Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[N:12]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)=O.O>O1CCCC1>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:12]2[C:13]3[C:18](=[CH:17][C:16]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:15][CH:14]=3)[CH:19]=[C:11]2[CH2:9][OH:8])=[CH:26][CH:27]=1
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2n1Cc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2c(c1)cc(CO)n2Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
To a solution of lithium aluminum hydride (366 mg) in tetrahydrofuran (20 ml), a solution of 1-(4-fluorobenzyl)-5-methanesulfonylindole-2-carboxylic acid methyl ester obtained in Example 27 (3) (1.86 g) in tetrahydrofuran (20 ml) was added dropwise at 0° C. under nitrogen atmosphere and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was poured into water, filtered through Celite and extracted with chloroform. The organic layer was washed with water and dried. The solvent was distilled off under reduced pressure to obtain (1-(4-fluorobenzyl)-5-methanesulfonylindol-2-yl)-methanol (1.8 g). To a solution of the resulting alcohol (1.8 g) in dichloromethane (100 ml) was added manganese dioxide (15.3 g) at 15 to 30° C. and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was filtered through Celite. The solvent was distilled off under reduced pressure to obtain 1.5 g (88.4%) of the desired product as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Cl)nc(OC)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a previously sonicated suspension of 2-chloro-6-methoxyisonicotinic acid (4.0 g, 21 mmol) in ethanol (50 mL) was added thionyl chloride (4.64 mL, 64.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and then at room temperature for 18 h. Thionyl chloride (4.64 mL, 64.0 mmol) was slowly added and the mixture was stirred at room temperature for 4 h. The reaction mixture was quenched by slowly pouring into a saturated aqueous solution of sodium bicarbonate (200 mL). Ice was added to the mixture to lower the temperature. The mixture was extracted with diethyl ether (150 mL×2). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a clear syrup as crude product. The crude product was dried for 2 h under high vacuum while heating to 80° C. The resulting residue was concentrated from toluene (500 mL) to afford ethyl 2-chloro-6-methoxyisonicotinate as an off white solid (3.205 g). 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 3H), 3.98 (s, 3H), 4.39 (s, 2H), 7.22 (s, 1H), 7.44 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](C=O)[C:5]([Cl:10])=[CH:4][N:3]=1.[CH:11](OC)([O:14][CH3:15])[O:12][CH3:13]>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C:5]([Cl:10])=[CH:4][N:3]=1
Reactant: O=Cc1cc(Br)ncc1Cl
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(OC)c1cc(Br)ncc1Cl
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a sol. of 2-bromo-5-chloro-pyridine-4-carbaldehyde (43.9 g, 199 mmol) in MeOH (800 mL) were successively added at rt trimethyl orthoformate (65.3 mL, 597 mmol) and p-toluenesulfonic acid monohydrate (1.90 g, 10.0 mmol). This reaction mixture was then heated to reflux for 3 h. The mixture was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and this mixture was washed with aq. 10% K2CO3. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying under high vacuum yielded the title compound (51.7 g, 97%). LC-MS: tR=0.92 min; ES+: 309.06.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:21][C:22](=O)CC(=O)C.C([O-])(O)=O.[Na+]>C(O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:6]([F:12])[C:7]2[N:11]=[C:21]([CH3:22])[NH:10][C:8]=2[CH:9]=1)=[O:20]
Reactant: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc2[nH]c(C)nc2c(F)c1Nc1ccccc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
4,5-Diamino-3-fluoro-2-phenylamino-benzoic acid methyl ester 6c (0.20 g, 0.73 mmol) is suspended in ethanol (3 mL) and 5 M aqueous NCl (1 mL, 5.00 mmol) is added. The reaction mixture is brought to reflux under N2 and then 2,4-pentanedione (0.150 mL, 1.45 mmol) is added. The reaction mixture is stirred at reflux for 60 minutes. The reaction mixture is cooled to room temperature and treated with saturated aqueous NaHCO3 until the pH of the reaction mixture is pH 7 and is then concentrated under reduced pressure to dryness. The residue is diluted with ethyl acetate and water, poured into a separatory funnel and the layer separated. The ethyl layer is washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The red solid residue is triturated with diethyl ether to yield a light brown solid and red filtrate. The solid is collected and washed with diethyl ether to yield 0.20 g (91%) of the pure desired product as a light brown solid. MS ESI (+) m/z 300 (M+1) detected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[NH:19][CH2:18][CH:15]1[CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[C:17]=2[O:16]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccccc1-c1cccc2c1OC(CN)C2
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1cccc2c1OC(CNC(=O)OCc1ccccc1)C2
Yield: 83.9 %

