Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[O:5][C:4]1=[O:14].[CH2:15](Br)[CH2:16][CH2:17][CH3:18]>CC(N(C)C)=O>[CH2:15]([N:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[O:5][C:4]1=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCBr
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCn1c(=O)oc(=O)c2cccnc21
Reaction time: 1 h
Yield: 32.7 %

Procedure:
A suspension of sodium hydride (95%, 0.96 g, 40 mmol) in dimethylacetamide (60 mL) at 10° C. under nitrogen was reacted with the product of Example 1A (5.7 g, 34.7 mmol) with stirring for 1 hour then treated with n-butylbromide (5.2 g, 38 mmol) and stirred for an additional 16 hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash column chromatography with silica gel eluting with hexane and ethyl acetate (3:1) to give the title compound as a white solid, (2.5 g, 33% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.92 (t, J=7.35 Hz, 3H), 1.36 (m, 2H), 1.65 (m, 2H), 4.13 (m, 2H), 7.38 (dd, J=7.72, 4.78 Hz, 1H), 8.39 (dd, J=7.72, 1.84 Hz, 1H), 8.77 (dd, J=5.15, 1.84 Hz, 1H).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:10][C:11]1[C:12](=[O:20])[CH:13]=[C:14]([CH:17]([F:19])[F:18])O[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ClCCl>CO.CCOCC>[CH2:3]([O:10][C:11]1[C:12](=[O:20])[CH:13]=[C:14]([CH:17]([F:19])[F:18])[N:2]([CH3:1])[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=c1cc(C(F)F)occ1OCc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: Cn1cc(OCc2ccccc2)c(=O)cc1C(F)F
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
A 2.0M methylamine solution in methanol (19.0 mL, 38.0 mmol) was added to a suspension of 5-benzyloxy-2-difluoromethyl-pyran-4-one (3.15 g, 12.5 mmol) in methanol (18 mL). The reaction mixture slowly turned into a clear yellow solution. The progress of the reaction was monitored by TLC using a mixture of methanol and dichloromethane (1/20, v/v) as eluant, and HPLC method 1 as described above. After 70 minutes, the reaction mixture was concentrated in vacuo to obtain an oil. The oil was diluted with ether and allowed to stir overnight at room temperature. A precipitate had formed and it was collected by filtration. The solid was washed with ether, and the title compound was obtained as an off white solid (2.50 g, 75% yield). The purity of this material was analysed by HPLC Method 1 (peak area percent is 98.8% at λ=288 nm) as described above. 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.75 (s, 1H), 7.44-7.34 (m, 5H, ArH), 7.12 (t, J=53.0 Hz, 1H, CF2H), 6.48 (s, 1H), 5.02 (s, 2H, OCH2), 3.71 (s, 3H, N—CH3).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C([C:10]([OH:18])([CH2:15][CH:16]=[CH2:17])[C:11]([CH3:14])([CH3:13])C)(C)(C)C.C(#N)C1C=CC=CC=1.Cl>CCCCC.C1COCC1.[Cl-].[Cl-].[Zn+2].C(OCC)C>[C:11]1([C:10](=[O:18])[CH2:15][CH:16]=[CH2:17])[CH:13]=[CH:3][CH:2]=[CH:1][CH:14]=1
Reactant: C=CCC(O)(C(C)(C)C)C(C)(C)C
Reactant: [Li]CCCC
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.94 ml of a 1.4 molar solution of n-butyllithium (2.71 mmol) in pentane were added dropwise at 0° C. under argon for 2 min to a stirred solution of 500 mg (2.71 mmol) 3-tert-butyl-2,2-dimethylhex-5-en-3-ol in 4 ml THF. The solution obtained was stirred for 15 minutes, a solution of 370 mg (2.71 mmol) ZnCl2 in 2 ml THF and then 278 μl (2.71 mmol) benzonitrile were added. The reaction mixture was heated to room temperature and stirred for 1 hour. Subsequently, 15 ml of a 0.25-molar HCl solution and 30 ml Et2O were added, and the mixture obtained was vigorously stirred for 10 minutes. The phases were separated, the organic components were extracted twice from the aqueous phase with 15 ml Et2O each, the combined organic phases were washed with 10 ml brine, then dried and concentrated under reduced pressure. The raw product obtained was cleaned by means of a silica column with 5% diethyl ether/light gasoline. The ketone was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][C:2]1[N:7]=[C:6]([O:8][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(=O)[nH]1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc(C=O)cc2)n1
Temperature: 130 °C
Yield: 82.9 %

