambient temperature, then evaporated to dryness. The residue is combined with toluene and evaporated to dryness. 77 mg (V-18) are obtained as an oil. Analytical HPLC-MS (method B): RT=1.18 min.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: Brc1cn2cncc2s1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (28 mg, 0.11 mmol) in diphenyl ether (1 ml) was stirred at 220° C. for 1.5 hr. The reaction solution was allowed to cool to room temperature, was diluted with hexane, and was extracted with 2 M hydrochloric acid (3 ml×3). The aqueous layer was neutralized with a 2 M aqueous solution of sodium hydroxide and was extracted with ethyl acetate (5 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:methanol=60:1) to give 2-bromoimidazo[5,1-b]thiazole (12 mg, 54%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7](Cl)=[N:6][CH:5]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[OH-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([NH:29][CH:26]2[CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27]2)=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1C(F)(F)F
Yield: 49 %

Procedure:
A solution of 6-chloro-4-trifluoromethyl-nicotinic acid methyl ester (2.00 g, 8.35 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.01 g, 10.02 mmol, 1.2 equiv; commercially available) in anhydrous DMF (10 mL) was heated by microwave irradiation to 110° C. for 4 h. A solution of 1 M NaOH (100 mL) was added and the reaction mixture extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (5:1→3:1) to yield 1.65 g (49%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.36-1.41 (m, 2H), 1.40 (s, 9H), 1.95-1.97 (m, 2H), 2.85-2.93 (m, 2H), 3.81 (s, 3H), 3.92-3.98 (m, 1H), 3.98-4.05 (m, 2H), 5.12 (d, J=8.1 Hz, 1H), 6.59 (s, 1H), 8.68 (s, 1H). 19F NMR (282 MHz, CDCl3): δ-62.38. MS (ISP): 404.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].CCO[C:22]([CH3:24])=O>C1(C)C=CC=CC=1.O>[CH:9]1[C:10]2[C:5](=[C:22]([CH2:24][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:9]([CH3:15])=[N:8][C:7]=3[OH:16])[CH:3]=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: CCOC(C)=O
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(C)nc(O)c(Cc3cccc4cnccc34)c2cc1OC
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (158 mg, 721 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.86 mL, 1.72 mmol) at RT followed by MDE 32016 (185 mg, 864 μmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) gave 48 mg of 4-(isoquinolin-5-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol. The free base was dissolved in MeOH (3 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (4.5 mL). The reaction mixture solution was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-(isoquinolin-5-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol dihydrochloride 22 as a brown solid (58 mg, 19% yield).
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].Cl.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([NH:19][CH3:20])[CH:15]=[CH:14][C:13]=2[CH:21]=1.C(O)(=O)C>C(#N)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([N:19]([CH3:3])[CH3:20])[CH:15]=[CH:14][C:13]=2[CH:21]=1
Reactant: [BH3-]C#N
Reactant: CNC1C=Cc2cc(Cl)ccc2CC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(C)C1C=Cc2cc(Cl)ccc2CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
7.7 ml of an aqueous solution of 40% formaldehyde and then 4.5 g of sodium cyanoborohydride were added to a mixture of 4.7 g of 2-chloro-7-methylamino-6,7-dihydro [5H] benzocycloheptene hydrochloride in 47 ml of acetonitrile and the mixture was stirred for 15 minutes at room temperature. Acetic acid was added to the reaction mixture until the pH was 7 and the mixture was stirred at room temperature for 45 minutes. The mixture was evaporated to dryness under reduced pressure to obtain 2.6 g of 2-chloro-7-dimethylamino-6,7-dihydro [5H] benzocycloheptene in the form of an oil. Addition of a solution of fumaric acid in methanol yielded 3.3 g of the fumarate of the said product melting at 160° C.
Reaction SMILES: [N+](=[C:3]1[CH2:11][CH2:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[C:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[CH:6][C:5]=2[C:4]1=[O:31])=[N-].[C:32]([OH:36])([CH3:35])([CH3:34])[CH3:33].C(OCC)C>N1C(C)=CC(C)=CC=1C>[C:32]([O:36][C:4]([C:3]1[C:5]2[C:9]([N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:7]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH:6]=2)=[CH:10][CH:11]=1)=[O:31])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)O
Reactant: [N-]=[N+]=C1CCc2c(cc(C(=O)OCc3ccccc3)n2Cc2ccc(Cl)c(Cl)c2)C1=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1=CC=C2C1=CC(C(=O)OCc1ccccc1)N2Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 97 %

Procedure:
Benzyl 5-diazo-1-(3,4-dichlorobenzyl)-4-oxo-4,5,6,7-tetrahydroindole-2-carboxylate (0.3 g) and t-butanol (1 mL) were heated at 180° C. in collidine (10 mL) for 30 minutes, cooled to room temperature, and poured into diethyl ether. The organic layer was washed with 2M HCl (100 mL), dried (MgSO4), and concentrated in vacuo to afford the title compound as an orange oil (0.32 g, 97%), NMR d(CDCl3) 1.45 (9H, s), 2.45-2.80 (4H, m), 3.78 (1H, dd), 5.20 (2H, d), 5.40 (2H, d), 6.80 (1H, dd), 6.95 (1H, s), 7.10 (1H, s), 7.30 (6H, m); M/z (+) 502, 500 (M+).