Procedure:
Treatment of (±)-1-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.296 g, 1.01 mmol) with diisopropylethylamine (1.52 g, 1.5 mmol) and benzyl chloroformate (0.190 g, 1.11 mmol) generally according to the procedure described for Intermediate 12 afforded 0.33 g (84%) (±)-benzyl[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate of a colorless oil Rf=0.72 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C24H23NO4: C, 74.02; H, 5.95; N, 3.6. Found: C, 73.68H, 5.81; N, 3.43.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:7])=[O:5].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28]I)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][C:6]([CH3:7])([C:4]([O:3][CH2:2][CH3:1])=[O:5])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ICCc1ccccc1OCc1ccccc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Product: CCOC(=O)C(C)(CCc1ccccc1OCc1ccccc1)C(=O)OCC

Procedure:
2-Methylmalonic acid diethyl eater and 2-(2-benzyloxyphenyl)ethyl iodide were used in the same manner as working example 52 (S) to give the subject compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:25]([NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]=[C:36]=[S:37])[CH2:29][CH2:28]3)=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:12][CH:11]=1>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:8][C:36]([NH:35][CH2:34][CH2:33][N:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:25]2[N:17]([CH2:16][C:13]3[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=3)[C:18]3[C:23]([N:24]=2)=[CH:22][N:21]=[CH:20][N:19]=3)[CH2:28][CH2:29]1)=[S:37]
Reactant: Nc1ccncc1N
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3cncnc32)cc1
Solvent: C1CCOC1
Product: Nc1ccncc1NC(=S)NCCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1

Procedure:
A mixture of 2.95 parts of 3,4-pyridinediamine, 16 parts of 9-[(4-fluorophenyl)methyl]-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-9H-purin-8-amine, and 90 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95/5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 10.5 parts of N-(4-amino-3-pyridinyl)-N'-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]thiourea (compound 182).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33].[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:34]([N:36]([CH2:37][CH3:38])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33])[CH3:35]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCl
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCOc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (68 mg), diethylamine (30 mg), and potassium carbonate (95 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (26 mg, yield 38%).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:16]>C1(C)C=CC=CC=1.CO>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14][CH3:16])=[O:13])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccccc2)on1
Reaction time: 0.5 h

Procedure:
A solution of 5-phenylisoxazole-3-carboxylic acid (0.86 g, 4.55 mmol) in toluene (15.0 mL) and methanol (3 mL) was added a 2M solution of TMS-diazomethane in hexanes (3.1 mL, 6.14 mmol) dropwise at room temperature. The reaction mixture was stirred for 30 minutes and concentrated. The residue was dispersed in methanol (3 mL), stirred for 5 minutes, and filtered to give methyl 5-phenylisoxazole-3-carboxylate (897 mg). The compound had an HPLC ret. time=2.67 min.: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=204+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]([C:28](OC)=[O:29])([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:13]3[C:18]([N:19]([CH3:22])[C:20]=2[CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3.O>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH2:28][OH:29])([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:13]3[C:18]([N:19]([CH3:22])[C:20]=2[CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: COC(=O)C1(CCN(C)C)c2ccccc2N(C)c2cc(Cl)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCC1(CO)c2ccccc2N(C)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
25.7 gm of the fumarate of 3-chloro-9-methoxy-carbonyl-9-(β-dimethylaminoethyl)-10-methyl-acridane were suspended in 250 cc of water and after refrigeration, 25 cc of sodium hydroxide solution were added. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried over magnesium sulfate and distilled to dryness in vacuo to obtain 20 gm of 3-chloro-9-methoxycarbonyl-9-(β -dimethylaminoethyl)-10-methylacridane. First 10 gm of lithium aluminum hydride and then 20 gm of 3-chloro-9-methoxycarbonyl-9-(β-dimethylaminoethyl)-10-methylacridane in solution in 200 cc of tetrahydrofuran were added to 200 cc of cold tetrahydrofuran at a temperature below 10°C and after stirring for 10 minutes at 0°C, it was refluxed for 15 minutes. After cooling the reaction mixture, excess reactants were decomposed by 200 cc of tetrahydrofuran containing 20% of water at a temperature below 10°C. After filtering and distilling the mixture to dryness in vacuo, the residue was dissolved in methylene chloride and the solution was washed with water, dried over magnesium sulfate and distilled to dryness in vacuo. The residue was dissolved in 80 cc of ethyl acetate and the resulting solution was filtered and concentrated to 50 cc after which crystallization began. After being iced for 30 minutes, the mixture was filtered and the precipitate was washed with ethyl acetate and then ether and dried to obtain 14.35 gm of 3-chloro-9-hydroxymethyl-9-(β-dimethylaminoethyl)-10-methyl-acridane melting at 120°C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH:3]=1.[Si]([N:25]=[N+:26]=[N-:27])(C)(C)C>C1(C)C=CC=CC=1>[N:18]1[NH:25][N:26]=[N:27][C:17]=1[C:16]1[CH:19]=[CH:20][C:13]([C:4]2[CH:3]=[C:2]([Cl:1])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(-c2cc(Cl)c3cc(O)ccc3n2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: Oc1ccc2nc(-c3ccc(-c4nn[nH]n4)cc3)cc(Cl)c2c1
Yield: 13.4 %

