Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]([C:17]([N:21]=[C:22]=[O:23])([CH2:19][CH3:20])[CH3:18])=[N:9][C:10]([N:14]=[C:15]=[O:16])([CH2:12][CH3:13])[CH3:11]>CCCCC>[N:8]([C:17]([NH:21][C:22]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:23])([CH2:19][CH3:20])[CH3:18])=[N:9][C:10]([NH:14][C:15]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16])([CH2:12][CH3:13])[CH3:11]
Reactant: Nc1ccccc1
Reactant: CCC(C)(N=C=O)N=NC(C)(CC)N=C=O
Solvent: CCCCC
Product: CCC(C)(N=NC(C)(CC)NC(=O)Nc1ccccc1)NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4.44 grams (0.0476 moles) of aniline in 30 ml of pentane in a 50 ml erlenmeyer flask cooled in a water bath was added 5.33 grams (0.0236 moles) of 2,2'-azobis (2 -isocyanatobutane) (from Example XXXVI) dropwise over 20 minutes while holding the reaction temperature below 30° C. After the addition was complete, the reaction was stirred for an additional 60 minutes at room temperature and filtered. The filter cake was washed with pentane and dried. The dry white solid weighed 1.5 grams (15% crude yield) and melted at 118°-120° C. The product had a strong carbonyl band at 1680 cm-1 and NH peaks at 3220 and 3420 cm-1 in its infrared spectrum and there was no isocyanate band at 2200 cm-1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:5]=[C:4]([S:17][CH3:18])[C:3]=1[C:19]#[N:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C(=O)C.CCOC(C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:19]([C:3]1[C:4]([S:17][CH3:18])=[CH:5][C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[N:7][C:2]=1[C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH:29]=1)#[N:20]
Reactant: CSc1cc(-c2ccc(C(=O)O)cc2)nc(Cl)c1C#N
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1ccc2cc(-c3nc(-c4ccc(C(=O)O)cc4)cc(SC)c3C#N)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
A mixture of 4-(6-chloro-5-cyano-4-(methylthio)pyridin-2-yl)benzoic acid (50 mg, 0.164 mmol) and 6-methoxynaphthalen-2-ylboronic acid (49.7 mg, 0.246 mmol), potassium phosphate (139 mg, 0.656 mmol) and palladium tetrakis(triphenylphosphine) (18.96 mg, 0.016 mmol) in N,N-dimethylacetamide (2 mL) was pumped under vacuum and backfilled with nitrogen three times. After 2 h at 100° C., the mixture was cooled to room temperature, diluted with EtOAc (60 mL), washed with saturated NH4Cl (5 mL), water (5 ml), brine (5 mL), dried (MgSO4) and concentrated. The residue was triturated with MeOH (10 ml) and filtered. The yellow solid was collected and dried under vacuum to give 4-(5-cyano-6-(6-methoxynaphthalen-2-yl)-4-(methylthio)pyridin-2-yl)benzoic acid (45 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.34-8.53 (2H, m), 8.21-8.34 (1H, m), 7.99-8.19 (4H, m), 7.85-7.98 (1H, m), 7.41-7.54 (1H, m), 7.18-7.37 (2H, m), 3.94 (3H, s); MS (ES+) m/z: 427 (M+H); LC retention time: 4.01 min (analytical HPLC Method A).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCCc1ccccc1
Product: FC(F)(F)c1cc2c(NCCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-phenethylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:11](=[O:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH2:8][C:7]=2[NH:6][CH:5]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:21][S:22]([N:6]1[C:7]2[CH2:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH2:10][C:11](=[O:13])[C:12]=2[C:4]([CH3:3])=[CH:5]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1C1CC(=O)c2c(C)c[nH]c2C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1C1CC(=O)c2c(C)cn(S(C)(=O)=O)c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a suspension of 60% sodium hydride (0.12 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindol-4-one (0.60 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of methanesulfonylchloride (0.43 g) in dimethylformamide (3 ml), and the mixture was stirred at the same temperature for 12 hours. To the mixture was added methanesulfonylchloride (0.74 g), and the mixture was stirred for 3 hours. To the mixture was added sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give crystals, which were recrystallized from ethyl acetate-hexane to give colorless crystals of 1-methanesulfonyl-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindol-4-one (0.35 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].[CH:16]([CH2:27]S([O-])(=O)=O)=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]C.O>CS(C)=O>[CH2:25]([N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:27]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCCCCCCCCC=CCS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.33 h
Yield: 46.1 %

