Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:3]=1[NH2:16].[C:17](C1NC=CN=1)(C1NC=CN=1)=[O:18]>O1CCCC1>[F:1][C:2]1[C:3]2[NH:16][C:17](=[O:18])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1c(F)cccc1Nc1ccccc1F
Solvent: C1CCOC1
Product: O=c1[nH]c2c(F)cccc2n1-c1ccccc1F

Procedure:
3-fluoro-N1-(2-fluorophenyl)benzene-1,2-diamine (0.44 g, 2 mmol) and carbonyl diimidazole (0.29 g, 1.8 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature overnight. Upon disappearance of the starting material, the reaction was partitioned between 1 N hydrochloric acid (100 mL) and ethyl acetate (100 mL). The organics were dried over sodium sulfate and concentrated to give 4-fluoro-1-(2-fluorophenyl)-1,3-dihydro-2H-benzimidazol-2-one as a white solid in near quantitative yield. MS (ES) m/z 247.0
Reaction SMILES: [C:1]1(=[O:7])[CH:5]=[CH:4][C:3](=[O:6])[CH2:2]1.[CH3:8][C:9]1[O:10][CH:11]=[CH:12][CH:13]=1>CO>[CH3:8][C:9]12[O:10][CH:11]([CH:12]=[CH:13]1)[CH:4]1[CH:5]2[C:1](=[O:7])[CH2:2][C:3]1=[O:6]
Reactant: O=C1C=CC(=O)C1
Reactant: Cc1ccco1
Solvent: CO
Product: CC12C=CC(O1)C1C(=O)CC(=O)C12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-cyclopentene-1,3-dione (10 g, 104 mmol) and 2-methylfuran (15 ml) are stirred at room temperature for 3 days. Methanol (50 ml) is then added and the solid is collected and dried on a Buchner funnel to give 1-methyl-10-oxa-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione (14.3 g)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[C:16]2[CH:17]=[CH:18][S:19][C:15]=2[CH:14]=[CH:13][C:12]=1[C:20](OC)=[O:21]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:20]([C:12]2[CH:13]=[CH:14][C:15]3[S:19][CH:18]=[CH:17][C:16]=3[C:11]=2[OH:10])=[O:21])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc2sccc2c1O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1ccc2sccc2c1O
Temperature: 120 °C
Yield: 68 %

Procedure:
A mixture of 4-chlorobenzylamine (1 mL) and methyl 4-hydroxy-1-benzothiophene-5-carboxylate (Preparation 13, 0.50 g) is heated to 120° C. under an atmosphere of nitrogen for 4 hours. After cooling, the residue is diluted with ethyl acetate and methanol (1:1) and absorbed onto silica gel. Chromatography on a Biotage column eluting with 500 mL of toluene gave 520 mg (68%) of the title compound as a white solid. Physical characteristics: Mp 168-169° C.; MS (ESI−) m/z 316.1 (M−H)−. Anal. Found: C, 60.82; H, 3.87; N, 4.33.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH:3]=[CH:2]1.[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1>CN(C=O)C>[Si:15]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH3:17]
Reactant: Oc1cccc2[nH]ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 1H-indole-4-ol (2.4 g) in DMF (50 mL) was added tert-butyldimethylchlorosilane (2.7 g) and 1H-imidazole (1.5 g) at ambient temperature. The reaction mixture was stirred for 17 hours at ambient temperature. The resulting mixture was evaporated in vacuo and diluted with EtOAc. The organic layer was washed with water and brine and then dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silicagel column chromatography (n-hexane:EtOAc=80:20-60:40) to give 4-{[tert-butyl(dimethyl)silyl]oxy}-1H-indole.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C(N(CC)CC)C>C(Cl)Cl>[N:17]1([CH2:16][CH2:15][CH2:14][NH:13][C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: NCCCn1ccnc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCn1ccnc1)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A solution of 4-nitrobenzoyl chloride (18.5 g, 0.1 mol) in DCM (200 ml) was added dropwise to a stirred solution of 1-(3-aminopropyl)imidazole (14.0 g, 0.112 mol) and triethylamine (15 ml, 0.107 mol) in DCM (200 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour, and the solid which had separated out was collected by filtration and washed with water (100 ml) and acetone (100 ml) to give the product (21.6 g, 79%). NMR: 1.9-2.0 (m, 2H), 3.2-3.3 (m, 2H), 4.0 (t, 2H), 6.85 (s, 1H), 7.2 (s, 1H), 7.65 (s, 1H), 8.05 (d, 2H), 8.3 (d, 2H), 8.8 (br s, 1H).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C[Si](C)(C)Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N>N1C=CC=CC=1.O>[C:23]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1)c1ccccc1
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
A suspension of cytidine (9.72 g, 40.0 mmol) in pyridine (200 ml) was added to trimethylchlorosilane (25.6 ml, 200 mmol). After 15 minutes of stirring, benzoyl chloride (23.2 ml, 200 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was then cooled on an ice bath, and water (40 ml) was added. Five minutes later, 28% aqueous ammonia (40 ml) was added, and the mixture was stirred at room temperature for 15 minutes. Then, the solvent was distilled off under reduced pressure, and acetone was added to precipitate a white solid. The precipitate was filtered off and recrystallized from water to give N4-benzoylcytidine (13.3 g, 96%). The N4-benzoylcytidine (13.0 g, 37.4 mmol), triphenylphosphine (28.0 g, 107 mmol) and lithium azide (13.0 g, 266 mmol) were suspended in dried DMA, and carbon tetrabromide (35.5 g, 107 mmol) was added to the suspension. After 3 hours of stirring at room temperature, ethyl acetate (1500 ml) was added, and the mixture was washed with water and a saturated aqueous solution of sodium chloride (1000 ml each). The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol to give 5′-azido-5′-deoxy-N-benzoylcytidine (12.4 g, yield 89%). A solution of 5′-azido-5′-deoxy-N4-benzoylcytidine (10.0 g, 26.9 mmol) in methanol-DMF (1:1 v/v, 100 ml) was vigorously stirred with 10% palladium-on-carbon (about 1.0 g) in a hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was evaporated under reduced pressure to give 5′-amino-5′-deoxy-N4-benzoylcyridine (9.04 g, yield 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:34]=[C:35]([CH2:39][C:40](O)=[O:41])[CH:36]=[CH:37][CH:38]=1.CCN(C(C)C)C(C)C>>[OH:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:43])([F:31])[F:44])[CH:34]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:29])[CH3:30]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)c2cnccc21

