Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[CH:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([OH:17])[CH:11]=1.[C:18]([O-:21])(=O)[CH3:19].[Na+]>C(C(C)=O)C>[OH:17][C:12]1[CH:13]=[CH:14][C:15]([NH:16][C:2]2[N:4]=[C:5]([NH:16][C:15]3[CH:14]=[CH:13][C:12]([OH:17])=[CH:11][CH:10]=3)[N:7]=[C:8]([NH:16][C:15]3[CH:10]=[CH:19][C:18]([OH:21])=[CH:13][CH:14]=3)[N:1]=2)=[CH:10][CH:11]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(O)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: Oc1ccc(Nc2nc(Nc3ccc(O)cc3)nc(Nc3ccc(O)cc3)n2)cc1
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
In a 300 ml three-neck flask equipped with a stirrer, a thermometer and a dropping funnel, 3.68 g (0.02 mol) of cyanuric chloride was dissolved in 60 ml of methyl ethyl ketone. Subsequently, 6.55 g (0.06 mol) of p-aminophenol was added slowly to the solution at an inner temperature not higher than 5° C. After the addition, the solution was stirred for 30 minute, and 30 ml of an aqueous solution of 4.92 g (0.06 mol) sodium acetate was added dropwise to the solution with keeping an inner temperature of 10° C. After the dropwise addition, the solution was stirred for 30 minutes at room temperature and was reacted with refluxing for 3 hours. During the reaction, the mixed solvent of methyl ethyl ketone and water was separated into two phases. When the reaction was complete, the reaction solution was poured into 500 ml of ice water to be crystallized. After the filtration, the obtained crystal was washed once with a weakly alkaline solution and twice with 500 ml of water, and dried, to give 7.6 g of a target compound in a 95% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH2:13]Br)=[CH:11][CH:12]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH3:18])[N:3]=1.[OH2:19]>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH2:13][OH:19])=[CH:11][CH:12]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH3:18])[N:3]=1
Reactant: O
Reactant: CSc1nc(N)nc(-c2ccc(CBr)o2)c1C#N
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: CSc1nc(N)nc(-c2ccc(CO)o2)c1C#N
Reaction time: 16 h
Yield: 35 %

Procedure:
To a stirred suspension of 100 mg (0.31 mmol) 2-amino-4-(5-bromomethyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile in 5 ml water and 5 ml acetone was added 104 mg (0.61 mmol) silver nitrate and stirring continued for 16 h at room temperature in the dark. The reaction mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate and water. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Chromatography (1/1 ethyl acetate/hexane then acetone) afforded 28 mg (35%) 2-amino-4-(5-hydroxymethyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile e as an orange crystalline solid. EI-MS m/e (%): 262 (M+, 100), 261 ([M—H]+, 90).
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[S:25][C:24]([C:26]3([O:37]COC)[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)=[N:23][CH:22]=2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.CO.Cl>[Cl-].[Na+].O.C(OCC)(=O)C>[F:1][C:2]1[C:3]([C:21]2[S:25][C:24]([C:26]3([OH:37])[CH2:29][NH:28][CH2:27]3)=[N:23][CH:22]=2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(F)cnc4c3ccn4S(=O)(=O)c3ccc(C)cc3)s2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cnc(C5(O)CNC5)s4)c(F)cnc32)cc1
Temperature: 60 °C

Procedure:
A flask was charged with tert-butyl 3-(5-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)-3-(methoxymethoxy)azetidine-1-carboxylate (Example 54B) (500 mg, 0.849 mmol), methanol (6.5 mL) and aqueous 2 molar HCl solution (2.58 mL, 8.49 mmol). The reaction mixture was heated to 60° C. for 5 hours, then 35° C. overnight. The reaction mixture was cooled to room temperature and diluted with saturated aqueous brine solution and ethyl acetate. The layers were separated, and the aqueous layer extracted with ethyl acetate (3×20 mL). The organic layers were combined and concentrated. The remaining solid was triturated with water (pH approximately 10). The solids were collected by vacuum filtration, washed with water, and dried at low temperature in a vacuum oven to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (d, 1H), 8.40 (s, 1H), 8.10 (d, 1H), 8.01 (d, 2H), 7.44 (d, 2H), 7.14 (d, 1H), 7.06 (s, 1H), 3.96 (d, 2H), 3.71 (d, 2H), 2.35 (s, 3H); MS APCI(+) m/z 445.22 (M+H)+.
Reaction SMILES: C[O-].[Na+].Cl.[CH3:5][NH:6][OH:7].[CH3:8][C:9](=[CH2:20])[CH2:10][N:11]([CH2:17][CH:18]=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].O>CO.C1(C)C=CC=CC=1>[CH3:5][N:6]1[O:7][CH2:8][C:9]2([CH3:20])[CH:18]1[CH2:17][N:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10]2
Reactant: C=C(C)CN(CC=O)C(=O)OCC
Reactant: CNO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CCOC(=O)N1CC2N(C)OCC2(C)C1