Procedure:
This example illustrates a synthesis for compound no. 1592. Sodium hydride(95%, 1.26 g, 50 mmol) was added to a solution of theobromine (7.2 g, 40 mmol) in dimethylsulfoxide (300 ml). After 20 minutes of stirring, undecenylmesylate (7.95 g, 30 mmol) was added and the resulting mixture stirred for 12 hours at room temperature. The reaction was warmed to 70°-80° C. and stirred for 4 hours. The reaction mixture was then poured into a separatory funnel containing 1 L of water and extracted with dichloromethane (5×200 ml). The organic extracts were combined, washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 20% hexane and dichloromethane eluent, producing 4.6 g of 1-(10-undecenyl)-3,7-dimethylxanthine (46.3% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.[C:39](Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:6]=[CH:7][C:2]([NH:1][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:3][CH:4]=3)[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(N)cn2)cc1
Reactant: CC(C)(C)C(=O)Cl
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(NC(=O)C(C)(C)C)cn2)cc1

Procedure:
N-{6-{2-(5-Aminopyridin-2-yloxy )ethoxy}-5-(4-methylphenyl)-pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide and pivaloyl chloride are treated in the same manner as in Example 135 to give N-[6-[2-{6-(4-tert-butylphenylsulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy}ethoxy]pyridin-3-yl]-pivalamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.Cl.[CH3:10][N:11]([CH3:17])[CH2:12][CH2:13][C:14](O)=[O:15].C(N(CCCC)CCCC)CCC.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:14](=[O:15])[CH2:13][CH2:12][N:11]([CH3:17])[CH3:10])[CH:3]=[N:4][CH:5]=1
Reactant: CN(C)CCC(=O)O
Reactant: Nc1cncc(Br)c1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: CN(C)CCC(=O)Nc1cncc(Br)c1
Temperature: 50 °C

Procedure:
To a solution of 3-amino-5-bromopyridine (Sigma-Aldrich, St. Louis, USA) (1 eq, 11.2 mmol, 2.00 g) and 3-dimethylaminopropionic acid hydrochloride (ABCR GmbH & Co. KG, Karlsruhe, Germany) (1 eq, 11.2 mmol, 1.74 g) in DCM (50 ml), tributylamine (3.6 eq, 40.4 mmol, 9.8 ml) and 2-chloro-1-methylpyridinium iodide (1.2 eq, 13.5 mmol, 3.54 g) are added. The resulting mixture is heated at 50° C. for 4 h, then the solvents are removed in vacuo, aqueous NaOH solution (1 M) is added, and the mixture is extracted with DCM. The organic layer is dried with MgSO4, filtered, and the solvent is removed in vacuo. Purification by column chromatography (DCM/MeOH) yields the title compound; [M+H]+=273.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)#[CH:2].I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]>>[O:18]1[C:1]([C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)=[CH:2][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2
Reactant: C#Cc1ccc(C#N)cc1
Reactant: Oc1ccccc1I
Product: N#Cc1ccc(-c2cc3ccccc3o2)cc1

Procedure:
The general procedure was used to convert 4-Ethynyl-benzonitrile and 2-iodophenol to the title product. Purification by flash chromatography (20% ethyl acetate in hexanes as the eluent) gave the analytically pure product as a white solid (337 mg, 77% yield). 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J=8.85, 2H), 7.71 (d, J=8.67, 2H), 7.62 (d, J=7.54, 1H), 7.53 (d, J=8.10, 1H), 7.38-7.24 (m, 2H), 7.16 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 155.08, 153.37, 134.25, 132.45, 128.52, 125.45, 124.93, 123.34, 121.40, 118.66, 111.33, 111.28, 104.23. Anal. Calcd. for C15H9NO: C, 82.18; H, 4.14; N, 6.39. Found C, 81.98; H, 4.09; N, 6.15. m.p.: 149° C. (lit., 4145-146° C.).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([O:34][CH3:35])=[C:26]([CH2:36][C:37]2[S:38][C:39](Br)=[CH:40][CH:41]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:48]1[N:53]=[CH:52][CH:51]=[CH:50][N:49]=1)CCC.BrC1C=CC(=O)N(CC2C=CC(CC)=CC=2)C=1>>[C@@H:6]1([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([O:34][CH3:35])=[C:26]([CH2:36][C:37]3[S:38][C:39]([C:48]4[N:53]=[CH:52][CH:51]=[CH:50][N:49]=4)=[CH:40][CH:41]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: COc1c(Cc2ccc(Br)s2)cc([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: CCc1ccc(Cn2cc(Br)ccc2=O)cc1
Product: COc1c(Cc2ccc(-c3ncccn3)s2)cc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2ccccc12

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methoxylnaphthalene obtained in Example 265-(3) and 2-tributylstannylpyrimidine were treated in a manner similar to Example 128-(5) and (6) to give 1-(β-D-glucopyranosyl)-3-(5-(2-pyrimidinyl)-2-thienylmethyl)-4-methoxylnaphthalene. APCI-Mass m/Z 495 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:22].OS([O-])(=O)=O.[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:15]([O:17][CH3:18])=[O:16])[CH3:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)N(C)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 93 %