Procedure:
Prepared according to Method 1 (Example 19) using (5-aminopyridin-3-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Preparation 28), 3-trifluoromethylphenylacetic acid and DIPEA. The residue was purified using silica gel column chromatography eluting with 80% EtOAc in hexane followed by acid deprotection using 10% HCl in dioxane at room temperature for 18 hours. The reaction was concentrated in vacuo and purified using preparative HPLC to afford the title compound.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:7]1=[N:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[O:11][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:6]1=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Product: ClC1=Nc2ccccc2Oc2ccccc21
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of 10,11-dihydrodibenz[b,f][1,4]oxazepin-11-one (1.00 g, 4.74 mmol) and phosphorus oxychloride (40 mL) was stirred for 5 h at reflux. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved into AcOEt and washed with water and brine. The organic layer was dried (Na2SO4), filtered and concentrated to give an orange oil. The residue was purified by silica gel column chromatography with EtOAc (10%) in Hexanes to afford 1 (939 mg, 86%) as a yellow solid. LRMS (ESI): (calc) 229.0 (found) 230.1 (MH)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>C1(C)C=CC=CC=1>[CH2:15]([C:2]1[CH:11]=[C:10]([F:12])[C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1)[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1OCc2cc(Br)cc(F)c21
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1cc(F)c2c(c1)COC2=O

Procedure:
To a flask charged with 5-bromo-7-fluoro-2-benzofuran-1 (3H)-one (300 mg, 1.3 mmol) and a stir bar was added allyl tri-n-butyltin (0.6 mL, 2.0 mmol), palladium tetrakis triphenylphosphine (230 mg, 0.19 mmol), lithium chloride (170 mg, 3.9 mmol), and toluene (5 mL). The mixture was purged three times with nitrogen, and heated to reflux for 4 hours. LC showed formation of the desired product, which was purified by silica gel chromatography to deliver 5-allyl-7-fluoro-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 193 [M+1]+;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:9][NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:6][CH2:7][CH3:8])[CH3:2].[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:9][N:10]([C:20]1[C:21]([N+:25]([O-:27])=[O:26])=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=1)[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCCC(CNC1CCCC1)C(=O)OCC
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCCC(CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
A solution of 1.14 g (0.005 mole) of (rac)-2-cyclopentylaminomethyl-pentanoic acid ethyl ester in 25 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 25 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.4 g of (rac)-2-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-pentanoic acid ethyl ester (IV-16).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH2:11][CH:12]3[O:14][CH2:13]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.Cl.C([NH:23][CH2:24][CH2:25][C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])C1C=CC=CC=1.C(=O)([O-])O.[Na+].O>C(O)(C)C>[O:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][NH:23][CH2:24][CH2:25][C:26](=[O:27])[NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=C(CCNCc1ccccc1)NCc1ccccc1
Reactant: c1cc(OCC2CO2)c2ccoc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=C(CCNCC(O)COc1cccc2occc12)NCc1ccccc1

