Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]([O:15][C:16]([NH:18][CH:19]1[CH2:24][NH:23][CH2:22][CH2:21][CH2:20]1)=[O:17])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:23]1[CH2:22][CH2:21][CH2:20][CH:19]([NH:18][C:16](=[O:17])[O:15][C:12]([CH3:13])([CH3:11])[CH3:14])[CH2:24]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccncc2[N+](=O)[O-])C1
Yield: 89 %

Procedure:
The method of Example 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, 3-N-Boc-amino piperidine and diisopropylethylamine yielding tert-butyl 1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (89%). LCMS (m/z): 323.1 (MH+); LC Rt=2.13 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH2:14][CH2:15][CH3:16])[C:7]([CH:17]=[O:18])=[CH:6]2>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH2:14][CH2:15][CH3:16])[C:7]([CH2:17][OH:18])=[CH:6]2
Reactant: CCCNc1nc2ccc(OC)cc2cc1C=O
Solvent: C1CCOC1
Product: CCCNc1nc2ccc(OC)cc2cc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a stirred solution of 6-methoxy-2-(propylamino)quinoline-3-carbaldehyde SLA 28172 (1.565 g, 6.41 mmol) in THF (120 mL) in a 250 mL round-bottomed flask equipped with a magnetic stirrer was added sodium borohydride NaBH4 (0.242 g, 6.41 mmol) and the mixture was stirred overnight at RT then cooled in an ice bath before quenching by addition of a 1 N aq. HCl solution (40 mL). After stirring for 15 min at that temperature, the mixture was basified to pH=9 with a 2 N aq. NaOH solution. THF was then removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (200 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give (6-methoxy-2-(propylamino)quinolin-3-yl)methanol SLA 28174 as an orange solid (1.55 g, 98% yield).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([F:29])[CH:28]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[F:29][C:27]1[CH:28]=[C:23]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:9]=3)[C:14]([OH:15])=[C:5]([C:3]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])[N:6]=2)[CH:24]=[N:25][CH:26]=1
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NCCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCCCNC(=O)c1nc(-c2cncc(F)c2)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 53.4 %

Procedure:
A mixture of 1-(5-fluoro-pyridin-3-yl)-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.13 mmol), 5-aminovaleric acid (751 mg, 6.41 mmol) and NaOMe (10 mL, 5.13 mmol, 0.5 M in MeOH) was refluxed for 16 h. After cooling the mixture to r.t., the solvent was evaporated. The residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (5-50% EtOAc/hexanes+2% AcOH) to give 33 mg of the title compound as an off-white solid. MS: (+) m/z 476.12 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(C(C)(C)C)cc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 19 h

Procedure:
To a stirred solution of 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.0 g, 4.03 mmol) in toluene (8.06 mL) was added 4-tert-butylphenylboronic acid (1.08 g, 6.05 mmol), potassium carbonate (1.67 g, 12.10 mmol) and palladium tetrakistriphenylphosphine (0.47 g, 0.40 mmol). The reaction was stirred at 100° C. and stirring continued for 19 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(4-(2-methyl-2-propanyl)phenyl)quinoline as a yellow oil. Mass Spectrum (ESI) m/e=346.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:16])=[C:4]([N+:17]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([NH2:16])=[CH:6][C:7]=1[N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][CH2:9]1
Reactant: CN1CCCN(c2cc(N)c([N+](=O)[O-])cc2F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCCN(c2cc(N)c(N)cc2F)CC1
Yield: 102.9 %