Procedure:
21.7 g of 30% strength sodium methylate solution are added dropwise to 10 g (0.12 mol) of N-methylhydroxylamine hydrochloride in 26 ml of methanol. The sodium chloride is filtered off with suction and washed with 8 ml of methanol and 80 ml of toluene. This solution is added dropwise to 19.2 g (0.11 mol) of N-(2-methyl-prop-2-enyl)-N-(2-oxoethyl)-urethane, which is heated under reflux in 160 ml of toluene using a water separator. The mixture is heated under reflux overnight, the product is extracted with 160 ml of 10% strength hydrochloric acid and the hydrochloric acid solution is rendered alkaline with potassium carbonate and extracted with six portions, of 200 ml of CHCl3. The extracts are dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:15](N)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O[N:24]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C>[CH2:15]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([OH:1])[C:3]([C:12]([NH2:24])=[O:14])=[CH:4][CH:5]=2)[N:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: On1nnc2ccccc21
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2ccc(Cc3ccccc3)nc2c1O
Temperature: 80 °C

Procedure:
A mixture of 8-hydroxyquinoline-7-carboxylic acid (0.50 g, 2.64 mmol), benzylamine (0.34 g, 3.17 mmol), 1-hydroxybenzotriazole (0.45 g, 2.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.56 g, 2.91 mmol), and triethylamine (1.6 mL, 11.6 mmol) in DMF (15 mL) was heated at 80° C. overnight. The reaction mixture was concentrated under vacuum. The residue was dissolved in methanol and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provide the title compound as yellow solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@@H:10]([C:12]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:30])[NH:17]2)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Br[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([S:58]([CH:61]2[CH2:65][CH2:64][CH2:63][CH2:62]2)(=[O:60])=[O:59])[CH:53]=1>CC#N.O>[CH:61]1([S:58]([C:54]2[CH:53]=[C:52]([CH2:51][CH2:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][C@@H:10]([C:12]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:18]4[C:13]=3[CH:14]=[CH:15][C:16](=[O:30])[NH:17]4)[OH:11])[CH:57]=[CH:56][CH:55]=2)(=[O:60])=[O:59])[CH2:65][CH2:64][CH2:63][CH2:62]1
Reactant: O=c1ccc2c([C@@H](O)CNCc3ccccc3)ccc(OCc3ccccc3)c2[nH]1
Reactant: O=S(=O)(c1cccc(CCCCOCCCCCCBr)c1)C1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: O=c1ccc2c([C@@H](O)CN(CCCCCCOCCCCc3cccc(S(=O)(=O)C4CCCC4)c3)Cc3ccccc3)ccc(OCc3ccccc3)c2[nH]1
Yield: 25.2 %

Procedure:
5-[(1R)-2-(Benzylamino)-1-hydroxyethyl]-8-(benzyloxy)quinolin-2(1H)-one (40 mg) was dissolved in MeCN (2 ml). N,N,-diisopropylethylamine (0.03 ml) and 1-{4-[(6-bromohexyl)oxy]butyl}-3-(cyclopentylsulfonyl)benzene (Example 1v) (30 mg) were added and the reaction mixture was heated at 80° under nitrogen for 48 h. The mixture was then diluted with water and extracted with EtOAc. The organic phases were combined, dried (MgSO4), and evaporated in vacuo. The residue was purified on a silica SPE bond elut cartridge, eluting with EtOAc-cyclohexane mixtures, to give the title compound, (13 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH:18][CH3:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:6].[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[N:31]=[C:32]=S)[C:24]([O:26][CH3:27])=[O:25].C(Cl)CCl>CN(C=O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[CH:15]=[CH:16][C:17]3[N:18]([CH3:19])[C:32]([NH:31][C:30]4[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=4[Cl:20])=[N:1][C:2]=3[CH:3]=2)=[O:6])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(N=C=S)c(Cl)c1
Reactant: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1N
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1ccc(Nc2nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3n2C)c(Cl)c1