Procedure:
To a solution of 6-methyl-2(1H)-pyridinone (2 g, 18.33 mmol) and 4-fluorobenzaldehyde (2 ml, 18.64 mmol) in DMF (60 mL), was added K2CO3 (3.80 g, 27.5 mmol). The mixture was heated at 130° C. overnight. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (3.24 g, 15.19 mmol, 83% yield) as a brown oil. LCMS: rt=2.77 min, [M+H+]=214
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:35]2[N:44]=[CH:43][C:42]3[C:37](=[C:38]([F:49])[CH:39]=[C:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:41]=3)[C:36]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:21][N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[C:45]([C:40]1[CH:41]=[C:42]2[C:37](=[C:38]([F:49])[CH:39]=1)[C:36](=[O:50])[N:35]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)=[O:26])=[CH:21][N:20]=4)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=3)[CH:10]=[CH:9][N:8]=1)[N:44]=[CH:43]2)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1nc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A mixture of 116e (150 mg, 0.20 mmol) and lithium hydroxide (85 mg, 2.0 mmol) in THF/i-propanol (5/3 mL) and water (2 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduce pressure and the residue was extracted with ethyl acetate (3×20 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 116 (80 mg, 80%) as a white solid. MS-ESI: [M+H]+ 641.3. 1H NMR (500 MHz, CDCl3) δ 8.78 (s, 1H), 8.75 (d, J=5.0 Hz, 1H), 8.47 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.34 (d, J=3.0 Hz, 1H), 7.79 (dd, J=2.0, 8.0 Hz, 1H), 7.64 (d, J=4.5 Hz, 1H), 7.57 (s, 1H), 7.52 (dd, J=1.5, 12.5 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 4.57-4.55 (m, 2H), 3.94 (s, 3H), 3.81-3.75 (m, 6H), 1.64-1.62 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: C(C1C(OC)=CC(OCCCC(O)=O)=CC=1OC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(CNC(CN2C3C(=CC=CC=3)C(C=O)=C2)=O)=CC=1.[N:61]([CH2:64][C@H:65]1[O:69][C:68](=[O:70])[N:67]([C:71]2[CH:76]=[CH:75][C:74]([S:77][C:78]([C:91]3[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=3)([C:85]3[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=3)[C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=3)=[C:73]([F:97])[CH:72]=2)[CH2:66]1)=[N+]=[N-].C([BH3-])#N.[Na+]>ClCCl.C1COCC1.N1C=CC=CC=1>[NH2:61][CH2:64][C@@H:65]1[O:69][C:68](=[O:70])[N:67]([C:71]2[CH:76]=[CH:75][C:74]([S:77][C:78]([C:79]3[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=3)([C:85]3[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=3)[C:91]3[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=3)=[C:73]([F:97])[CH:72]=2)[CH2:66]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Agent: COc1cc(OCCCC(=O)O)cc(OC)c1C=O
Agent: O=Cc1cn(CC(=O)NCc2ccccc2)c2ccccc12
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC[C@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diisopropylcarbodiiimide (4.24 ml, 27.0 mmol) was added to 4-(4-formyl-3,5-dimethoxyphenoxy)butyric acid (13.19 g, 49.2 mmol) and pyridine (20 mL) in dichloromethane (190 mL), and the mixture was stirred at room temperature for 1 h. Tentagel S-NH2 resin (Rapp Polymere, 30.0 g, 12.3 mmol) was added, and the mixture agitated at room temperature overnight. Resulted BAL resin was filtered, washed liberally with methanol and dichloromethane and dried under vacuum. Triphenylphosphine (7.97 g, 0.0304 mol) was added to a mixture of above BAL aldehyde resin (50.9 g, 0.0209 mol) and 5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one (15.5 g, 30.4 mmol) in THF (200 ml) under nitrogen at r.t. (room temperature). The mixture was agitated at r.t. for 2 h and then heated at 75° C. for 16 h. The mixture was cooled to r.t., and 1 M sodium cyanoborohydride in THF (62.7 ml, 62.7 mmol) was added. The mixture was agitated for 8 h at r.t. The resin was filtered, washed liberally with methanol and dichloromethane and dried under vacuum.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[O:7].[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8]/[CH:9]=[CH:10]/[C:11]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])=[O:7]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)/C=C/CC(=O)c1ccco1
Solvent: C1CCOC1
Product: O=C(C/C=C/C(=O)N1CCC[C@H]1C(=O)O)c1ccco1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 0.02 moles of 4-(2-furoyl)crotonic acid in 100 ml. of tetrahydrofuran is added 0.022 moles of N,N'-carbonyldiimidazole. The mixture is stirred for 3 hours at room temperature and 0.021 moles of L-proline are added. The mixture is refluxed 2 hours and stirred at room temperature for 16 hours to give 1-[4-(2-furoyl)crotonyl]-L-proline.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2Cl)n1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2Cl)n1