Procedure:
20.9 g of 4-fluoro-5-(4-methylperhydro-1,4-diazepin-1-yl)-2-nitrophenylamine in solution in 750 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 2 g of palladium-on-charcoal at 25° C. for 16 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 19.1 g of 4-fluoro-5-(4-methylperhydro-1,4-diazepin-1-yl)benzene-1,2-diamine in the form of a black oil are isolated. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.82 (m, 2H); 2.26 (s, 3H); 2.56 (m, 4H); 3.11 (m, 4H); 4.19 (broad m, 4H); from 6.22 to 6.31 (m, 2H). EI m/z=238: M+. (base peak)—m/z=223: (M-CH3)+—m/z=168: (M−C4H8N)+—m/z=70: C4H8N+—m/z=57: C3H7N+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].C(=O)(O)[O-].[Na+].[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>C(OCC)(=O)C>[NH2:30][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[C:8]([N:15]([CH2:17][C:18]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20][N:21]([C:39]([CH:36]3[CH2:38][CH2:37]3)=[O:40])[CH2:22][CH2:23]2)[CH3:16])[N:7]=1
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc2nc(N(C)CC3(c4ccccc4)CCN(C(=O)C4CC4)CC3)nc(N)c2cc1OC
Reaction time: 0.5 h

Procedure:
A mixture of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 (125 mg), ethyl acetate (10 ml) and aq. sodium bicarbonate (10 ml) was stirred vigorously while 40 μL of cyclopropylcarbonyl chloride were added slowly via syringe. After 30 min., the reaction mixture was worked up as usual to yield 1-(4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidin-1-yl)-1-cyclopropyl-methanone 12, MS: 476 ([M+H]+) The crude base was converted to the hydrochloride salt as a white powder (120 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH:10]([CH3:13])[CH:11]=O)=O)=[CH:5][CH:4]=1.[C:16]([NH:19][S:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21])(=[O:18])[CH3:17].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:16]([NH:19][S:20]([C:23]1[CH:29]=[CH:28][C:26]([N:27]2[CH:11]=[C:10]([CH3:13])[CH:9]=[C:7]2[C:6]2[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])(=[O:18])[CH3:17]
Reactant: COc1ccc(C(=O)CC(C)C=O)cc1
Reactant: CC(=O)NS(=O)(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc(C)cn2-c2ccc(S(=O)(=O)NC(C)=O)cc2)cc1
Yield: 16.1 %

Procedure:
A solution of 2.82 g (12.8 mmol) of 3-(4-methoxybenzoyl)-2-methylpropionaldehyde [prepared as described in step (i) above] and 2.74 g (12.8 mmol) of 4-acetylaminosulfonylaniline in 30 ml of acetic acid was heated under reflux for 3 hours, after which the acetic acid was removed by distillation under reduced pressure. The residue thus obtained was dissolved in chloroform and a saturated aqueous solution of sodium hydrogencarbonate was added to the resulting solution to separate it into liquid phases. The organic extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate, after which it was concentrated by evaporation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 2:3 by volume mixture of hexane and ethyl acetate. It was then recrystallized from ethanol, to give 0.79 g (yield 16%) of the title compound as a white powder, melting at 215-217° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[S:12])[CH:7]=[CH:8][CH:9]=1)=[O:3].[CH3:13][NH:14][NH2:15]>C(O)C>[CH3:13][N:14]([C:11]([NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:2]([CH3:1])=[O:3])[CH:5]=1)=[S:12])[NH2:15]
Reactant: CNN
Reactant: CC(=O)c1cccc(N=C=S)c1
Solvent: CCO
Product: CC(=O)c1cccc(NC(=S)N(C)N)c1
Yield: 78.9 %

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 20.0 g (0.113 mole) of 3-methylcarbonylphenyl isothiocyanate and 5.21 g (0.113 mole) of methylhydrazine in 150 ml of ethanol yielded 19.9 g of 2-methyl-4-(3-methylcarbonylphenyl)-3-thiosemicarbazide as a solid, mp 125°-127° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na].[CH2:24]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([CH:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(F)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: [Na]
Product: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (S)-2-(4-fluoro-benzenesulfonylamino)-3-phenyl-propionic acid, sodium salt, and 4-benzyl-piperidine were condensed to give the title compound, mp 164-165° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1.[P:26](Cl)([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][P:26](=[O:27])([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)(=[O:23])=[O:24])=[CH:20][CH:21]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: COc1ccc(-c2c(Cl)ncn2-c2ccc(S(N)(=O)=O)cc2)cc1F
Product: COc1ccc(-c2c(Cl)ncn2-c2ccc(S(=O)(=O)NP(=O)(Oc3ccccc3)Oc3ccccc3)cc2)cc1F
Yield: 10 %