Procedure:
In a similar manner to that described above but using a mixture of 1-(benzo[b]furan-4-yloxy)-2,3-epoxypropane (1.9 g.), β-benzylamino-N-benzylpropionamide hydrochloride (3.05 g.), sodium hydrogen carbonate (0.84 g.), water (5 ml.) and isopropanol (40 ml.) there is obtained 1-(benzo[b]furan-4-yloxy)-3-β-(N-benzylcarbamoyl)ethylamino-2-propanol, m.p. 109°-110° C. The β-benzylamino-N-benzylpropionamide hydrochloride used as starting material may also be prepared in the manner described above, m.p. 237°-239° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Li+].[C:14](#[N:17])[CH:15]=[CH2:16]>C(O)(=O)C>[C:14]([CH2:15][CH2:16][O:1][CH2:2][CH2:3][N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#[N:17]
Reactant: C=CC#N
Reactant: CN(CCO)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(CCOCCC#N)c1ccccc1
Temperature: 50 °C

Procedure:
In a one-gallon autoclave was charged 1019 gm (6.75 moles) of hydroxyethylmethylaniline, 3 gm of anhydrous lithium hydroxide, and 532 gm (10 moles) of acrylonitrile. The autoclave was sealed and slowly heated to 50° C. until the initial exotherm was over. The reaction was then heated to 65°-70° C. for 6 hours. The reaction contents were cooled to room temperature and made slightly acidic with acetic acid. The reaction contents were then filtered. The crude filtered reaction product was stripped of all excess acrylonitrile under vacuum (15-30 mm Hg) at a temperature not exceeding 80° C. to give the orange liquid, 2-cyanoethoxyethylmethylaniline. Liquid chromatography showed the product to be about 97.4% purity. The IR, NMR, and GC mass spectra of the product were consistent with 2-cyanoethoxyethylmethylaniline.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[CH:7]=[C:6]([F:17])[C:3]=1[C:4]#[N:5].[O-:18][CH2:19][CH3:20].[Na+]>CCO>[CH2:19]([O:18][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[CH:7]=[C:6]([F:17])[C:3]=1[C:4]#[N:5])[CH3:20]
Reactant: CC[O-]
Reactant: N#Cc1c(F)cc(N2CCC(O)CC2)cc1F
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(N2CCC(O)CC2)cc(F)c1C#N
Temperature: 70 °C
Yield: 21.6 %

Procedure:
To a solution of 0.200 g (0.839 mmol) of the above benzonitrile in EtOH (2 mL), cooled to 0° C., was added 1.0 mL (3.1 mmol) of sodium ethoxide. The reaction was heated to 70° C. for 15 h then cooled to room temperature and an additional 1.0 mL (3.1 mmol) of sodium ethoxide was added. The mixture was heated to 70° C. for an additional 15 h. The reaction was cooled to room temperature and excess base was consumed by the addition of a saturated aqueous solution of NH4Cl. The mixture was diluted with H2O and washed with CH2Cl2. The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide after 0.048 g (21%) of 2-ethoxy-6-fluoro-4-(4-hydroxy-piperidin-1-yl)-benzonitrile as a white solid.
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[CH2:3][NH2:4].[CH3:7][C:8]([O:11][C:12](ON=C(C1C=CC=CC=1)C#N)=[O:13])([CH3:10])[CH3:9].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(Cl)(Cl)Cl>[NH2:6][C:2]([CH3:5])([CH3:1])[CH2:3][NH:4][C:12](=[O:13])[O:11][C:8]([CH3:10])([CH3:9])[CH3:7]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CC(C)(N)CN
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(N)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
2-Methylpropane-1,2-diamine (5.0 g) was dissolved in dichloromethane (200 ml) and stirred for 15 minutes at 0° C. A solution of BOC-ON (15 g) in dichloromethane (60 ml) was added dropwise thereto and then stirred for 2 hours at room temperature. The reaction mixture was diluted with chloroform with ice cooling and then acidified by 10% citric acid solution, and the organic phase was separated. The aqueous phase was alkalinized by 5 N sodium hydroxide solution, then extracted with ethyl acetate, and the extract was dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give t-butyl (2-amino-2-methyl-1-propyl)carbamate (7.9 g, Y.:74%).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([C:15]([O:17]C)=O)=[CH:3][CH:2]=1.C[N:20](C)CCN.N#N>C(O)CC>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([C:15]([NH2:20])=[O:17])=[CH:3][CH:2]=1
Reactant: CN(C)CCN
Reactant: COC(=O)c1cccc2cc3ccccc3nc12
Agent: N#N
Solvent: CCCO
Product: NC(=O)c1cccc2cc3ccccc3nc12
Yield: 80.4 %

