Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]1[CH2:15][O:14][C:13]2[CH:16]=[CH:17][C:18]([N+:25]([O-])=O)=[C:19]([CH2:20][C:21](OC)=[O:22])[C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)C>[CH2:1]([NH:8][CH2:9][CH:10]1[O:11][C:12]2=[C:19]3[C:18](=[CH:17][CH:16]=[C:13]2[O:14][CH2:15]1)[NH:25][C:21](=[O:22])[CH2:20]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c([N+](=O)[O-])ccc2c1OC(CNCc1ccccc1)CO2
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1Cc2c(ccc3c2OC(CNCc2ccccc2)CO3)N1
Temperature: 70 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
The methyl ester from Example 5 (43 mg) was dissolved in 1:1 ethyl acetate/ethanol (10 mL) and filtered through a syringe filter to remove insoluble material. Platinum oxide (35 weight percent) was added and the mixture placed under 50 psi of hydrogen gas on a Parr shaker overnight. TLC analysis with 95:5 CH2Cl2/MeOH showed consumption of starting material with a more polar product having been formed. The mixture was filtered through a 0.5 μm syringe filter, washing with 1:1 EtOAc/EtOH, and the filtrate concentrated under reduced pressure to a pale red-brown glass. The crude material was redissolved in ethanol (20 mL) and 20 μL of concentrated HCl were added. The solution was warmed to 70° C. and allowed to stir overnight. TLC of the reaction mixture (96:4 CH2Cl2/MeOH) showed the formation of a new product with no remaining starting material. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to a light orange film. This was chromatographed over silica gel eluting with 96:4 CH2Cl2/MeOH. The title product was isolated in 22% yield.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[O:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[N:7]2.C([Li])CCC.CN(C)[CH:27]=[O:28]>O1CCCC1>[CH3:19][C:16]1[O:15][C:14]([CH2:13][NH:12][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH:27]=[O:28])=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CNc2ccc3c(Br)cccc3n2)o1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(CNc2ccc3c(C=O)cccc3n2)o1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
(5-Bromo-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (example 3, step A, 700 mg, 2.2 mmol) was dissolved in 30 mL tetrahydrofuran and cooled to −78° C. n-Butyllithium (3.45 mL, 1.6 M in hexane, 5.5 mmol) was added and the reaction mixture was allowed to warm to −10° C. Stirring was continued at −10° C. for 45 minutes. The reaction was cooled again to −78° C. and N,N-dimethylformamide (404 mg, 5.5 mmol) was added. The reaction mixture was slowly warmed up and quenched at 5° C. by addition of 100 mL water. The mixture was extracted three times with ethyl acetate (100 mL each). The organic phases were pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->50:50 gradient). 2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinoline-5-carbaldehyde was obtained as a brown oil (242 mg, 41%), MS: m/e=267.1 (M+H+).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[O:14]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][NH2:30])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:30]([CH2:29][CH2:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][CH:23]=1)[CH2:11]2
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: NCCCc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cccc2CN1CCCc1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.106 g, 0.3 mmol), 3-(4-phenoxy-phenyl)-propylamine (0.136 g, 0.6 mmol), and K2CO3 (0.110 g, 0.8 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-[3-(4-phenoxy-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.025 g, 18%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.01 (m, 2H), 2.68 (t, 2H), 3.67 (t, 2H), 4.28 (s, 2H), 6.86-7.42 (m, 11H), 7.88 (d, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([Cl:10])=[CH:8][N:7]([CH:11]([F:13])[F:12])[N:6]=1)=[O:4].[OH-].[Li+].O.CO>O1CCCC1>[Cl:10][C:9]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][N:7]([CH:11]([F:12])[F:13])[CH:8]=1
Reactant: COC(=O)c1nn(C(F)F)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1nn(C(F)F)cc1Cl
Reaction time: 1 h
Yield: 108.6 %