Procedure:
Following a similar procedure to that described in sections a and b of example 12, but using 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (obtained as described in WO 00/23426) instead of 4-[4-chloro-5-(4-ethoxyphenyl)imidazol-1-yl]benzenesulfonamide and diphenyl chlorophosphate instead of diethyl chlorophosphate, the title compound of the example was obtained in 10% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH2:18][NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH2:18][N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26](=[O:29])[CH2:27][CH3:28])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCCCC(CNc2ccccc2)C1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCCN(C(=O)OCc2ccccc2)C1)c1ccccc1
Temperature: 0 °C
Yield: 72 %

Procedure:
Et(iPr)2N (0.24 mL, 1.38 mmol) was added to a stirring solution of crude 3-phenylaminomethyl-azepane-1-carboxylic acid benzyl ester (148) in CH2Cl2 (2.3 mL) under N2. The reaction was cooled to 0° C. in an ice bath, then propionyl chloride (0.22 mL, 2.53 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight. The reaction was then judged complete by TLC. It was concentrated in vacuo and EtOAc and 10% NaOH (aq) were added. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo, and purified by automated silica gel chromatography with 96:2:2 Hexanes:CH2Cl2:2N NH, in EtOH to obtain 3-[(phenyl-propionyl-amino)-methyl]-azepane-1-carboxylic acid benzyl ester (149) (0.3266 g) in 72% yield for two steps.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[N+:15](=[CH2:17])=[N-:16]>C(OCC)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[CH:17]=[N+:15]=[N-:16])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: C=[N+]=[N-]
Reactant: Cc1ccc(C(=O)Cl)cc1S(N)(=O)=O
Solvent: CCOCC
Product: Cc1ccc(C(=O)C=[N+]=[N-])cc1S(N)(=O)=O

Procedure:
12 g of 4-methyl-3-sulfamoylbenzoyl chloride were reacted as prescribed in Example 66(b) with diazomethane in diethyl ether and the substance precipitating as fair yellow precipitate was filtered off. Melting point: 176° C. (decomposition).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[CH3:11])=O.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:12]([N:14]([CH2:1][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[CH3:11])[CH2:15][CH3:16])[CH3:13]
Reactant: CCNCC
Reactant: Cc1cc(C(=O)O)sc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN(CC)Cc1sc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.8 %

Procedure:
To a solution of 5-formyl-4-methyl-thiophene-2-carboxylic acid (6.90 g, 40.5 mmol) in THF (150 mL), diethylamine (5.93 g, 81.1 mmol) and acetic acid (10 mL) followed by sodium triacetoxyborohydride (14.32 g, 60.8 mmol) is added. The mixture becomes slightly warm. The reaction mixture is stirred at rt for 16 h before it is concentrated and separated by CC on silica gel eluting with EA containing 0-50% of methanol to give the title compound (4.95 g) containing large amount of diethylammonium salts. The material (4.94 g, 21.8 mmol) is therefore dissolved in methanol (70 mL) and treated with chloro trimethylsilane (23.7 g, 218 mmol). The mixture is stirred at 50° C. for 18 h before it is concentrated, dissolved in EA and washed with sat. aq. NaHCO3 solution. The organic extract is dried over Na2SO4, filtered, concentrated and dried to give 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid methyl ester (4.05 g) as a yellow oil; 1H NMR (CDCl3): δ 1.08 (t, J=7.0 Hz, 6H), 2.19 (s, 3H), 2.59 (q, J=7.0 Hz, 4H), 3.67 (s, 2H), 3.87 (s, 3H), 7.28 (s, 1H), 7.52 (s, 1H). This material is dissolved in 1 N aq. HCl (80 mL) and stirred at 65° C. for 214 h. The solvent is evaporated and the residue is dried under high vacuum to give the title compound (3.56 g) as a pale beige solid; LC-MS: tR=0.26 min; [M+1]+=228.20; 1H NMR (D6-DMSO): δ 1.28 (t, J=7.3 Hz, 6H), 2.31 (s, 3H), 3.12 (q, J=6.8 Hz, 4H), 4.48 (s, 2H), 7.59 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[N:13]=[CH:12][C:6]2[N:7]=[CH:8][NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)#[N:2].C([Sn]([N:27]=[N+:28]=[N-:29])(CCCC)CCCC)CCC>COCCOCCOC>[NH:27]1[C:1]([C:3]2[N:13]=[CH:12][C:6]3[N:7]=[CH:8][NH:9][C:10](=[O:11])[C:5]=3[CH:4]=2)=[N:2][N:29]=[N:28]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1cc2c(=O)[nH]cnc2cn1
Solvent: COCCOCCOC
Product: O=c1[nH]cnc2cnc(-c3nnn[nH]3)cc12
Yield: 440.9 %

