Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:6].C(Cl)(Cl)Cl.Cl[C:18]([O:20][C:21]1([CH3:25])[CH2:24][CH2:23][CH2:22]1)=[O:19]>C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH:6][C:18]([O:20][C:21]1([CH3:25])[CH2:24][CH2:23][CH2:22]1)=[O:19]
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: CC1(OC(=O)Cl)CCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](NC(=O)OC1(C)CCC1)C(=O)OC
Reaction time: 8 h

Procedure:
A suspension of 0.05 moles of aspartic acid dimethyl ester hydrochloride in 50 ml. of chloroform is cooled to 0°C. and the pH adjusted to 8 by addition of triethylamine. 1-Methylcyclobutyl chloroformate 0.10 moles prepared according to the procedure of Example 1 is added portion-wise at 0°C. and the pH of the reaction is maintained at 8 by addition of triethylamine. Upon completion of the addition, the reaction is stirred overnight at 20°-25°C. The reaction solution is washed successively with 10 ml. portions of a saturated sodium bicarbonate solution, 50% saturated solution of sodium chloride, 0.2 N sulfuric acid saturated with sodium sulfate, 50% saturated solution of sodium chloride (twice), and the chloroform solution is dried over sodium acetate. Removal of the chloroform affords N-(1-methylcyclobutyloxycarbonyl)-aspartic acid dimethyl ester. Saponification is accomplished by dissolving the ester in 50 ml. of methanol, water 50 ml. is added, and the pH is adjusted to 12 by addition of 2 N sodium hydroxide. After stirring overnight at 25°C., the pH is adjusted to 7 with 2N sulfuric acid. The methanol is removed in vacuo and saturated sodium bicarbonate solution is added to the water solution. The aqueous bicarbonate solution is washed two times with ether and then the pH is adjusted to 3 by addition of concentrated hydrochloric acid. The acidified solution is extracted three times with ethyl acetate and the organic extracts combined, washed twice with sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo to afford N-(1-methylcyclobutyloxycarbonyl) aspartic acid.
Reaction SMILES: [OH-:1].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[C:17]([O:32][CH3:33])=[C:18]([C:24]4[CH:29]=[CH:28][N:27]=C(C#N)[CH:25]=4)[C:19]([CH3:23])=[C:20]([Cl:22])[CH:21]=3)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12.[ClH:34].[CH2:35]([OH:37])[CH3:36]>>[ClH:22].[ClH:34].[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[C:17]([O:32][CH3:33])=[C:18]([C:24]4[CH:29]=[CH:28][N:27]=[C:36]([C:35]([OH:1])=[O:37])[CH:25]=4)[C:19]([CH3:23])=[C:20]([Cl:22])[CH:21]=3)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12
Reactant: [OH-]
Reactant: CCO
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Agent: Cl
Agent: [Na+]
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)O)c1
Temperature: 95 °C

Procedure:
1.0 M Sodium hydroxide (2.9 mL, 2.9 mmol) was added to a mixture of 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile (0.250 g, 0.576 mmol) in ethanol (4.0 mL) and the resulting mixture was heated at 95° C. for 6 h. At this time, conc. HCl was added to adjust the pH to ˜3. The solvent was removed and the residue was used in the next step without further purification. LCMS calculated for C22H22ClN6O3 (M+H)+: m/z=453.1; Found: 453.2.
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+](C1C=CC([O:38][C:39]([O:41][CH2:42][C:43]2[S:47][CH:46]=[N:45][CH:44]=2)=O)=CC=1)([O-])=O>CN(C=O)C>[C:24]([O:23][C:21]([NH:20][C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:11][C@H:10]([OH:28])[C@@H:2]([NH:1][C:39]([O:41][CH2:42][C:43]1[S:47][CH:46]=[N:45][CH:44]=1)=[O:38])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reaction time: 4 h
Yield: 79.6 %