Procedure:
Prepared analogously to example 106a from 3-amino-N-(4-bromophenyl)-4-(methylamino)-benzamide and methyl 3-chloro-4-isothiocyanatobenzoate in DMF with EDC.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.C(O)CCC.[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)#[N:14]>CN(C)C=O>[CH2:7]([O:3][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([C:13]#[N:14])=[CH:16][CH:17]=1)[CH2:6][CH2:5][CH3:4]
Reactant: C1CCOC1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCO
Product: CCCCOCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
To a mixture of sodium hydride (270 mg, 11 mmol, 66% in oil) and tetrahydrofuran (20 mL) was added n-butanol (1.1 mL, 12 mmol) at 0° C., which was stirred for 45 minutes at room temperature. The reaction mixture was cooled to 0° C., and a mixture of 4-cyanobenzyl bromide (1.5 g, 7.4 mmol) and tetrahydrofuran (10 mL) was added dropwise at that temperature. The reaction mixture was stirred for 3 hours at room temperature, and N,N-dimethylformamide (10 mL) was added to the reaction mixture and stirred for further 4.5 hours at the same temperature. The reaction mixture was partitioned into water and diethyl ether. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:6) to obtain the title compound (1.2 g, 84%).
Reaction SMILES: [C:1]12[C:14](=[O:15])[O:13][C:11](=O)[C:2]=1[CH2:3][CH2:4][C:5]1[C:10]2=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:16]([CH2:18][NH2:19])[OH:17]>C(O)(=O)C>[OH:17][CH2:16][CH2:18][N:19]1[C:11](=[O:13])[C:2]2[CH2:3][CH2:4][C:5]3[C:10]([C:1]=2[C:14]1=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: NCCO
Reactant: O=C1OC(=O)C2=C1CCc1ccccc12
Solvent: CC(=O)O
Product: O=C1C2=C(C(=O)N1CCO)c1ccccc1CC2

Procedure:
A solution of 70 g (0.35 mol) of 3,4-dihydronaphthalene-1,2-dicarboxylic acid anhydride [prepared according to Org. Syntheses, Col., Vol. 2, 194 (1943)] and 23.5 g (0.385 mol) of ethanolamine in 1.7 liters of glacial acetic acid is kept under reflux for 24 hours. The glacial acetic acid is then removed by distillation, the residue is dissolved in 2 liters of absolute ethanol, 50 g of an ion exchanger ("Dowex 50 W" from Fluka AG) are added and the suspension is kept under reflux for 24 hours. The ion exchanger is then filtered off, the ethanol is distilled off and the residue is recrystallised from diethyl ether/ethanol. This yields 61.8 g (73% of theory) of N-(2'-hydroxyethyl)-3,4-dihydronaphthalene-1,2-dicarboximide; melting point 120.5°-121° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:13][CH3:14])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:12][C:10]1[CH:11]=[C:2]([NH:1][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[C:3]([CH2:13][CH3:14])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCOCC1
Reactant: CCc1c(N)cc(Cl)cc1C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1c(NC2CCOCC2)cc(Cl)cc1C(=O)OC
Reaction time: 20 h

Procedure:
To a solution of methyl 3-amino-5-chloro-2-ethylbenzoate (1.5 g, 7.02 mmol) in 1,2-dichloroethane (28 ml) at room temperature under nitrogen was added oxan-4-one (1.3 ml, 14. mmol) followed by acetic acid (2.41 ml, 42 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (4.46 g, 21 mmol) at room temperature. After stirring for 20 hours, deionized water (28 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×28 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 8:2 Heptane:EtOAc) to give 1.76 g of crude methyl 5-chloro-2-ethyl-3-[(oxan-4-yl)amino]benzoate as a white solid. The material was taken through the next step without further purification. LC-MS 60%, m/z=298.0/300.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.07 (d, J=2.0 Hz, 1H), 6.71 (d, J=1.9 Hz, 1H), 4.01 (dt, J=11.8, 3.4 Hz, 2H), 3.87 (s, 3H), 3.82-3.76 (m, 1H), 3.64-3.47 (m, 3H), 2.79-2.63 (m, 2H), 2.06 (d, J=13.2 Hz, 2H), 1.55-1.46 (m, 2H), 1.18 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.O>[N:33]([CH2:21][C@@H:20]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[N+:34]=[N-:35]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Yield: 78.3 %