Procedure:
Followed Scheme 4, route A. To a solution of 4-(4-chloro-6-hydroxyquinolin-2-yl)benzonitrile (65 mg, 0.23 mmol) in toluene (2 mL), was added TMSN3 (455 mg, 4.18 mmol) and Bu2SnO (15 mg, 0.069 mmol) at room temperature. The mixture was heated to reflux overnight. The volatiles were removed under reduced pressure. The residue was purified by prep-HPLC to afford Compound 11 (10 mg, 13.5%). 1H NMR (MeOD-d4, 500 MHz): δ 8.34 (d, J=8.5 Hz, 2H), 8.21 (s, 1H), 8.19 (s, 2H), 8.07 (d, J=9.0 Hz, 1H), 7.51 (d, J=2.5 Hz, 1H), 7.47 (dd, J=2.5 Hz, J=9.5 Hz, 1H). MS (ESI): m/z 324.0 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]([N:10]([C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=2)[C:17]([O:19]CC2C=CC=CC=2)=[O:18])[CH:11]([CH3:13])[CH3:12])=[O:9])[N:6]=[N:5][C:4]=1[C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])#[N:2].[H][H]>CO.[Pd]>[C:1]([C:3]1[N:7]([C:8]([N:10]([C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=2)[C:17]([OH:19])=[O:18])[CH:11]([CH3:13])[CH3:12])=[O:9])[N:6]=[N:5][C:4]=1[C:30]1[C:31]([F:37])=[CH:32][CH:33]=[CH:34][C:35]=1[F:36])#[N:2]
Reactant: CC(C)N(C(=O)n1nnc(-c2c(F)cccc2F)c1C#N)c1cccc(C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)N(C(=O)n1nnc(-c2c(F)cccc2F)c1C#N)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzyl ester (6) (1.0 equiv) in methanol (0.1 M) under argon was added 5% Pd/C (0.1 equiv) and the inert atmosphere was replaced with hydrogen. The resulting mixture was stirred at rt for 30 min, filtered through a pad of Celite with aid of methanol and the resulting filtrate concentrated in vacuo. The residue was purified by preparative HPLC (0.1% formic acid in acetonitrile/water) to afford 3-(5-cyano-4-(2,6-difluorophenyl)-N-isopropyl-1H-1,2,3-triazole-1-carboxamido)benzoic acid (7) as a lyophilized powder.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:25](=O)([O:36][CH2:37][CH2:38][N:39]1[CH:43]=[CH:42][CH:41]=[N:40]1)[O:26]C1C=CC([N+]([O-])=O)=CC=1.Cl>N1C=CC=CC=1.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([C:25]([O:36][CH2:37][CH2:38][N:39]5[CH:43]=[CH:42][CH:41]=[N:40]5)=[O:26])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(OCCn1cccn1)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(C(=O)OCCn4cccn4)CC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.6 %

Procedure:
A mixture of 3.3 g (0.01 mol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid and 2.8 g (0.01 mol) of 4-nitrophenyl 2-(pyrazol-1-yl)-ethyl carbonate in 40 ml of pyridine is stirred for 1 day at room temperature. Thereafter, it is diluted with 30 ml of water and acidified with 2N hydrochloric acid, and the precipitate is filtered off under suction and recrystallised from glycol monomethyl ether. 2.8 g (60% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-{-4-[(pyrazol-1-yl)-ethoxycarbonyl]-piperazin-1-yl}-quinoline-3-carboxylic acid of melting point 205°-208° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[N:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].CN(C=O)C>O>[CH2:31]([N:12]1[C:11](=[O:23])[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:13]1)[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCI
Reactant: COc1ccc(-c2n[nH]c(=O)nc2-c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCn1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nc1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.3 %