Procedure:
A solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at room temperature with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a 1:1-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was dissolved in water (10 ml) and acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying of the organic layer over sodium sulphate, and evaporation at reduced pressure yielded a white solid (555 mg) which was triturated with pentane (10 ml). The solid material was filtered, washed with pentane and dried. After drying at reduced pressure the 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid was obtained as a white solid (477 mg, 95% of theory). MS (ISP): m/z=195.0 [M−H]−.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([CH:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7].BrCC.Cl>C1COCC1.O>[CH2:6]([C:8]1([CH2:1][CH3:2])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:7]
Reactant: [Li]CCCC
Reactant: CCC1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: CCBr
Solvent: O
Solvent: C1CCOC1
Product: CCC1(CC)c2ccccc2-c2ccccc21
Temperature: -75 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of n-butyllithium (77.34 cm3, 0.1934 mol, 2.5M in hexane) was added slowly to a solution of 9-ethylfluorene (25.00 g, 0.1289 mol) in THF (250 cm3) at −70° C. The solution was stirred for 1 hour at −75° C. and 1-bromoethane (17.59 cm3, 0.1934 mol) was added slowly. The solution was allowed to warm to room temperature and then stirred overnight. Dilute hydrochloric acid (200 cm3, 20%) was added to the reaction mixture and stirred for a further 10 minutes. Water (250 cm3) was added and the product extracted into diethyl ether (3×300 cm3). The combined organic extracts were dried (MgSO4) and the solvent removed on a rotary evaporator. The resulting oil was cooled to room temperature and recrystallised with ethanol to yield white crystals (19.50 g, 68%, m.pt. 60–62° C.).
Reaction SMILES: [O:1]=[C:2]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH2:9][O:10][C:11](=[O:23])[CH2:12][CH2:13][C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:6].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.C([BH3-])#N.[Na+]>CO.Cl>[OH:1][CH:2]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH2:9][O:10][C:11](=[O:23])[CH2:12][CH2:13][CH:14]([OH:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:6]
Reactant: CCCCCCCC(=O)CCC(=O)OCCOC(=O)CCC(=O)CCCCCCC
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCCCCCCC(O)CCC(=O)OCCOC(=O)CCC(O)CCCCCCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 21.54 g 4-oxo-undecanoic acid 2-(4-oxo-undecanoyloxy)-ethyl ester and a of bromocresol green in 150 ml of methanol, 6.34 g sodium cyanoborohydride was added. The resulting reaction mixture was stirred for 2.5 hours at room temperature,while dropping in 2N HCl to adjust the pH<3.8. The solvent was then evaporated, the solid residue was dissolved in ether and washed with water. The organic phase was dried and evaporated to dryness to yield the compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: Nc1ccccc1B(O)O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1B(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
A mixture of 2-aminophenylboronic acid (900 mg; 6.6 mmol), triethylamine (0.57 ml; 7 mmol) and acetylchloride (0.5 ml; 7 mmol) was stirred at rt. for 1 h. The reaction mixture was evaporated to dryness, stirred with H2O and filtered to give 750 mg (63%) product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:17][CH2:18][C:19]([OH:21])=O)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].[OH-].[Na+]>CS(O)(=O)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16])[C:19](=[O:21])[CH2:18][CH2:17]2
Reactant: COCCOc1ccc(CCC(=O)O)cc1OCCOC
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COCCOc1cc2c(cc1OCCOC)C(=O)CC2
Temperature: 100 °C
Yield: 142.6 %

Procedure:
3-[3,4-Bis-(2-methoxy-ethoxy)-phenyl]-propionic acid (2 g×5) was dissolved in methanesulfonic acid (10 ml×5) in microwave process vial (20 ml×5), and the mixture was heated at 100° C. for 10 minutes under microwave irradiation. The reaction mixture was poured into ice (250 g), neutralized by 2M NaOH to PH 8-9, and then extracted by EtOAc/isopropyl alcohol. The organic layer was concentrated to give product (2.68 g, 28.3%). LC-MS: m/e 281 (MH+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:4]([F:16])[CH:3]=1.[N:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][N:26]3[CH:29]=[CH:30][N:31]=[C:25]3[CH:24]=2)=[CH:19][CH:18]=1>>[C:12]([O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2[N:26]3[CH:27]=[CH:28][C:23]([C:20]4[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=4)=[CH:24][C:25]3=[N:31][CH:30]=2)=[CH:3][C:4]=1[F:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Cc1ccc(Br)cc1F
Reactant: c1cc(-c2ccn3ccnc3c2)ccn1
Product: CC(C)(C)OC(=O)Cc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1F