Procedure:
Following the procedure in Example 118A, 3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-amine (1.30 g, 5.21 mmol) and phenyl chloroformate (2.0 mL, 15.63 mmol) were reacted to give phenyl 3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-ylcarbamate. 1H NMR (300 MHz, DMSO-d6) δ 10.18 (br s, 1H), 7.67 (d, 1H), 7.55-7.48 (m, 3H), 7.41-7.36 (m, 2H), 7.24 (t, 1H), 7.02 (br s, 2H), 6.31 (s, 1H), 1.23 (s, 9H); LC-MS (ESI) m/z 370 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([I:11])[C:3]=1[CH3:12].OS(O)(=O)=O.[CH3:18][CH2:19]O>>[CH2:18]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:12])[C:4]=1[I:11])[CH3:19]
Reactant: CCO
Reactant: Cc1c(Br)ccc(C(=O)O)c1I
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Br)c(C)c1I

Procedure:
A mixture of 4-Bromo-2-iodo-3-methyl-benzoic acid (5.43 g, 0.016 mol) and conc.H2SO4 (5 mL) in EtOH (50 mL) is refluxed overnight. After reaction, evaporated out EtOH, extracted with ethyl acetate (3×50 mL), The combined organic phase is washed with water and brine, dried over Na2SO4, concentrated in vacuo, and purified by column chromatography on silica gel eluted with petrol ether and ethyl acetate to afford the desired compound. Yield: 5.2 g (88%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]=3[CH:28]=2)=[CH:7][CH:6]=1)=[O:4].[ClH:29]>CO.O1CCOCC1>[ClH:29].[O:20]1[C:14]2[CH:13]=[CH:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[CH:28][C:15]=2[CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CCO3)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc3c(c2)CNCCO3)cc1
Temperature: 55 °C
Yield: 97 %

Procedure:
To a solution of 1,1-dimethylethyl 7-{4-[(methyloxy)carbonyl]phenyl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.90 g, 4.96 mmol) in dry methanol (10 mL) was added drop wise 4 N hydrogen chloride in dioxane (10 mL) at room temperature. The reaction mixture was warmed to 55° C. for 60 min, at which time it was cooled to room temperature. The precipitated product was isolated by filtration, washed with diethyl ether, and dried to yield methyl 4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoate hydrochloride (1.53 g, 97% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[F:30])[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[F:30])[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:2]2[CH:12]=[C:6]3[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]3[C:4](=[O:13])[N:3]=2)=[CH:21][CH:20]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)cc1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)cc1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (4-(3,4-difluorophenoxy)phenyl)methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH2:19][CH2:20][N:21]2C(=O)C3=CC=CC=C3C2=O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.NN>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH2:19][CH2:20][NH2:21])=[O:9])=[CH:33][CH:34]=1)([O-:3])=[O:2]
Reactant: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1OCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1OCCCN
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.5 %