Procedure:
The product of Example 68D (6.0 g, 15.6 mmoles) was dissolved in 60 mL of DMF under nitrogen atmosphere. To this stirred solution at room temperature was added 5-(p-nitrophenyloxycarbonyloxymethyl)thiazole (4.67 g, 15.6 mmole) and the resulting solution was stirred for 4 h. The solvent was removed under reduced pressure by rotary evaporation and the residue dissolved in 150 mL EtOAc. This solution was washed with 5×75 mL 1N NaOH solution, 100 mL brine, dried over Na2SO4. The solvent was removed to afford 8.02 g of a slightly yellowish oil. This material was crystallized from 30 mL EtOAc and 40 mL hexane to afford 6.53 g (80%) of the desired product as a white solid. mp 118°-120° C. H 1NMR (CDCl3) δ8.79 (s, 1H), 7.83 (s, 1H), 7.30-7.15 (m, 8H), 7.08 (m, 2H), 5.23 (s, 2H), 5.14 (d, 1H, J=9 Hz), 4.52 (m, 1H), 3.92-3.72 (m, 3H), 3.65 (m, 1H), 2.85 (d-apparent, 2H, J=7.5 Hz), 2.72 (d-apparent, 2H, J=7 Hz), 1.61 (m, 2H), 1.38 (s, 9H). CIMS m/z (526) (M+H)+, 543 (M+18)+.
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])[CH3:3].C([O-])=O.[NH4+]>CC(O)=O.O.[Pd]>[CH:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])[CH3:3]
Reactant: COc1ccc(O)c(C(C)(C)O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(O)c(C(C)C)c1
Temperature: 100 °C
Yield: 96.8 %

Procedure:
To a solution of 2-(1-hydroxy-1-methyl-ethyl)-4-methoxy-phenol (50.57 g, 278 mmol) in 550 ml AcOH was added 10% Pd/C (as a slurry in 20 ml H2O). Ammonium formate (87.52 g, 1388 mmol) was added in portions. The mixture was warmed to 100° C. for 1 hour, cooled and filtered through a pad of celite. The celite pad was washed with ethyl acetate. The mother liquor was mixed with H2O and extracted with ethyl acetate. The combined organics were washed with H2O, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 2-isopropyl-4-methoxy-phenol (44.74 g, 97%) as a pale yellow oil.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl.B([O-])([O-])[O-]>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[B:20]([OH:25])[OH:21])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Agent: [O-]B([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N-tert-Butylbenzenesulfonamide (2.00 g, 12.7 mmol) was dissolved in anhydrous THF (10 mL). After being cooled to −78° C., n-BuLi (2.5 M, 6.0 mL) was injected slowly to the above solution. After being stirred at this temperature for another 1 h, triisopropyl borate (11.9 g, 63.5 mmol) was added at −78° C. The resulting mixture was then allowed to warm to room temperature slowly for 8 h. 1N HCl (10 mL) was added to hydrolyze the borate. The organic layer was dried over Na2SO4. After removal of the solvent, the residue was used for the next step without further purification.
Reaction SMILES: [ClH:1].CO.[CH2:4]([N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[N:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C3CCCCO3)=[O:26])=[CH:19][CH:18]=2)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[ClH:1].[ClH:1].[CH2:4]([N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[N:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])=[CH:19][CH:18]=2)[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(/C=C/c1ccc(NC2CCN(Cc3ccccc3)C2)nc1)NOC1CCCCO1
Agent: Cl
Solvent: CO
Product: O=C(/C=C/c1ccc(NC2CCN(Cc3ccccc3)C2)nc1)NO
Reaction time: 2 h

Procedure:
A solution of 10% HCl-MeOH solution (0.75 ml) was added to a mixture of (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (170 mg) in MeOH 3 ml) and stirred at 15-25% for 2 hours. The reaction mixture was evaporated in vacuo and the residue was triturated with small amount MeOH and acetone and the precipitate was collected by filtration to give (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-N-hydroxyacrylamide dihydrochloride (107 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH:12]=[CH2:13])[CH:3]=1.Br[CH2:15][C:16]1[C:17](Cl)=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[C:9]([N:8]1[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH:12]=[CH:13][C:17]2[N:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=2[CH2:15]1)(=[O:11])[CH3:10]
Reactant: Clc1ccc(CBr)c(Cl)n1
Reactant: C=Cc1cc(Cl)ccc1NC(C)=O
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2ccc(Cl)nc2C=Cc2cc(Cl)ccc21