Procedure:
Couple 4-bromo-2-fluoro-phenylacetic acid, tert-butyl ester (3.65 g, 18.68 mmol) with 7-pyridin-4-yl-imidazo[1,2-a]pyridine (5.40 g, 18.68 mmol) as described in Preparation 153. MS(ES), m/z 404 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH:40]1([NH2:48])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>O1CCCC1>[CH:40]1([NH:48][C:18](=[O:20])[C@@H:17]2[CH2:21][CH2:22][CH2:23][N:16]2[C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NC1CCCCCCC1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCCCC1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 59.4 %

Procedure:
6.4 g (0.02 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline were dissolved in 75 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 2.54 ml (0.02 mol) of N-ethylmorpholine and 2.62 ml (0.02 mol) of isobutyl chloroformate were added and the resulting solution was stirred at -10° C. for 20 minutes. A solution of 2.5 g (0.02 mol) of cyclooctylamine in 25 ml of dry tetrahydrofuran was then added. The resulting mixture was stirred at 0° C. for 1 hour and then left to stand at room temperature for 16 hours. The tetrahydrofuran was removed by evaporation and the residue extracted with two 50 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed successively with 1-N hydrochloric acid, water, 5% sodium bicarbonate solution and water and then dried over magnesium sulphate. Evaporation yielded an oil which solidified upon trituration with ether/petroleum ether. After recrystallisation from ethyl acetate/petroleum ether, there were obtained 5.1 g (59.3%) of N-benzyloxycarbonyl-L-alanyl-L-proline cyclooctylamide of melting point 94°-96° C.; [α]D20 =-95.0° (c=1.02% in methanol).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]([O:22][CH2:23][CH2:24][OH:25])=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl:26][C:27]1[C:32](Cl)=[N:31][CH:30]=[CH:29][N:28]=1.O>O1CCOCC1>[Cl:26][C:27]1[C:32]([O:25][CH2:24][CH2:23][O:22][C:17]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:11][CH2:12]3)=[N:21][CH:20]=[CH:19][N:18]=2)=[N:31][CH:30]=[CH:29][N:28]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2nccnc2Cl)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
NaH (50% in mineral oil; 0.153 g, 3.50 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol; prepared in Example 52, Step 2) and 2,3-dichloropyrazine (1.0 g, 6.71 mmol) in dioxane (10 mL). The reaction was stirred in a sealed tube at 100° C. overnight. The reaction mixture was poured into water and extracted with diethyl ether. The ether phase was dried (MgSO4), concentrated and purified by column chromatography on silica using toluene/EtOAc (7:3) as eluent to give 0.823 g (61%) of the title product: Pos-EI-MS shows M+ and 14 ions supporting the stated structure. HRMS m/z calcd for C19H25CIN6O4 (M)+436.1626, found 436.1606.
Reaction SMILES: S(F)(=O)(=O)[OH:2].[Sb](F)(F)(F)(F)F.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][CH2:23][C:24]#N)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:16]=1[CH2:21][CH2:22][CH2:23][C:24]2=[O:2])([O-:14])=[O:13]
Reactant: O=S(=O)(O)F
Reactant: N#CCCCc1ccccc1[N+](=O)[O-]
Agent: F[Sb](F)(F)(F)F
Product: O=C1CCCc2c1cccc2[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 12 h