Procedure:
To a solution of 4-nitro-N-methyl-N-[2-(3-phthalimidoprop-1-yloxy)phenyl]benzamide (760 mg) in ethanol (15 ml) was added hydrazine hydrate (828 mg) and the solution was stirred at ambient temperature for 1 days. After evaporation in vacuo, the residue was diluted with ethyl acetate and then the organic solution was washed successively with saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of solvents afforded 4-nitro-N-methyl-N-[2-(3-aminoprop-1-yloxy)phenyl]benzamide (422 mg) as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.[CH3:16][C:17]1[N:21]([CH:22](S(OC)(=O)=O)[CH3:23])[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:19][CH:18]=1>CN(C)C=O.O>[CH3:16][C:17]1[N:21]([CH2:22][CH2:23][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COS(=O)(=O)C(C)n1c(C)ccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2)n1CCOc1ccc(C=O)cc1
Reaction time: 4 h

Procedure:
To a suspension of potassium carbonate (16.43 g) in dimethyl formamide (50 mL), 4-hydroxy benzaldehyde (4.37 g) was added and warmed to 90° C. to 95° C. To the solution, methyl 1-[5-methyl-2-phenyl-1H-pyrrol-1-yl]ethane sulfonate (10 g) (compound no. 64 dissolved in dimethyl formamide (50 mL) was added within 30 min and the reaction was continued for further 4 hours. The reaction mixture was diluted with water (100 mL) and was extracted with ethyl acetate (3×100 mL), washed with water (3×100 mL), brine (200 mL), and was dried over sodium sulfate. The solvent was evaporated under reduced pressure, to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:22])=[C:17]([CH:21]=1)[C:18](O)=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:22])=[C:17]([CH2:18][C:9]2[S:8][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:11][CH:10]=2)[CH:21]=1
Reactant: Clc1ccc(-c2cccs2)s1
Reactant: Cc1ccc(Br)cc1C(=O)O
Product: Cc1ccc(Br)cc1Cc1ccc(-c2ccc(Cl)s2)s1

Procedure:
The above 2-(5-chloro-2-thienyl)thiophene and 5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) were used and treated in a manner similar to Reference Example 5 to give 5-bromo-1-(5-(5-chloro-2-thienyl)-2-thienylmethyl)-2-methylbenzene as a colorless solid. APCI-Mass m/Z 383/385 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[S:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[CH:27][O:26][C:25]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:20][CH:19]=1)(=[O:17])(=[O:16])[NH2:15]>CC(N(C)C)=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:27]2[O:26][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:24]([C:21]3[CH:20]=[CH:19][C:18]([S:14](=[O:16])(=[O:17])[NH2:15])=[CH:23][CH:22]=3)[CH:28]=2)=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CCOC(=O)c1occc1-c1ccc(S(N)(=O)=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc(-c2ccc(Cl)cc2)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 150 °C
Yield: 9.8 %

Procedure:
1-Bromo-4-chlorobenzene (0.214 g, 1.11 mmol) and potassium acetate (0.199 g, 2.03 mmol) were added to a solution of ethyl 3-(4-sulfamoylphenyl)furan-2-carboxylate (60a, 0.3 g, 1.01 mmol) in dimethyl acetamide (5 ml) at 25° C. in a tube. A nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added palladium (II) acetate (0.023 gm, 0.102 mmol) under nitrogen atmosphere and the tube was sealed. The reaction mixture was then heated at 150° C. for 20 hr with stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and concentrated under reduced pressure. The residue so obtained was dissolved in ethyl acetate (30 ml). The solution so obtained was then washed with water (2×10 ml), dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (0.040 gm, 9.70%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([C:16](O)([CH3:18])[CH3:17])=[CH:15][C:4]=2[N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:17]=[C:16]([C:14]1[CH:13]=[CH:12][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:15]=1)[N:10]=[CH:9][CH:8]=[CH:7]3)[CH3:18]
Reactant: CC(C)(O)c1ccc2c(c1)nc(N)c1ncccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C(C)c1ccc2c(c1)nc(N)c1ncccc12

