Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[K+].Br[CH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>C(C(C)=O)C(C)C.O>[C:22]([C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[CH2:19][N:3]1[CH2:4][CH2:5][S:1][C:2]1=[O:6])#[N:23]
Reactant: O=C1NCCS1
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: N#Cc1ccccc1CN1CCSC1=O
Reaction time: 0.5 h

Procedure:
A mixture containing 3.09 g (0.03 mol) of 2-thiazolidinone, 11.2 g (0.081 mol) of potassium carbonate, 1.8 g (0.018 mol) of potassium hydrogen carbonate, 0.5 ml (0.027 mol) of water and 6.47 g (0.033 mol) of 2-bromomethylbenzonitrile in 30 ml of methyl isobutyl ketone is refluxed for 5 hours, then cooled down. After adding 30 ml of water the mixture is stirred for 30 minutes, the insoluble precipitate is filtered off, washed twice with 10 ml of water each and dried. After recrystallizing 4.71 g of crude product from 20 ml of ethanol under simultaneous clarification with activated carbon 3.39 g (51.8%) of white, crystalline title compound are obtained, m.p.: 116°-117° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[O:16]1[CH2:33][C@@H:17]1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](OCC#N)=[O:28])=[CH:22][CH:21]=1>C1COCC1>[O:16]1[CH2:33][C@@H:17]1[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)=[O:28])=[CH:24][CH:25]=1
Reactant: N#CCOC(=O)Cc1ccc(OC[C@H]2CO2)cc1
Reactant: NCCN1CCN(c2ccccc2)CC1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(OC[C@H]2CO2)cc1)NCCN1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 10.7 g (52.1 mmol) 1-(2-aminoethyl)-4-phenylpiperazine and 13.5 g (54.6 mmol) (R)-4-(2,3-epoxypropoxy)phenylacetic acid, cyanomethyl ester in 125 dry THF was stirred at room temperature for 40 hours. The solvent was removed in vacuo and the residue was triturated with ether to give the crude amide as a white solid. The solid was dissolved in 35 ml. CH2Cl2 and placed on a column of 170 g Woelm basic alumina (grade 3) made up in CHCl2. Elution with 1 liter CH2Cl2 furnished essentially pure material. Crystallization from acetone afforded the end product, m.p. 124°-125°. A second crop, m.p. 121°-123° was obtained from the mother liquors.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](Br)(=[O:11])[CH3:10]>O>[C:9]([N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]1=[O:1])(=[O:11])[CH3:10]
Reactant: CC(=O)Br
Reactant: Oc1cccnc1O
Solvent: O
Product: CC(=O)n1cccc(O)c1=O

Procedure:
2,3-Dihydroxypyridine (5.55 g) is refluxed with acetylbromide (10 ml) overnight. The reaction mixture is allowed to cool and water (10 ml) is added. The resulting suspension is extracted with methylene chloride and the methylene chloride solution is dried over Na2SO4 and evaporated. The resultant residue is recrystallised from petroleum ether (80°-100° C.) to give 1-acetyl-3-hydroxypyrid-2-one as white crystals (2.8 g), m.p. 140°-141° C.; νmax (nujol) 1680, 3120 cm-1 ; δ(d6DMSO), 2.2 (s, 3H), 6.1 (t, 1H), 6.65 (m, 1H), 7.2 (d, 1H)
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[C:13]([F:20])[CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:13]([F:20])[CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: O=Cc1cnccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cnccc1-c1ccc(Cl)cc1F
Temperature: 85 °C
Reaction time: 6 h
Yield: 39.5 %

Procedure:
To a mixture of 4-bromonicotinaldehyde (3.00 g, 16.13 mmol), (4-chloro-2-fluorophenyl)boronic acid (2.81 g, 16.13 mmol), cesium carbonate (10.51 g, 32.3 mmol) and Pd(PPh3)4 (0.932 g, 0.806 mmol) was added THF (50 mL) and water (8 mL). Nitrogen gas was bubbled through the stirred suspension for 5 min. The reaction mixture was stirred under nitrogen atmosphere at 85° C. for 6 h. The reaction mixture was then cooled to room temperature and filtered through celite. The filtrate was diluted with ethyl acetate (30 mL) and washed with water (1×25 mL) and brine (1×25 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (ethyl acetate/hexanes) to yield 4-(4-chloro-2-fluorophenyl)nicotinaldehyde (1.5 g, 6.37 mmol, 39% yield for two steps). 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 9.18 (s, 1H), 8.86 (d, J=5.1 Hz, 1H), 7.30 (m, 4H).
Reaction SMILES: Cl.Cl.[CH2:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)[CH2:7][CH2:6]1)[CH3:4].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>CN(C=O)C>[CH2:3]([N:5]1[CH2:6][CH2:7][CH:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[O:22])=[CH:15]3)[CH2:9][CH2:10]1)[CH3:4]
Reactant: C1COCCN1
Reactant: CCN1CCC(Nc2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCC(Nc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Yield: 60.6 %