Procedure:
1.00 g of fluorosulfuric acid (10 mmol) are added to 1.30 g of antimony(V) fluoride (6 mmol) in a 50 ml glass round-bottomed flask under protective gas and the mixture is cooled to 0° C. Then, 380 mg of 4-(2-nitrophenyl)butyronitrile (2 mmol) are added carefully. The mixture heats up to about 50° C. and is stirred for a farther 12 h at room temperature. The mixture is poured on to ice-cold sodium hydroxide solution, stirring is continued for 30 min at room temperature and then extraction is performed with toluene. Largely complete hydrolysis is made possible by the secondary stirring period. The organic phase is dried over sodium sulfate, filtered off and the solvent is distilled off under reduced pressure. The residue is purified by chromatography on silica gel (eluent cyclohexane/ethyl acetate 5:1 v/v). The yield of 5-nitro-3,4-dihydro-1(2H)-naphthalenone is 297 mg with a GC purity of 97% (76% of theoretical value).
Reaction SMILES: [C:1]([C:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH2:10][CH2:11][C:12]([O:14]CC)=O)[CH2:4][C:5]([O:7]CC)=O)#[N:2].C(=O)([O-])[O-:24].[K+].[K+]>>[NH:2]1[C:12](=[O:14])[CH2:11][CH2:10][C:3]2([C:17]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:5](=[O:7])[C:4]2=[O:24])[CH2:1]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCC(C#N)(CC(=O)OCC)c1ccccc1
Agent: [K+]
Product: O=C1CCC2(CN1)C(=O)C(=O)c1ccccc12
Reaction time: 5 h
Yield: 4.4 %

Procedure:
A mixture of 310 grams of polyphosphoric acid and 30.24 grams (0.1 M) of diethyl β-cyano-β-phenyladipate, prepared by the general method of Branchini et al., Annali di Chimica, 51, 1382 (1961), Chem. Abstr., 56, 15362f (1962), were heated and stirred under nitrogen atmosphere on a steam bath for five hours. The reaction mixture was poured into an icewater slurry keeping the mixture temperature at about 10° C. by additions of crushed ice. Solid potassium carbonate was added to the reaction mixture until the pH was five. On cooling overnight, a precipitate formed. Careful crystallization from acetone and then from isopropyl alcohol gave 1.1 grams (4.4%) of spiro-[indane-1,3'-piperidine]-2,3,6'-trione, melting point 227°-228° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.[H][H]>CO.[Pd]>[C:20]1([C:14]2([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [H][H]
Reactant: c1ccc(CN2CCN(C3(c4ccccc4)CCCCC3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1ccc(C2(N3CCNCC3)CCCCC2)cc1

Procedure:
1-benzyl-4-(1-phenylcyclohexyl)piperazine (0.47 g) was dissolved in 86 mL methanol and 14 mL 0.2N HCl in methanol. The mixture was hydrogenated over palladium black (0.1175 g) and 3 atm. of hydrogen at room temperature for 1 hour. The reaction was filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluted with the appropriate mixture of methanol and chloroform to yield pure 1-(1-phenylcyclohexyl)piperazine.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][CH2:18][C:9]=2[N:10]=[C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:12]=1)(=O)=O.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH2:36])=[O:35])=[CH:29][CH:28]=1>>[CH:13]1([C:11]2[N:12]=[C:7]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][C:34]([NH2:36])=[O:35])=[CH:31][CH:32]=3)[C:8]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][CH2:18][C:9]=3[N:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=S1(=O)CCCc2nc(C3CCCC3)nc(OS(=O)(=O)C(F)(F)F)c21
Reactant: NC(=O)Cc1ccc(N)cc1
Product: NC(=O)Cc1ccc(Nc2nc(C3CCCC3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 54.9 %