Procedure:
A solution of 2-(5-aminobenzo[f][1,7]naphthyridin-8-yl)propan-2-ol (from the previous step) (1.0 eq.) and p-TsOH (2 eq.) in toluene (0.01 M) was stirred at 90° C. for 6 hours. The reaction was quenched by saturated NaHCO3 and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give 8-(prop-1-en-2-yl)benzo[f][1,7]naphthyridin-5-amine as a yellow solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[CH2:6]1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:7]1[C:8](=[O:11])[CH2:9][CH2:10][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]1
Reactant: COC(=O)C1CCC(=O)N(Cc2ccc(OC)cc2OC)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN2CC(C(=O)O)CCC2=O)c(OC)c1
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of the crude product of 1-(2,4-dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid methyl ester (26.8 g) in methanol/tetrahydrofuran (1/1, 174 ml) was added a 1M aqueous solution of sodium hydroxide (174 ml) at room temperature, and the mixture was stirred overnight. To this reaction solution was added a 1M aqueous solution of hydrochloric acid (174 ml), the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the titled compound (15.1 g).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](/[CH:24]=[CH:25]/[C:26]4[CH:36]=[CH:35][C:29]([C:30]([O:32]CC)=[O:31])=[CH:28][CH:27]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[OH-].[Na+]>[C:1]12([C:11]3[CH:12]=[C:13](/[CH:24]=[CH:25]/[C:26]4[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:35][CH:36]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc(OCOCCOC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COCCOCOc1ccc(/C=C/c2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
2.0 g (4.0 mmol) of ethyl 4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl)ethenyl]benzoate and methanolic sodium hydroxide solution (1.6 g of sodium hydroxide in 50 ml of methanol) were introduced into a round-bottomed flask. The mixture was refluxed for four hours and evaporated to dryness, and the residue was taken up in water and acidified to pH 1. The aqueous phase was extracted with ethyl acetate and the organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was triturated from the minimum amount of ethyl ether, filtered and dried. 1.4 g (74%) of the expected acid, with a melting point of 207-208° C., was collected.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:8]([OH:10])=[O:9].[N:11]([O-])=[O:12].[Na+].Cl.C(OCC)(=O)C>O>[N:11]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: O=C(O)C1CCCCCN1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=NN1CCCCCC1C(=O)O
Reaction time: 1 h

Procedure:
At 0° C., a solution of 7.80 g (43.4 mmol) of azepan-2-carboxylic acid and 4.10 g (59.5 mmol) of sodium nitrite in 50 ml of water is acidified to pH 3 using HCl (conc.) and then stirred for 1 h. 50 ml of ethyl acetate are added to the reaction mixture, the organic phase is separated off and the aqueous phase is extracted with 2×50 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and freed from the solvent under reduced pressure. The 1-nitrosoazepan-2-carboxylic acid obtained (6.80 g, 67%) is taken up in 15 ml of acetonitrile without further purification, and 12.4 g (59.2 mmol) of trifluoroacetic anhydride are added dropwise at 0° C. After 2 h of stirring at room temperature, 8.19 g (59.2 mmol) of potassium carbonate are added, and stirring is continued for a further 20 min. 40 ml of ethyl acetate and 20 ml of water are added to the reaction mixture, and the aqueous phase is extracted with 3×40 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and freed from the solvent under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 5.50 g (90%) of the desired product; log P(HCOOH): 0.6; 1H-NMR (DMSO-d6): 4.45 (m, 2H), 2.56 (m, 2H), 1.83 (m, 4H), 1.57 (m, 2H)