Procedure:
6-Cyano-pyrido[3,4-d]pyrimidin-4-one (0.3 g) in diglyme (2 ml) was treated with tributyl tin azide (0.49 g) at reflux under N2 for 15 hours. The cooled mixture was partitioned between ethyl acetate and water and the aqueous phase extracted further with ethyl acetate. The aqueous phase was concentrated in vacuo, the residue taken up in methanol and inorganics removed by filtration. Subsequent concentration gave the title compound (1.4 g) as a beige solid; δH [2H6]DMSO 8.96 (1H,s), 8.50 (1H,s), 8.27 (1H,s); m/z (M+1+)216.
Reaction SMILES: [C:1](=[NH:24])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:18]=2)=[C:8]([F:23])[CH:7]=1)[NH2:2].FC(F)(F)C([O-])=O.[CH:32]([CH:34]([CH2:39][C:40]1[CH:41]=[N:42][C:43]([O:46][CH3:47])=[N:44][CH:45]=1)[C:35](OC)=O)=[O:33].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:23][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]([F:20])([F:22])[F:21])=[N:17][CH:18]=1)[CH2:5][CH2:4][O:3][C:1]1[NH:2][CH:35]=[C:34]([CH2:39][C:40]2[CH:41]=[N:42][C:43]([O:46][CH3:47])=[N:44][CH:45]=2)[C:32](=[O:33])[N:24]=1
Reactant: N=C(N)OCCc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc2=O)cn1
Temperature: 100 °C

Procedure:
To the solution of 3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenethyl carbamimidate, trifluoroacetate (50 mg, 0.109 mmol) and methyl 2-formyl-3-(2-methoxypyrimidin-5-yl)propanoate (30 mg, 0.134 mmol) in 1,4-dioxane (1 mL) was added K2CO3 (60 mg, 0.434 mmol). The mixture was heated with a microwave reactor at 100° C. for 0.5 h. Purification via MDAP then afforded the title compound (13.5 mg, 23.82 yield). LCMS: rt=2.97 min, [M+H+]=519
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:26])[CH:10]2[NH:14][C:15](=[O:25])[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[S:22]([CH3:24])=[O:23])[C:7]=1[C:27]([OH:29])=[O:28])(=O)C.C(=O)(O)[O-].[Na+].[CH3:35][C:36]1[S:37][C:38](=[S:41])[NH:39][N:40]=1.Cl>O>[C:27]([C:7]1[N:8]2[CH:11]([S:12][CH2:13][C:6]=1[CH2:5][S:41][C:38]1[S:37][C:36]([CH3:35])=[N:40][N:39]=1)[CH:10]([NH:14][C:15](=[O:25])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[S:22]([CH3:24])=[O:23])[C:9]2=[O:26])([OH:29])=[O:28]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cn3ccnc3S(C)=O)C2SC1
Reactant: Cc1n[nH]c(=S)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cn4ccnc4S(C)=O)C3SC2)s1
Temperature: 60 °C
Yield: 27.3 %