Procedure:
A solution of 8a (1.83 g, 7.72 mmol) and N,N-dimethylethylenediamine (3.40 g, 38.6 mmol) in propan-1-ol (80 ml) was flushed with N2, and the mixture was heated at reflux for three days under N2. Solvent was then removed under reduced pressure, and the residue was partitioned between CH2Cl2 (100 ml) and 1M Na2CO3 (100 ml). The organic layer was evaporated and the residue chromatographed on alumina, eluting with CH2Cl2 /MeOH (199:1) to give N-[2-dimethylamino)ethyl]acridine-4-carboxamide 3a (1.38 g, 61%), mp (diHCl salt) 191-195° C., identical with an authentic sample.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17](OC(C)C)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][OH:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCc1ccc2c(c1)ncn2-c1cccc(Br)c1
Temperature: 0 °C

Procedure:
A stirred suspension of 26 from Example 5 (18 g, 50.18 mmol) in 300 ml dry diethyl ether is kept under a stream of nitrogen at room temperature. LiAIH4 (1.9 g, 50 mmol) is added in portions and the mixture is stirred over night. The mixture is poured into a mixture of ice-water and ethyl acetate. The resulting emulgation is filtered through celite and the phases are separated. The aqueous phase is extracted once with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographied on silica gel using successively ethyl acetate and a mixture of ethyl acetate and methanol (9:1) as eluents. Yield of 27: 7.69 g (51%). Mp 107-109° C.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CS(C)=O.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:7]([O:8][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1=CCCCC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C1=CC(COCc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 500 mL round bottom flask equipped with a mechanical stirrer was charged with 19.8 g (0.177 mol) cyclohexene-1-methanol, and 150 mL of DMSO. Sodium hydride (4.90 g, 95% in purity; 0.194 mol) was slowly added to above mixture in an ice bath over 20 min. After the above mixture was reacted at room temperature for 1 hr, 30.2 g (0.177 mol) of benzylbromide was slowly added to the above mixture over 15 min. The reaction was carried out at 60° C. for 2 hrs. The reaction mixture was cooled to room temperature and was added to water (200 mL), and then extracted with chloroform (3×200 mL), washed with water (2×250 mL) and dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]2[CH2:21][C:20]([F:23])([F:22])[CH2:19]2)=[O:16])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].CC1(C)OB([C:31]2[CH:32]=[N:33][N:34]([CH:36]3[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]3)[CH:35]=2)OC1(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:31]3[CH:32]=[N:33][N:34]([CH:36]4[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]4)[CH:35]=3)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]2[CH2:21][C:20]([F:23])([F:22])[CH2:19]2)=[O:16])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC2CC(F)(F)C2)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)cc2N(C(=O)OC2CC(F)(F)C2)C[C@@H]1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
A 100-mL round-bottom flask was purged with nitrogen and then charged with 3,3-difluorocyclobutyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (300 mg, 0.70 mmol), tert-butyl 3-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (487 mg, 1.39 mmol), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) dichloromethane complex (69 mg, 0.08 mmol), cesium carbonate (456 mg, 1.40 mmol), 1,4-dioxane (10 mL) and water (3 mL). The resulting mixture stirred overnight at 90° C. in an oil bath. After cooling to room temperature, the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 8:1 ethyl acetate/petroleum ether) to afford 3,3-difluorocyclobutyl (S)-4-acetyl-7-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (300 mg, 79%) as a yellow oil. MS (ESI, pos. ion) m/z 546 [M+H]+.
Reaction SMILES: C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:5].[Mg+2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1>CO.ClCCl>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:23])=[O:5])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1
Reactant: CSc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
4-Fluoro-1-methylsulfinyl-2-nitrobenzene can be obtained in the following way: 4.7 g of magnesium monoperoxyphthalate are added portionwise to a solution, under argon, of 1.9 g of 4-fluoro-1-methylsulfanyl-2-nitrobenzene in 6 ml of methanol and 30 ml of dichloromethane. The reaction mixture is then stirred at a temperature in the region of 20° C. for 3 hours, and is then filtered through sintered glass and the solid is washed with dichloromethane. The filtrate is washed with an aqueous sodium hydrogencarbonate solution then with water, dried over magnesium sulfate, treated with 3S black, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography on a column of 125 g of silice (particle size 40-63 μm), eluting with pure dichloromethane. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.3 g of 4-fluoro-1-methylsulfinyl-2-nitrobenzene are thus obtained in the form of a yellow foam (Rf=0.23, silica gel thin layer chromatography, eluent: dichloromethane/ethyl acetate 90/10)).