Procedure:
(R)-8-(Benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)quinolin-2(1H)-one (5.0 g, 10.2 mmol) was dissolved in dimethyl formamide (90 mL) and water (10 mL). Sodium iodide (1.7 g, 11.3 mmol) and sodium azide (0.7 g, 11.3 mmol) were added sequentially. The reaction mixture was stirred at RT until all the solid was in solution. The solution was heated at 80° C. for 40 hours and then cooled to RT and diluted with water (300 mL). The aqueous layer was extracted with DCM, and the combined organic extracts were dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The crude residue was recrystallised from ethyl acetate and iso-hexane to afford the desired compound (3.6 g, 78%), which was used without further purification in the next step.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]([CH3:71])[N:68]=[N:69][CH:70]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[N:67]([CH3:71])[N:68]=[N:69][CH:70]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: Cn1nncc1SCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: COc1ccccc1
Product: Cn1nncc1SCC1=C(C(O)=S)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(3-methyl-1,2,3-triazol-4-yl) thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (900 mg: 0.869 mMol.) in a mixture of anisole (4 ml) and nitromethane (16 ml) is added a solution of aluminum chloride (924 mg: 6.95 mMol.) in anisole (2 ml) at -40° C., and the mixture is stirred for 1 hour at -40°--30° C. The reaction mixture is diluted with 1N-hydrochloric acid (7 ml) and water and washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure to remove organic solvent and passed through a column of styrene-divinylbenzene copolymer adsorbent. The product is eluted with methanol-water (4:1) to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(3-methyl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid as pale yellow powder (366 mg). Yield: 80%.
Reaction SMILES: O.[OH-].[Li+].O.C([O:7][C:8]([C:10]1[CH:11]=[N:12][N:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19]4[CH2:28][CH2:27][CH2:26][C:20]=4[CH:21]=3)[N:16]=2)[CH:14]=1)=[O:9])C.C([O:31][C:32]([C:34]1[CH:35]=[N:36][N:37]([C:39]2[NH:48][C:47](=[O:49])[C:46]3[C:45]4[CH2:50][CH2:51][CH2:52][C:44]=4[CH:43]=[CH:42][C:41]=3[N:40]=2)[CH:38]=1)=[O:33])C>C1COCC1>[O:25]=[C:23]1[C:22]2[C:21]3[CH2:20][CH2:26][CH2:27][C:28]=3[CH:19]=[CH:18][C:17]=2[N:16]=[C:15]([N:13]2[CH:14]=[C:10]([C:8]([OH:7])=[O:9])[CH:11]=[N:12]2)[NH:24]1.[O:49]=[C:47]1[C:46]2[C:41](=[CH:42][C:43]3[CH2:44][CH2:52][CH2:51][C:50]=3[CH:45]=2)[N:40]=[C:39]([N:37]2[CH:38]=[C:34]([C:32]([OH:31])=[O:33])[CH:35]=[N:36]2)[NH:48]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)CCC4)c1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc4c(c3c(=O)[nH]2)CCC4)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)CCC4)c1
Product: O=C(O)c1cnn(-c2nc3ccc4c(c3c(=O)[nH]2)CCC4)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
Lithium hydroxide monohydrate (0.611 g, 14.6 mmol) and water (9.1 mL) were added to a 10:1 mixture of 1-(4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester and 1-(1-oxo-2,7,8,9-tetrahydro-1H-cyclopenta[f]quinazolin-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.18 g, 0.228 mmol) in THF (13.6 mL) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was redissolved in water (20 mL). This solution was brought to pH 1 with 1M aqueous HCl. The resulting precipitate was collected and dried to yield a 10:1 mixture of the titled compound and 1-(1-oxo-2,7,8,9-tetrahydro-1H-cyclopenta[f]quinazolin-3-yl)-1H-pyrazole-4-carboxylic acid (1.05 g, 98% yield). A portion of the precipitate (0.511 g) was triturated twice from 10 mL DMSO to yield a pure sample of the titled compound (0.310 g, 61% recovery). MS (ESI/Cl): mass calcd. for C15H12N4O3, 296.1; m/z found, 297.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.00 (s, 1H), 12.68 (s, 1H), 8.93 (s, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.52 (s, 1H), 3.05-2.93 (m, 4H), 2.09 (p, J=7.4 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:27]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:28])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C1CCCCC1