Procedure:
3-Acetoxymethyl-2-carboxy-7-[(2-methylsulphinylimidazol-1-yl)-acetamido]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]-oct-2-ene (8.5 g.) and sodium bicarbonate (1.62 g.) are dissolved in water (75 cc.). A solution of 2-methyl-5-thioxo-1,3,4-thiadiazoline (2.54 g.) and sodium bicarbonate (1.62 g.) in water (75 cc.) is added and the mixture is heated at 60° C. for 6 hours. After cooling, the pH is adjusted to 6 by adding hydrochloric acid (4 N) and the mixture is washed twice with ethyl acetate (a total of 200 cc.). The mixture is acidified to pH 2 by adding hydrochloric acid (4 N); a product precipitates and is filtered off and dried under reduced pressure (1 mm.Hg) to give 7.9 g. of product. Recrystallisation from methanol (25 cc.), filtration and drying under reduced pressure (0.1 mm.Hg) gives 2-carboxy-3-[(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl]-7-[(2-methylsulphinyl-imidazol-1-yl)-acetamido]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (2.7 g.), m.p. 227° C. (with decomposition), [α]D20 = -35° ± 1° (c= 1, dimethylformamide).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[Cl:7][C:8]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=[O:11]>O1CCCC1.C(OCC)(=O)C>[Cl:7][C:8]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=[O:11]
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: NCCCCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCCCO)ccc1Cl
Temperature: 60 °C

Procedure:
4-Amino-1-butanol (0.11 ml) was added to a solution of 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.25 g, Example 6e) in tetrahydrofuran (4 ml) and heated at 60° C. in a sealed tube for 12 h. On cooling to ambient temperature, the mixture was diluted with ethyl acetate and extracted twice with saturated aqueous sodium hydrogencarbonate solution and once with brine, dried over magnesian sulfate and concentrated under reduced pressure. Purification by preparative reverse phase HPLC (eluting with a gradient of acetonitrile in 0.1% aqueous ammonium acetate/25–95%) gave the title compound as the acetate salt. Treatment with aqueous 2M sodium hydroxide and extraction into ethyl acetate gave the title compound (0.065 g).
Reaction SMILES: [C:1](Cl)(=O)C.[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:40]=[CH:39][CH:38]=[CH:37][C:15]=1[C:16]([NH:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1)=[O:17])([OH:7])=[O:6]>CO>[CH3:1][O:6][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:40]=[CH:39][CH:38]=[CH:37][C:15]=1[C:16]([NH:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1)=[O:17])=[O:7]
Reactant: O=C(O)c1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Reaction time: 0.5 h

Procedure:
To a solution of acetyl chloride (1 ml) and methanol (20 ml) was added 1-{4-[2-(2-carboxyphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (350 mg) at 0° C. The solution was stirred for 30 minutes at the same temperature and then stirred for 3 hours at ambient temperature. The solvent was evaporated in vacuo and triturated from dichloromethane to give 1-{4-[2-(2methoxycarbonylphenyl)benzoylamino]benzoyl}-1,2,3,4tetrahydroquinoline (300 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].[C:28]([O:33]C)(=[O:32])[C@H:29]([CH3:31])O.BrBr>>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][C@H:29]([CH3:31])[C:28]([OH:33])=[O:32]
Reactant: COC(=O)[C@H](C)O
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: BrBr
Product: C[C@@H](Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)C(=O)O

Procedure:
Prepared from of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenol (Example 21) and commercially available (S)-lactic acid, methyl ester. White solid: mp 131-133 ° C.: NMR (CDCl3);δ8.37 (d, J=9 Hz, 1 H), 7.84 (d, J=8 Hz, 1 H), 7.71-7.65 (m, 3 H), 7.57-7.50(m, 2 H), 7.45 (ddd, J=8, 7, 1 Hz, 1 H), 7.18 (ddd, J=8,7, 1 Hz, 1 H), 6.73 (d, J=8 Hz, 1 H), 5.36 (q, J=7 Hz, 1 H), 1.82 (d, J=7 Hz, 3 H); MS (EI): [M-H]+, 3 bromine isotope pattern, 631 (14%), 633 (44 %), 635 (42%), 637 (16%); Anal. Calc. for C25H15Br3O3S: C, 47.27, H, 2.38, N, 0.00. Found: C, 47.57, H, 2.33, N, 0.03.