Procedure:
A mixture of 0.15 g 5-(1-ethyl-piperidin-4-ylamino)-1H-indole-2-carboxylic acid (intermediate 3), 0.16 g O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), 0.323 g DIPEA and 0.044 g morpholine in 2 ml DMF was reacted for 1 h at room temperature and evaporated to dryness. The residue was treated with ethyl acetate, water and NaHCO3 aq. The aqueous phases were further extracted with ethyl acetate and the combined organic phases were dried over Na2SO4, filtered and evaporated. The residue was further purified by chromatography and crystallization to yield 0.09 g (60%) of the title compound as light brown solid. MS (m/e): 357.4 (MH+, 100%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][N:44]=1>CN(C=O)C>[NH2:42][C:43]1[N:44]=[CH:45][C:46]([C:47]([N:3]2[C@@H:4]([CH3:8])[CH2:5][O:6][CH2:7][C@H:2]2[CH3:1])=[O:48])=[CH:50][CH:51]=1
Reactant: C[C@@H]1COC[C@H](C)N1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1COC[C@H](C)N1C(=O)c1ccc(N)nc1
Reaction time: 18 h
Yield: 27.6 %

Procedure:
To a solution of (3S,5R)-3,5-dimethylmorpholine (1.15 g, 10 mmol) in DMF (15 mL) was added HATU (3.8 g, 10 mmol), DIPEA (2.6 g, 20 mmol), and 6-aminonicotinic acid (1.38 g, 10 mmol) at room temperature. The reaction mixture was stirred for 18 h. It was then filtered and the filtrate was purified with Combiflash (A: 1% NH4HCO3/water, B: in acetonitrile) to afford 320a (650 mg, 27%) as a yellow solid. MS-ESI: [M+H]+ 236.1.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=O)[CH2:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.[NH:15]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])[NH2:16]>C(O)(=O)C.CCOC(C)=O>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[N:15]([C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])[N:16]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Reactant: NNc1ccccc1C(=O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1-n1nc(C(F)(F)F)cc1-c1ccco1