Procedure:
A solution of 1.01 g (3.91 mmol) of 4-methoxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (intermediate 38A) in 15 ml of DMF was treated at 0° C. with 0.26 g (5.86 mmol) of NaH (55% in oil) and after 30 min with 1.95 ml (31.28 mmol) of iodomethane. The reaction was stirred for 16 h at RT, neutralized with cold aqueous 10% KHSO4 and extracted with Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane/EtOAc 1:1) to yield 0.99 g (93%) of the title compound as colorless oil. MS: 273.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][CH:5]=[C:4]([CH3:10])[N:3]=1.[Br:11]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([Br:11])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1cnc(C#N)c(N)n1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N)c(C#N)nc1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A stirred solution of 8.5 grams (0.063 mole) of 2-amino-3-cyano-6-methylpyrazine [prepared by the method of Taylor and Kobayashi; JOC, 41, 1299 (1976)] in 125 mL of N,N-dimethylformamide is cooled in an ice bath, and a solution of 11.2 grams (0.063 mole) of N-bromosuccinimide in 125 mL of N,N-dimethylformamide is added dropwise during a 30 minute period, while maintaining the reaction mixture temperature at about 15°-25° C. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 20 hours. After this time, the reaction mixture is poured into 1 liter of aqueous 3N sodium hydroxide. The mixture is then diluted to a volume of about 1700 mL with distilled water. A solid precipitate is collected by filtration and dried under reduced pressure, yielding 2-amino-3-cyano-5-bromo-6-methylpyrazine.
Reaction SMILES: [NH:1]([CH:3]1[CH2:8][CH2:7][S:6][CH2:5][CH2:4]1)[NH2:2].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])N(CCO)N=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22](=[O:29])[N:1]([CH:3]3[CH2:8][CH2:7][S:6][CH2:5][CH2:4]3)[N:2]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: NNC1CCSCC1
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(C3CCSCC3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 4-hydrazinotetrahydrothiopyran as described for compound 35. Crystallized from methanol. M.p. 140°-141° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19](O)=O)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:13]([O:12][C:10]([N:17]1[CH2:24][CH2:23][CH2:22][CH:18]1[C:19]1[NH:9][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1ccc(Br)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1
Temperature: 120 °C
Reaction time: 16 h
Yield: 66.4 %

Procedure:
To a mixture of 4-Bromo-benzene-1,2-diamine (5.0 g), Boc-L-proline (6.0 g), and 4-methylmorpholine (5.88 mL) in DMF (100 mL) was added HATU (10.7 g). Reaction mixture was stirred for 16 hours and then concentrated. Residue was dissolved in ethyl acetate and washed with 5% lithium chloride solution (2×), brine and dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 30 to 60% ethyl acetate/hexanes) to a dark brown foam. Brown foam was dissolved in ethanol (100 mL) and heated in a sealed tube at 110-130° C. for 2 days. Reaction mixture was cooled and concentrated. Residue was dissolved in ethyl acetate and extracted with 1N HCl (3×). Aqueous layer was basified with 50% NaOH solution to pH 10 and extracted with ethyl acetate (2×). The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 10% isopropanol/hexanes) to give 2-(6-Bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (6.5 g) as an off-white foam: LCMS-ESI+: calc'd for C16H21BrN3O2: 367.26 (M+H+); Found: 365.8, 367.8 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:24].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:24])=[C:2]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:11]=3)[C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8]2)=[CH:17][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)cc32)cc1
Reactant: C1CNCCN1
Product: N#Cc1ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CCNCC4)cc32)cc1

Procedure:
In the described fashion as Example 1(e), the above acid (7) (R6 =C2H5, R=p-cyanophenyl), after reacting with piperazine, can give the desired 1-p-cyanophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid (9) ##STR30## R=p-cyanophenyl) and its hydrochloride salt.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25]([O:27][CH3:28])=[O:26])=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[S:15][C:16]=1Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.ClCCl.[Pd]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25]([O:27][CH3:28])=[O:26])=[C:14]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[S:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(C)cc2)sc(Br)c1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(NC(=O)OCc2ccccc2)csc1-c1ccc(C)cc1
Reaction time: 4 h

Procedure:
10% Pd/C is added to methyl 4-(benzyloxycarbonylamino)-5-bromo-2-p-tolylthiophene-3-carboxylate (176) in ethanol:ethyl acetate:dichloromethane (2:1:1). The mixture is degassed and placed under H2 (1 atm) and stirred for 4 h. The mixture is filtered through a 0.45 μm syringe filter and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provides 177.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:11][S:12]([OH:15])(=O)=[O:13]>S(=O)(=O)(O)N>[C:9]1([S:12]([Cl:11])(=[O:15])=[O:13])[C:10]2[CH:1]=[CH:2][CH:3]=[C:4]([S:12]([Cl:11])(=[O:15])=[O:13])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2ccccc2c1
Reactant: O=S(=O)(O)Cl
Agent: NS(=O)(=O)O
Product: O=S(=O)(Cl)c1cccc2c(S(=O)(=O)Cl)cccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.8 %