Procedure:
The title compound was prepared from 9B and 13B by a route analogous to that used for the preparation of 1D. HPLC Rt=2.842 min; LCMS Found: (M+H)+=319.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([N+:12]([O-:14])=[O:13])=[CH:5][C:4]=1[O:15]C.Br>C(O)(=O)C>[OH:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([N+:12]([O-:14])=[O:13])=[CH:5][C:4]=1[OH:15]
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OC
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(O)c(O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 9869.8 %

Procedure:
8B, FIG. 8. In a dry 500 mL round bottom flask, 1,2-dimethoxy-4,5-dinitrobenzene (3.2 g, 0.12 mmol) 8A was stirred vigorously in 40 mL of glacial acetic acid at 30° C. Once a homogeneous solution 200 mL of 48% HBr was added to the flask and the reaction was slowly heated to reflux. The reaction was complete as indicated by TLC after 4 hours. The work up involved pouring the cooled solution into 800 mL of ice water and then extracting the aqueous phase with CHCl3 (3×150 mL) in order to remove any organic impurities. The dinitro catechol was extracted out of the aqueous layer with ethyl acetate (3×150 mL). The combined ethyl acetate extracts were washed with water and brine (3×100 mL), then dried over MgSO4 and concentrated to an orange residue. Approximately 100 mL of dichloromethane was added to the residue and then placed in the freezer for several hours. The light yellow needles that formed were filtered and washed with dichloromethane to yield 2.37 g of product (84%). 1H NMR (d6 -acetone): δ3.45 (OH), 7.42 (Ar--H); 13C NMR (d6 -acetone): δ112.44, 137.00, 149.97, EI MS M+ 200.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=CC=1.[Mg].OS(O)(=O)=O.[CH3:22]COCC>>[CH3:13][CH:14]([CH2:15][CH3:10])[CH2:22][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCOCC
Reactant: Brc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Product: CCC(C)Cc1ccccc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A phenylmagnesium bromide solution repapred from 40 g of bromobenzene, 6.2 g of magnesium and 300 ml of ether was cooled at 5° C., and a mixture liquid of 125 g of 2'-methylbutyl 4-methylbenzenesulfonate (II) prepared above and 130 ml of ether was added dropwise. After 2 hours of stirring, the mixture was elevated in temperature to effect 2 hours of refluxing, followed by standing overnight. To the reaction liquid, 10 % H2SO4 was added with pH 2. The organic layer was washed successively with an aqueous sodium bicarbonate solution and water, followed by drying with anhydrous magnesium sulfate, and distilling-off of the solvent. The product was distilled under reduced pressure to obtain 48 g of 4-(2'-methylbutyl)benzene (III) which showed the following IR data:
Reaction SMILES: [CH3:1][CH:2]([OH:22])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>ClCCl>[O:31]1[C@H:12]2[CH2:11][C@H:10]3[C@:15]([CH3:16])([CH2:14][C@@H:13]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@:20]([CH3:21])([CH2:19][CH2:18]1)[C@@H:3]([CH:2]([OH:22])[CH3:1])[CH2:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Product: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of 5-α-pregn-2-en-20-ol (12) (660 mg, 2.18 mmol) in anhydrous dichloromethane (20 mL) at 0° C. under an atmosphere of argon was added in six portions m-CPBA (733 mg, 3.27 mmol). The solution was stirred over a period of 1 h at 0° C. and then allowed to return to room temperature overnight. The resulting solution was diluted with dichloromethane (30 mL) and successively washed with a Na2S2O3 aqueous solution (10%) and a Na2CO3 aqueous solution (10%), dried with MgSO4, filtered and evaporated to dryness. Purification by FCC (EtOAc/hexanes, 5:95) yielded 511 mg (73%) of title compound 13 as a white solid. 1H NMR (acetone-d6) δ: 0.74 (s, 18-CH3), 0.79 (s, 19-CH3), 1.07 (d, J=6.1 Hz, 21-CH3), 0.60-2.30 (residual CH and CH2), 3.06 (m, 2×CH of epoxide), 3.62 (m, 20-CH); 13C NMR (CDCl3) δ: 12.4, 12.9, 20.7, 23.6, 24.4, 25.6, 28.4, 29.0, 31.7, 33.6, 35.4, 36.2, 38.2, 39.9, 42.3, 51.1, 52.4, 53.7, 55.7, 58.5, 70.6, LRMS for C21H34O2 [M+H]+: 319.1 m/z.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.Cl.[NH2:17][CH2:18][C:19](O)=[O:20].[NH2:22][C:23]1[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:24]=1[C:25](=[N:33][CH2:34][CH2:35][OH:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32]>CN(C)C=O.O.O1CCCC1>[NH2:17][CH2:18][C:19]([NH:22][C:23]1[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:24]=1[C:25](=[N:33][CH2:34][CH2:35][OH:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])=[O:20]
Reactant: Nc1ccc(Br)cc1C(=NCCO)c1ccccc1F
Reactant: NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NCC(=O)Nc1ccc(Br)cc1C(=NCCO)c1ccccc1F
Yield: 57.9 %