Procedure:
4,4,4-Trifluoro-1-(2-furyl)-1,3-butanedione (2.4 mL, 16 mmol) was added to 2-hydrazinobenzoic acid (3.01 g, 16 mmol) in acetic acid (20 mL) and heated at reflux for 25 h. The reaction was cooled, diluted with EtOAc, and extracted twice with water. The organic layer was dried over Na2SO4, filtered, and evaporated to yield a thick red paste (5.71 g, >100%). 1H NMR (CDCl3) δ8.18 (dd, 1H, J=7.7, J′=1.8), 7.74 (td, 1H, J=7.7, J′=1.4), 7.65 (td, 1H, J=7.7, J′=1.5), 7.50 (dd, 1H, J=7.3, J′=1.1), 7.35 (m, 1H), 6.89 (s, 1H), 6.28 (m, 1H), 5.76 (d, 1H, J=3.3).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:63]1[C:68]2[O:69][CH2:70][C:71](=[O:73])[NH:72][C:67]=2[C:66]([OH:74])=[CH:65][CH:64]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14]CC1C=CC(C2C=CC(NC(C3C=C(S(C4C=C5C(=C(C)C=4)N=CC(C(N)=O)=C5NC4C=CC=C(OC)C=4)(=O)=O)C=CC=3)=O)=CC=2)=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:75][O:76][C:77]1[CH:78]=[C:79]([NH:83][C:84]2[C:93]3[C:88](=[C:89]([CH3:114])[CH:90]=[C:91]([S:94]([C:97]4[CH:102]=[CH:101][CH:100]=[C:99]([C:103](=[O:113])[N:104]([CH3:112])[CH2:105][CH2:106][CH2:107]CCC=O)[CH:98]=4)(=[O:96])=[O:95])[CH:92]=3)[N:87]=[CH:86][C:85]=2[C:115]([NH2:117])=[O:116])[CH:80]=[CH:81][CH:82]=1>>[Si:1]([O:8][C@H:9]([C:63]1[C:68]2[O:69][CH2:70][C:71](=[O:73])[NH:72][C:67]=2[C:66]([OH:74])=[CH:65][CH:64]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:107][CH2:106][CH2:105][N:104]([CH3:112])[C:103]([C:99]1[CH:98]=[C:97]([S:94]([C:91]2[CH:92]=[C:93]3[C:88](=[C:89]([CH3:114])[CH:90]=2)[N:87]=[CH:86][C:85]([C:115]([NH2:117])=[O:116])=[C:84]3[NH:83][C:79]2[CH:80]=[CH:81][CH:82]=[C:77]([O:76][CH3:75])[CH:78]=2)(=[O:96])=[O:95])[CH:102]=[CH:101][CH:100]=1)=[O:113])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c7ccc(O)c8c7OCC(=O)N8)cc6)cc5)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCCCCC=O)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6c5OCC(=O)N6)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described in Intermediate 151, using Intermediate 114 in place of Intermediate 124. ES/MS calcd. C48H60N6O9SSi 942.4. Found m/z=925 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[CH2:26][N:25]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[CH2:24][CH2:23][CH2:22][C:21]=4[CH:35]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>CCOCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[CH2:26][N:25]([CH2:27][C:28]([OH:30])=[O:29])[CH2:24][CH2:23][CH2:22][C:21]=4[CH:35]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(CC(=O)OC(C)(C)C)C4)no2)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(CC(=O)O)C4)no2)cc1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
1,1-Dimethylethyl [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]acetate (Preparation 8) (65 mg, 0.131 mmol) was treated with HCl (1305 μl, 5.22 mmol) (4N in dioxan) and left standing for 2 hours. The reaction mixture was then warmed at 50° C. for 1 hour then heated at 60° C. for a further 1.25 hours before solvent removal by evaporation. Trituration with ether/EtOAc failed and the material obtained was purified by MDAP. A white solid (20 mg) was obtained freeze drying appropriate MDAP fractions. Further drying under vacuum at 70° C. for 16 hours yielded the title compound (16 mg) as a solid. δH (400 MHz, d6DMSO) 1.36 (6H, d), 1.51-1.53 (2H, m), 2.98-3.00 (2H, m), 3.4 (2H, br.s), 4.10 (2H, s), 4.86-4.92 (1H, m), 7.32 (1H, d), 7.44 (1H, d), 7.83-7.88 (2H, m), 8.11 (1H, dd), 8.18 (1H, d); MS (ES) C23H2435ClN3O4 requires 441; found 442 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([NH2:19])=[O:18].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](OC)=O)=[CH:23][CH:22]=1.[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[NH:19][C:17](=[O:18])[C:3]3[C:4]([CH3:16])=[N:5][N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[C:2]=3[N:1]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: CCCCCCC(CC)n1nc(C)c(C(N)=O)c1N
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CC)n1nc(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc21
Yield: 34.7 %

Procedure:
10 mg (0.037 mmol) of 5-amino-3-methyl-1-(3-nonyl)-1H-pyrazole-4-carboxamide and 45 mg (0.274 mmol) of methyl 4-aminophenylacetate are refluxed for 6 hours in 0.5 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 4.9 mg (35%) of a solid, Rf=0.45 (dichloromethane/methanol=15:1).
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:12])[CH2:4][CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.[NH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:16][C:15]=1[S:25]([NH2:28])(=[O:27])=[O:26]>Cl>[ClH:20].[CH3:1][NH:2][CH:3]([CH3:12])[CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2([NH:13][C:14]3[CH:19]=[C:18]([Cl:20])[C:17]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:16][C:15]=3[S:25](=[O:27])(=[O:26])[NH:28]2)[CH2:7][CH2:6]1
Reactant: CNC(C)CC1CCC(=O)CC1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1S(N)(=O)=O
Agent: Cl
Product: CNC(C)CC1CCC2(CC1)Nc1cc(Cl)c(S(N)(=O)=O)cc1S(=O)(=O)N2