Procedure:
Following general procedure H, 2-cyclopentyl-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.200 g, crude) was reacted with 2-(4-aminophenyl)acetamide (0.038 g, 0.25 mmol) to afford the title compound (0.055 g, 27%) as a white solid. MW=400.49. 1H NMR (DMSO-d6, 500 MHz) δ 8.60 (s, 1H), 7.55 (d, J=8.5 Hz, 2H), 7.44 (s, 1H), 7.25 (d, J=8.5 Hz, 2H), 6.87 (s, 1H), 3.71-3.64 (m, 2H), 3.36 (s, 2H), 3.10 (quin, J=8.0 Hz, 1H), 2.94 (t, J=6.5 Hz, 2H), 2.38-2.29 (m, 2H), 1.99-1.91 (m, 2H), 1.84-1.55 (m, 6H); APCI MS m/z 401 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[NH:17][C:18](=[NH:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:25]=[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCCCCCC(=N)NO
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Solvent: Cc1ccccc1
Product: CCCCCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Reaction time: 1.25 h

Procedure:
To a solution of 0.63 g (2.08 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 6 mL of toluene, 0.540 g (3.33 mmol) of 1,1-carbonyldiimidazole was added in portions at 25° C. to 30° C. under inert atmosphere. To the thickened mixture, 5 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of N-hydroxy-heptanimidamide (compound of Example 41; 0.9 g, 6.2 mmol) in 5 mL of toluene was added to the above reaction mixture at 25° C. to 30° C. The reaction mixture was stirred at 25° C. to 30° C. under nitrogen for 12-14 h, followed by stirring at 100° C. to 105° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and quenched with 10 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 5 mL of toluene. The organic layers were combined and washed with 10 mL of 1N HCl solution, 10 mL of 5% sodium bicarbonate solution and 10 mL of 10% sodium chloride solution. The organic layer was distilled completely to obtain a crude residue, which was purified using column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [N:1]1([C:8]2[C:9]3[S:25][CH:24]=[CH:23][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([Cl:21])=[CH:16][C:15]=3F)[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].CO.Cl.[O:32]1CCOC[CH2:33]1>C(Cl)(Cl)Cl.CO>[ClH:21].[N:1]1([C:8]2[C:9]3[S:25][CH:24]=[CH:23][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([Cl:21])=[CH:16][C:15]=3[O:32][CH3:33])[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1cc(-c2nc(N3CCCCCC3)c3sccc3n2)c(F)cc1Cl
Reactant: C1COCCO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(Cl)c(F)cc1-c1nc(N2CCCCCC2)c2sccc2n1
Temperature: 120 °C
Reaction time: 120 h

Procedure:
A mixture of 514 mg of 4-azepane-1-yl-2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine, 300 mg of sodium methoxide and 10 ml of MeOH was stirred in a sealed tube for 5 days at 120° C. After the reaction mixture was concentrated under reduced pressure, 40 ml of water was added to the obtained residue and extracted twice with 40 ml of chloroform. After the organic layer washed with a saturated saline solution and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-MeOH) to give a solid. After 0.6 ml of 4M HCl-dioxane solution was added to 10 ml of chloroform-MeOH with this solid, the resultant was concentrated under reduced pressure to give a solid. After the obtained solid was recrystallized three times from EtOAc and EtOH, the crystal generated was filtered and washed with EtOAc to give 223 mg of 4-azepane-1-yl-2-(4-chloro-5-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidine hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][S:9][C@@H:8]([CH2:11][SH:12])[CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([S:12][CH2:11][C@H:8]1[CH2:7][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][S:9]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)[C@@H]1CS[C@@H](CS)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CS[C@@H](CSC(=O)c2ccccc2)C1
Reaction time: 0.17 h
Yield: 86 %

Procedure:
To a stirred solution of trans-4-ethoxycarbonyl-2-mercaptomethyltetrahydrothiophene (compound No. 15-1, 60 mg) and triethylamine (42 μl) in methylene chloride (2 ml), benzoyl chloride (43 mg) dissolved in methylene chloride (1 ml) was added under ice-cooling. The mixture was stirred for 10 minutes and concentrated in vacuo. 0.1N hydrochloric acid was added to the residue and extracted with diethylether. The organic layer was washed with aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 77 mg (86%) of the titled compound (compound No. 23-1).