Procedure:
To a solution of 4.5g of N,N'-dicyclohexylcarbodiimide in 100ml of dimethylformamide is added a solution of 2.2g of glycine hydrochloride in 2.2ml of water in a period of about 30 seconds under stirring and ice-cooling. Immediately a solution of 3.4g of 2-{[2-amino-5-bromo-α-(2-fluorophenyl)benzylidene]amino}ethanol in 10ml of tetrahydrofuran is added dropwise to the reaction mixture, and the mixture is stirred for further 3 hours at room temperature. After completion of the reaction, one liter of water is added to the reaction mixture which is extracted once with 100ml and four times with 50ml of benzene. The organic layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off to give an oily substance, which is purified by chromatography of alumina column and then recrystallized from benzene-n-hexane (3:2 in volume) mixture yielding 2.3g of the desired product melting at 167°-168° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1C1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
100 mg (0.34 mmol) of the compound from Example 34A, 83 mg (0.34 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 57 mg (0.68 mmol) of sodium bicarbonate are initially charged in 5 ml of dry DMF. The reaction mixture is stirred at RT for 16 h. After removal of the solvent on a rotary evaporator the residue is triturated with about 2 ml of acetonitrile. This results in the formation of a precipitate which is filtered off with suction and dried.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:14][C@H:12]([C:10]2[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]3[CH:21]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=3[N:11]=2)[CH3:13])[N:26]=[CH:25][N:24]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 64.3 %

Procedure:
(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (328 mg, 1.00 mmol) was placed in a sealed tube with 4-amino-6-chloropyrimidine-5-carbonitrile (154.5 mg, 1.00 mol), DIPEA (0.7 mL, 4.00 mol) and IPA (1 mL). The tube was flushed with argon, sealed and the contents heated at 90° C. for 16 h. The cooled mixture was evaporated then diluted with EtOAc and water. The organic layer was washed with brine, dried (MgSO4) and evaporated. The crude residue was purified by chromatography on silica (Si—PCC, 1-80% EtOAc in DCM). The product containing fractions were pooled and evaporated almost to dryness. The residue was triturated in ether to afford 246 as a cream solid (240 mg, 65%). 1H NMR (CDCl3, 400 MHz): δ 8.01 (1H, s), 7.69 (1H, dd, J=8.8, 4.7 Hz), 7.59-7.49 (3H, m), 7.43-7.36 (2H, m), 7.02 (1H, td, J=9.2, 1.1 Hz), 6.77 (1H, dd, J=8.6, 2.4 Hz), 6.18 (1H, d, J=7.5 Hz), 5.52 (1H, quin, J=7.2 Hz), 5.30 (2H, br s), 1.54 (3H, d, J=6.9 Hz). LCMS (Method K): RT 3.80 min [M+H]+ 374
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([O:26][CH3:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].[NH3:28]>>[NH2:28][C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([O:26][CH3:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:15])=[CH:9][CH:8]=1)=[O:2]
Reactant: N
Reactant: COC(=O)COc1ccc(CC(C)NCC(OC)c2cccc(Cl)c2)cc1
Product: COC(CNC(C)Cc1ccc(OCC(N)=O)cc1)c1cccc(Cl)c1