Procedure:
A mixture of 4-(2-methylaminopropyl) cyclohexanone (4.0 g., 0.024 mole) and 4-amino-6-chloro-1,3-benzenedisulfonamide (4.4 g., 0.0154 mole) in 2 N ethanolic HCl (75 ml.) is refluxed for one hour and cooled to give 7.0 g. of 4'-(2-methylaminopropyl)-6-chlorospiro[2H-1,2,4-benzothiadiazine-3(4H)-1'-cyclohexane]-7-sulfonamide-1,1-dioxide hydrochloride which melts at 296° C.
Reaction SMILES: [CH3:1][N:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2Cl)[CH:6]=1)=[O:4].[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH2:32])=[CH:27][CH:26]=2>>[CH3:1][N:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[NH:32][C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH3:22])=[CH:31]3)[CH:6]=1)=[O:4]
Reactant: CN(Cc1ccccn1)C(=O)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N(C)Cc5ccccn5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid methyl-pyridin-2-ylmethyl-amide and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 428 (MH+); HPLC Rf: 4.30 min.; HPLC purity: 97%.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C(Cl)(=O)C(Cl)=O.Cl.[CH3:32][NH:33][O:34][CH3:35].C(N(CC)CC)C>ClCCl>[CH3:35][O:34][N:33]([CH3:32])[C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CNOC
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)N(C)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoic acid (31.0 g, 95.3 mmol) in dichloromethane (200 mL) in an ice bath was added oxalyl chloride (21.9 g, 172 mmol) dropwise over a 30 minute period. The reaction mixture was then stirred for one hour at room temperature then concentrated under reduced pressure, and dichloromethane (400 mL) and N,O-dimethylhydroxylamine hydrochloride (18.6 g, 190 mmol) were added to the residue followed by the dropwise addition of triethylamine (38.5 g, 380 mmol). After stirring at room temperature overnight, the reaction mixture was washed successively with a saturated aqueous sodium bicarbonate solution and brine (100 mL each), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide N-methoxy-N-methyl-6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanamide (28.0 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:45])([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=1[OH:44])[CH2:3][N:4]1[C:9](=[O:10])[N:8]([CH2:11][C:12]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[OH:22])([CH3:14])[CH3:13])[C:7](=[O:23])[N:6]([CH2:24][C:25]([C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=2[OH:35])([CH3:27])[CH3:26])[C:5]1=[O:36].OS(O)(=O)=O>[N+](C1C=CC=CC=1)([O-])=O.C(OCC)(=O)C>[CH3:14][C:12]([CH3:13])([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([C:12]([CH3:14])([CH3:13])[CH3:11])[C:16]=1[OH:22])[CH2:11][N:8]1[C:7](=[O:23])[N:6]([CH2:24][C:25]([C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([C:2]([CH3:1])([CH3:3])[CH3:37])[C:29]=2[OH:35])([CH3:26])[CH3:27])[C:5](=[O:36])[N:4]([CH2:3][C:2]([C:37]2[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([C:19]([CH3:21])([CH3:20])[CH3:18])[C:38]=2[OH:44])([CH3:45])[CH3:1])[C:9]1=[O:10]
Reactant: Cc1ccc(O)c(C(C)(C)Cn2c(=O)n(CC(C)(C)c3cc(C)ccc3O)c(=O)n(CC(C)(C)c3cc(C)ccc3O)c2=O)c1
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)Cn2c(=O)n(CC(C)(C)c3cc(C)cc(C(C)(C)C)c3O)c(=O)n(CC(C)(C)c3cc(C)cc(C(C)(C)C)c3O)c2=O)c1
Temperature: 90 °C
Yield: 102.1 %

Procedure:
To a 50 ml 3-neck round bottom flask is charged 2 g product of Example 2 in 10 ml nitrobenzene. 0.1 ml H2SO4 is added and isobutylene is bubbled through the solution while warming to 90° C. After TLC shows the reaction to be complete, the mixture is diluted with an equal volume of ethyl acetate and washed 2 times with 50 ml 5% sodium bicarbonate. The organic layer is dried and concentrated in vacuo. The residue is purified by dry column chromatography (Et2O/hexane) to yield 1.3 g of product, mp 215°-217° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1.[CH2:16](Br)[CH:17]=[CH2:18]>>[CH2:18]([O:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: CCC(=O)c1cc2c(cc1O)CCCC2
Product: C=CCOc1cc2c(cc1C(=O)CC)CCCC2
Yield: 108.4 %