Yield: 76.2 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with cyclohexanecarbonyl chloride (0.55 mL, 4.1 mmol) to provide 1.07 g of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclohexanecarboxamide as an off white solid, m.p. 191.6-192.6° C. Analysis: Calculated for C22H29N5O.0.25H2O: % C, 68.81; % H, 7.74; % N, 18.24; Found: % C, 68.85; % H, 7.75; % N, 17.95.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)[CH:10]=[CH:9]1>>[CH3:34][CH:32]([CH3:33])[C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]2[CH2:20][CH2:19][N:18]([CH2:17][C:15]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:16]=3[N:8]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=[CH:10]4)[CH2:23][CH2:22]2)[CH:25]=1)=[O:35]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4cc[nH]c34)CC2)c1
Reactant: Ic1cccnc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4ccn(-c5cccnc5)c34)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 3-iodopyridine and N-{3-[1-(1H-indol-7-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 453.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:9]([O:11][C@H](C1C=CC=CC=1)C)=[O:10]>C(O)C.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:9]([OH:11])=[O:10]
Reactant: C[C@H](OC(=O)[C@@H](c1ccccc1F)N1CCCCC1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H](c1ccccc1F)N1CCCCC1
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A mixture of (R)-((S)-1-phenylethyl) 2-(2-fluorophenyl)-2-(piperidin-1-yl)acetate (0.737 g, 2.16 mmol) and 20% Pd(OH)2/C (0.070 g) in ethanol (30 mL) was hydrogenated at room temperature and atmospheric pressure (H2 balloon) for 2 hours. The solution was then purged with Ar, filtered through diatomaceous earth (Celite®), and concentrated in vacuo. This provided the title compound as a colorless solid (0.503 g, 98%). 1H NMR (400 MHz, CD3OD) δ 7.65 (ddd, J=9.1, 7.6, 1.5 Hz, 1H), 7.47-7.53 (m, 1H), 7.21-7.30 (m, 2H), 3.07-3.13 (m, 4H), 1.84 (br s, 4H), 1.62 (br s, 2H). LCMS: Anal. Calcd. for C13H16FNO2: 237; found: 238 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[S:11][C:10]3[CH:12]=[C:13]([O:16]C)[CH:14]=[CH:15][C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:18]1([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:1]1([C:7]2[S:11][C:10]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:9]=3[C:8]=2[C:31]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:35][CH:34]=2)=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2cc(C3CCCCC3)sc2c1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(C2CCCCC2)sc2cc(O)ccc12

Procedure:
The product from Example 19, Step 2 and 4-(2-Piperidin-1-yl-ethoxy)-benzoyl chloride were coupled according to procedure C above and the methyl protecting group removed using etanethiol/aluminum trichloride to yield the title compound.
Reaction SMILES: [C:1]1(C)C(C)=CC=CC=1.[CH3:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11]>>[CH3:1][CH2:16][O:15][CH2:14][CH2:13][O:12][C:10]([CH3:9])=[O:11].[C:10]1(=[O:11])[O:12][CH2:13][CH2:14][CH2:9]1
Reactant: Cc1ccccc1C
Reactant: COCCOC(C)=O
Product: CCOCCOC(C)=O
Product: O=C1CCCO1

Procedure:
When the polyamide-imide resin obtained in this invention is made into a varnish, there may be used, as co-solvents, xylene, NISSEKI HISOL-100, 150 (trade names, mfd. by Nippon Petrochemicals Co., Ltd., aromatic hydrocarbons obtained from petroleum, b.p. 80°-300° C.), methyl Cellosolve acetate, ethyl Cellosolve acetate, γ-butyrolactone and the like in combination with the basic organic solvents described above.