Procedure:
64.1 g (0.5 mol) of naphthalene are introduced with ice cooling into 640.7 g (5.5 mol) of chlorosulfonic acid, to which 1 g of sulfamic acid has been added. The mixture is then stirred at room temperature for 4 hours. The reaction mixture is added dropwise to ice water, and the precipitated crystals are filtered off with suction and washed with water. 172.1 g of naphthalene-1,5-disulfonyl chloride having a water content of 26.5% and a chloride content of 71.6%, corresponding to 123.2 g (75.7%), are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[N+](=[CH2:14])=[N-]>C(OCC)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:14])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1ccc(C)c(O)c1
Reaction time: 24 h

Procedure:
A solution of 3-hydroxy-4-methylbenzoic acid (26.1 g, 0.17 mol) in 200 mL of diethylether is treated with a solution of diazomethane in ether until a persistent yellow color develops. The resulting solution is stirred for 24 hours. The resulting solution is concentrated and the residue is crystallized from CH2Cl2. A white solid which is methyl 3-hydroxy-4-methylbenzoate is obtained (26.5 g, 93%).
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>>[F:1][CH2:2][C:3]([N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(CF)Nc1ccccc1
Reactant: Brc1ccccn1
Product: O=C(CF)N(c1ccccc1)c1ccccn1
Yield: 75.2 %

Procedure:
Using 2-fluoroacetanilide (4.6 g) and 2-bromopyridine (9.5 g), a reaction was made in the same manner as in 1) of Production Example 14. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:1.5) produced 2-fluoro-N-(2-pyridyl)acetanilide (5.2 g, crude product) as a red oil.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].Cl.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:28]=[C:27]3[C:23]([C:24]4[CH2:33][CH2:32][NH:31][CH2:30][C:25]=4[N:26]3[CH3:29])=[CH:22][CH:21]=2)[C:16](=[O:34])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:28]=[C:27]3[C:23]([C:24]4[CH2:33][CH2:32][N:31]([CH:2]([CH3:4])[CH3:3])[CH2:30][C:25]=4[N:26]3[CH3:29])=[CH:22][CH:21]=2)[C:16](=[O:34])[CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCNC2
Reactant: CC(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)N1CCc2c(n(C)c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc23)C1
Temperature: 55 °C
Reaction time: 72 h

Procedure:
2-Bromopropane (1.5 mL, 16 mmol) was added to a mixture of 4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride (138 mg, 0.327 mmol) and Cs2CO3 (1.2 g, 3.7 mmol) in acetonitrile (25 mL). The mixture was stirred at 55° C. for 72 h. The resulting mixture was cooled, and the precipitate was filtered off. The mother liquor was concentrated under vacuum. The residue was purified by preparatory TLC (silica gel, 10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford 4-(benzyloxy)-1-(2-isopropyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one. The free base was converted to the HCl salt using 1.25 M HCl in methanol to provide the title compound (26 mg, 19%) as a off white solid: 1H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.56 (d, J=4.5 Hz, 2H), 7.52-7.38 (m, 6H), 7.01 (dd, J=4.5, 1.0 Hz, 1H), 6.11 (dd, J=4.5, 1.0 Hz, 1H), 5.97 (s, 1H), 5.16 (s, 2H), 4.60-4.53 (m, 2H), 3.78-3.70 (m, 2H), 3.70 (s, 3H), 3.40-3.28 (m, 1H), 3.18-2.98 (m, 2H), 1.44-1.39 (m, 6H); ESI MS m/z 428 [M+H]+; HPLC (Method A) 95.7% (AUC), tR=15.1 min.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1.[C:11]12([C:21](O)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2>>[F:1][C:2]([F:10])([F:9])[C:3]1[NH:4]/[C:5](=[N:8]/[C:21]([C:11]23[CH2:20][CH:15]4[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]4)[CH2:18]2)[CH2:12]3)=[O:22])/[S:6][CH:7]=1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1nc(C(F)(F)F)cs1
Product: O=C(/N=c1/[nH]c(C(F)(F)F)cs1)C12CC3CC(CC(C3)C1)C2
Yield: 51.3 %

Procedure:
4-Trifluoromethyl-thiazol-2-ylamine (1.0 g, 6.0 mmol) and 1-adamantanecarboxylic acid (1.0 g, 5.5 mmol) were processed as described in Example 3B to afford 0.932 g (51%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.65-1.73 (m, 6H) 1.93 (d, J=3 Hz, 6H) 2.02 (d, 3H) 7.93 (s, 1H); MS (DCI/NH3) m/z 331 (M+H).