Procedure:
The product of step (b) (14.5 g) was treated with allyl bromide (11.5 g) under the conditions of Example 1(a) to give the title compound (18.8 g) as a pale brown oil, whose structure was confirmed by MS and NMR spectroscopy.
Reaction SMILES: O1CCCC1.O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].[O:27]1[CH2:31][CH:30]=[CH:29][C:28]1=[O:32]>O>[O:32]=[C:28]1[O:27][CH2:31][CH:30]([CH2:20][C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:29]1
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C1C=CCO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CC1COC(=O)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Tetrahydrofuran (50 mL) and Lithium diisopropylamide mono tetrahydrofuran complex (20 mL of 1.5 M in cyclohexane) was cooled in a dry ice/Isopropanol bath for 10 min. Tert-butyl acetate (3.5 mL 26 mmoles) was added via syringe and stirred at −78° C. for 30 min. 2(5H)-Furanone (1.59 g, 19 mmoles) was added dropwise and the reaction was stirred for 1 h at −78° C. The reaction was poured into water and extracted with ether 2×150 mL The ether extracts were combined and washed with water 100 mL then brine 3×100 mL, dried and the ether removed under reduced pressure to give 2.74 g of product (72%). MS (ESI+) for C10H16O4 m/z 223 (M+Na)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:47])[C:22]1[CH:27]=[CH:26][C:25](Br)=[C:24]([S:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:39][Si](C(C)(C)C)(C)C)(=[O:31])=[O:30])[CH:23]=1>C1COCC1>[CH3:19][O:20][C:21]([C:22]1[CH:27]=[CH:26][C:25]2[O:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][S:29](=[O:31])(=[O:30])[C:24]=2[CH:23]=1)=[O:47]
Reactant: COC(=O)c1ccc(Br)c(S(=O)(=O)Cc2ccccc2O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)Cc1ccccc1O2
Reaction time: 1 h

Procedure:
Tetra-n-butylammonium fluoride (0.693 g, 2.2 mol) in THF (15 mL) was added dropwise to a solution of Example 1g (0.55 g, 1.1 mmol) in dry THF (5 mL) at 0° C. The reaction mixture was stirred for 1 h and treated with crushed ice to obtain the title compound as a solid. It was filtered, washed with water and dried. Yield: 0.25 g, (75%); 1H NMR (CDCl3): δ 3.90 (s, 3H, OCH3), 4.60 (s, 2H, CH2), 7.30-7.40 (m, 5H, Ar), 8.20 (d, 1H, Ar), 8.60 (d, 1H, Ar);
Reaction SMILES: [N+]([C:4]1C=C(N)C=C[C:5]=1C(O)=O)([O-])=O.[F:14][C:15]1[C:23]([F:24])=[C:22]([NH2:25])[C:21]([F:26])=[C:20]([F:27])[C:16]=1[C:17]([OH:19])=[O:18].C(O)C.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:14][C:15]1[C:23]([F:24])=[C:22]([NH2:25])[C:21]([F:26])=[C:20]([F:27])[C:16]=1[C:17]([O:19][CH2:4][CH3:5])=[O:18]
Reactant: Nc1c(F)c(F)c(C(=O)O)c(F)c1F
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1c(F)c(F)c(N)c(F)c1F

Procedure:
Thus, in accordance with Reaction Scheme 6, 3-nitro-6-methyl-fluorobenzene (Aldrich) is subjected to oxidation, conversion of the resulting carboxylic acid to an acid chloride and thereafter to an ethyl ester, followed by reduction of the nitro group, to yield ethyl 2-fluoro-4-amino-benzoate (Compound C1)- 3-Nitro-6-methyl-bromobenzene (Aldrich) and 3-nitro-6-methyl-chlorobenzene (Aldrich) are subjected to essentially to the same series of reactions to yield ethyl 2-bromo-4-amino-benzoate (Compound D1) and ethyl 2-chloro-4-amino-benzoate (Compound E1), respectively. 2-Nitro-4-aminobenzoic acid (Research Plus) is converted to its methyl ester (Compound F1) through the corresponding acid chloride. 2,3,5,6-Tetrafluoro-4-amino-benzoic acid (Aldrich) is esterified by treatment with ethanol in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine in CH2Cl2 to give ethyl 2,3,5,6-tetrafluoro-4-amino-benzoate (Compound G1). 2,4,6-Trifluorobenzoic acid (Aldrich) is converted to the methyl ester through the acid chloride, and the 4-fluoro atom is displaced by reaction with sodium azide, followed by hydrogenation, to yield methyl 2,6-difluoro-4-amino benzoate (Compound H1). Compounds C1, D1, E1, F1, G1 and H1 serve as amine reagents in accordance with Formula 3. Further examples of reagents in accordance with Formula 3 are nitro, fluoro, chloro, bromo and trifluoromethyl derivatives of amino substituted heteroaryl carboxylic acids, or their lower alkyl esters, such as ethyl 2-amino-4-chloropyridine 2-carboxylate, ethyl 5-amino-3-chloropyridine 5-carboxylate, and 3,4-dibromo-5-aminothiophene-2-carboxylic acid. The latter examples can be prepared by respective chlorination or bromination of 2-aminopyridine-5-carboxylic acid or of its ester, 3-aminopyridine-6-carboxylic acid or of its ester (described in WO 93/06086) and of 2-aminothiophene-5-carboxylic acid (described in PCT/US92/06485).