Procedure:
A mixture of 5,6-bis-(4-methoxyphenyl)-1,2,4-triazin-3-one (2.14 g, 6.9 mmol), freshly ground potassium carbonate (1.45 g, 10.5 mmol), 1.43 g of iodopentane (7.2 mmol) and 11 mL of DMF were stirred at room temperature for 6 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and stripped. Column chromatography gave 0.4 g of Compound 8.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([N:43]=[C:44]=[O:45])[CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:44]([NH:43][C:35]4[CH:34]=[C:33]([O:32][CH3:31])[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=4)=[O:45])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(NC(=O)Nc2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 44.7 mg (0.21 mmol) of 3,4,5-trimethoxyphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 11 mg (17.4% of theory) of the title compound are obtained.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH:10]([O-])([O-])OC>>[CH3:10][O:1]/[C:2](/[CH2:8][CH3:9])=[CH:3]/[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: COC([O-])[O-]
Product: CC/C(=C\C(=O)OC)OC

Procedure:
reacting methyl 3-oxovalerate with methyl orthoformate (commercially available) to give methyl (E)-3-methoxy-2-pentenoate,
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([N+:16]([O-])=O)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5].[H][H]>CO.[Pd]>[CH3:21][N:2]([CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([NH2:16])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N)N(C(=O)CN(C)C)CCC2
Yield: 74.7 %

Procedure:
N,N-dimethyl-2-[6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-quinolinyl]-2-oxoethanamine (crude from previous reaction, assumed 0.91 mmol) was dissolved in methanol (5 mL), treated with 10% palladium on carbon (40 mg, Aldrich), and stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite, the filtrate was concentrated and purified by chromatography on SiO2 (0 to 20% methanol/dichloromethane) to provide 1-[(dimethylamino)acetyl]-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (0.18 g, 0.68 mmol, 75% over three steps). 1H NMR (400 MHz, CDCl3) δ ppm 1.88-1.97 (m, J=6.5, 6.5, 6.5, 6.5 Hz, 2 H), 2.35 (s, 6 H), 2.65 (m, 2 H), 3.24 (s, 2 H), 3.74-3.80 (m, 2 H), 3.84 (s, 3 H), 6.55 (s, 1 H), 6.76 (very broad singlet due to amide rotomers, 1 H), aniline NH2 not visible probably due to fast exchange.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[F:21][C:22]([F:43])([F:42])[C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH:35]([CH3:39])[C:36](Cl)=[O:37])=[CH:32][CH:31]=2)=[N:27][CH:28]=1>C1(C)C=CC=CC=1>[F:42][C:22]([F:21])([F:43])[C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH:35]([CH3:39])[C:36]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:37])=[CH:32][CH:31]=2)=[N:27][CH:28]=1
Reactant: CCCCCCCCCCCCO
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 10 °C

Procedure:
n-Dodecanol(2.5 grams; 0.134mol), toluene (80 ml) and triethylamine (5 ml) were placed into a 300 ml, 3-necked glass reaction flask equipped with stirrer, thermometer, reflux condenser, and nitrogen line. 2-[4-(5-trifluoromethyl-2-pyridinyloxy)phenoxy]propanoic acid chloride (4.45 grams; 0.0125 mol) in toluene (30 ml) was added dropwise to the reaction mixture with stirring at a temperature of about 10° C. The temperature of the reaction mixture was allowed to rise to room temperature and stirred overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]=O)=O)=[CH:4][CH:3]=1.Cl.[NH2:13][C:14]1[N:18]([NH2:19])[C:17]([CH3:20])=[N:16][N:15]=1.[OH-].[Na+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:10]=[N:19][N:18]3[C:17]([CH3:20])=[N:16][N:15]=[C:14]3[N:13]=2)=[CH:4][CH:3]=1
Reactant: O=CC(=O)c1ccc(Cl)cc1
Reactant: Cc1nnc(N)n1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nnc2nc(-c3ccc(Cl)cc3)cnn12

Procedure:
A solution of 7.8 g. of p-chlorophenylglyoxal, 6.3 g. of 3,4-diamino-5-methyl-4H-1,2,4-triazole hydrochloride and 1.7 g. of sodium hydroxide in 90 ml. of 67% acetic acid is heated on a steam bath for 1/2 hour. Water is added and heating is continued until yellow crystals separate. These crystals are collected by filtration and washed with hot ethanol, giving the desired product as a yellow solid, m.p. 240° C. (dec.).