Procedure:
The title compound was prepared, as an oil, from N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-methoxy-2-(3-chlorophenyl)ethanamine and 0.88 ammonia, by an analogous procedure to that described in Example 4. The product was used in Example 24 without further purification.
Reaction SMILES: C[Mg]I.[CH2:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([CH3:15])=[CH:11]2)[CH3:5].[Cl:16][C:17]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].[NH4+].[Cl-]>CCOCC>[CH2:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([CH3:15])=[C:11]2[C:19]([C:18]1[CH:22]=[CH:23][CH:24]=[C:25]([Cl:26])[C:17]=1[Cl:16])=[O:20])[CH3:5]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: CCc1cccc2cc(C)[nH]c12
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCc1cccc2c(C(=O)c3cccc(Cl)c3Cl)c(C)[nH]c12
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
14.2 ml of 3M of MeMgI in Et2O are placed under argon and 6.78 g of 7-ethyl-2-methyl-1H-indole in 40 ml of Et2O are added dropwise. After 30 minutes, 17.84 g of 2,3-dichlorobenzoyl chloride in 60 ml of Et2O are added dropwise and the reaction medium is left stirring for 2 hours. The reaction medium is run quickly onto a saturated NH4Cl solution. The extraction is carried out with Et2O (twice) and then the organic phase is washed with a 10% NaOH solution, water and then a saturated NaCl solution. 5.5 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[N:11]12[CH2:18][CH2:17][C:14]([C:19]([O:21]CC)=O)([CH2:15][CH2:16]1)[CH2:13][CH2:12]2>C1COCC1>[N:11]12[CH2:12][CH2:13][C:14]([C:19]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=3)([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[OH:21])([CH2:15][CH2:16]1)[CH2:17][CH2:18]2
Reactant: COc1cccc([Mg]Br)c1
Reactant: CCOC(=O)C12CCN(CC1)CC2
Solvent: C1CCOC1
Product: COc1cccc(C(O)(c2cccc(OC)c2)C23CCN(CC2)CC3)c1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A solution of 3-(methyloxy)phenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1608 g, 0.877 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.2881 g, 92.9%). EI-MS m/z 354 (M+H+) Rt (1.46 min).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[OH:14].[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:21]([O:14][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH:1]=1)[C:18]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccc3c(c2)[nH]c2ccccc23)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
A mixture of 9H-carbazol-2-ol (8.57 g, 46.78 mmol, 1.0 eq), BnBr (5.56 mL, 46.78 mmol, 1.0 eq) and K2CO3 (6.47 g, 46.78 mmol, 2.0 eq) in DMF (70 mL) was stirred at room temperature for two days. Then water (70 mL) was added, the mixture was stirred at room temperature for another 5 minutes. The precipitate was filtered and washed with water three times first, then washed with ethyl acetate once. The collected solid was dried in air under reduced pressure to afford the desired product as a grey solid (10.68 g in 83% yield). 1H NMR (DMSO-d6, 400 MHz): δ 5.21 (s, 2H), 6.86 (dd, J=7.2, 2.0 Hz, 1H), 7.06 (d, J=1.6 Hz, 1H), 7.10-7.13 (m, 1H), 7.28-7.31 (m, 1H), 7.35 (t, J=6.0 Hz, 1H), 7.40-7.44 (m, 3H), 7.52 (d, J=5.6 Hz, 2H), 7.97-8.00 (m, 2H), 11.12 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][C:14]2[C:15]([C:21]#[N:22])=[N:16][C:17](Cl)=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-:25].[K+].C(OCC)(=O)C.O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][C:14]2[C:15]([C:21]#[N:22])=[N:16][C:17]([F:25])=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1nc(Cl)cnc1Oc1ccc(OCc2ccccc2)cc1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1nc(F)cnc1Oc1ccc(OCc2ccccc2)cc1
Temperature: 105 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
In 70 ml of dimethyl sulfoxide was dissolved 3.50 g of 3-[4-(benzyloxy)phenoxy]-6-chloro-2-pyrazinecarbonitrile. After adding 3.01 g of potassium fluoride, the mixture was stirred at 100-110° C. for 3 hours. The reaction mixture was returned to room temperature and added to a mixture of 70 mL of ethyl acetate and 350 mL of water, and the organic layer was separated. The organic layer thus obtained was washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: toluene:ethyl acetate=5:1] to obtain 1.88 g of 3-[4-(benzyloxy)phenoxy]-6-fluoro-2-pyrazinecarbonitrile as a white-colored solid product.