Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]=[C:6]1[O:10][C:8](=[O:9])[CH2:7]1>C(Cl)(Cl)Cl>[CH:1]1([NH:4][C:8](=[O:9])[CH2:7][C:6]([CH3:5])=[O:10])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: C=C1CC(=O)O1
Solvent: ClC(Cl)Cl
Product: CC(=O)CC(=O)NC1CC1
Yield: 79.8 %

Procedure:
Cyclopropylamine (42.2 g, 0.74 mole) is dissolved in chloroform (300 ml) and thereto is added dropwise diketene (62.1 g, 0.74 mole) over a period of 1-1.5 hour with stirring in an ice bath. After the addition, the mixture is stirred at 40° C. for one hour, and the solvent is distilled off under reduced pressure, and the residue is recrystallized from benzene-n-hexane to give the title compound (83.4 g, yield 80%) as colorless needles, m.p. 65°-66° C.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6]1[CH2:10][C:9](=[O:11])[N:8]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[N:7]=1.C(Cl)(=O)OCC>C(N(CC)CC)C>[OH:17][CH2:16][C:15]1[CH:14]=[CH:13][C:12]([N:8]2[C:9](=[O:11])[CH2:10][C:6]([CH3:5])=[N:7]2)=[CH:20][CH:19]=1
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1=NN(c2ccc(CO)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
Into 250 ml of anhydrous chloroform were added 5.0 g of 4-(3-methyl-5-oxo-2-pyrazolin-1-yl)benzoic acid and 25 ml of triethylamine and, further under ice-cooling, 12.5 ml of ethyl chlorocarbonate was added dropwise into the mixture. After evaporation of the solvent, the residue was dissolved in 200 ml of THF, the insolubles were filtered off, and then a solution of 2.08 g of NaBH4 dissolved in 60 ml of water was added dropwise into the filtrate, followed by stirring at room temperature for 2 hours. After evaporation of the solvent, water was added to the residue, and the mixture was adjusted with dil. hydrochloric acid to pH 4-5 and then extracted with chloroform. The organic layer was dried, concentrated and purified on silica gel column chromatograph with the use of chloroform-ethanl (100:1) as eluant, followed by recrystallization from chloroform-ethyl ether to give 1.16 g of 1-(4-hydroxymethylphenyl)-3-methyl-2-pyrazolin-5-one as colorless crystals.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([Cl:23])=[C:21]([Cl:24])[CH:20]=[CH:19][C:18]=2[N+:25]([O-])=O)[CH:13]([C:28]([OH:30])=O)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]>[Fe]>[C:1]([N:11]1[CH2:16][CH2:15][N:14]2[C:17]3[C:18]([NH:25][C:28](=[O:30])[CH:13]2[CH2:12]1)=[CH:19][CH:20]=[C:21]([Cl:24])[C:22]=3[Cl:23])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [Fe]
Product: O=C1Nc2ccc(Cl)c(Cl)c2N2CCN(C(=O)OCc3ccccc3)CC12
Yield: 50.7 %

Procedure:
By the same procedure described for Example 7B, from 0.75 g of 4-carbobenzyloxy-1-(5,6-dichloro-2-nitrophenyl)piperazine-2-carboxylic acid and 0.28 g of iron powder, there was obtained 0.34 g (49%) of the desired product as a brown solid.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]([O-:10])=[O:9].C1COCC1.CN>C(OCC)(=O)C>[CH3:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1sccc1C(=O)[O-]
Agent: CN
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1sccc1C(=O)O
Yield: 89.3 %

Procedure:
2-Methyl-3-thiophenecarboxylate chloride (60.5 g)/THF (300 ml) solution was added dropwise to a 40% aqueous solution of methylamine (400 ml) at 0° C. Ethyl acetate (2 l) was added thereto, and then the organic layer was washed sequentially with water, a 5N aqueous solution of hydrochloride acid, an aqueous solution of saturated of saturated sodium bicarbonate, water and brine, dried and evaporated. The resulting residue was crystallized from n-hexane, to give the title compound as a white powder (43.5 g, yield; 71.8%).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=1)(C)C.[C:14]([N:22]=C=O)(=[O:21])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:6]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([NH2:22])=[O:21])[CH:8]=1)#[CH:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: C[Si](C)(C)C#Cc1ccnc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C#Cc1ccnc(NC(N)=O)c1
Temperature: 50 °C
Yield: 5.2 %

Procedure:
4-Trimethylsilanylethynyl-pyridin-2-ylamine (7.8 g, 42 mmol) and benzoyl isocynate (12.2 g, 82.9 mmol) are added into DCM (350 mL). The reaction mixture is heated at 50° C. for 16 hrs. Then the solvent is removed and the residue is dissolved in ethanol (350 mL). Potassium carbonate (8.58 g, 62.2 mmol) is added and the mixture is heated at 80° C. for 1 hr. The solvent is removed and the residue is partitioned between water (100 mL) and EtOAc (100 mL). The aqueous layer is separated and extracted with EtOAc (2×100 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using 33% EtOAc in hexanes affords 350 mg of the desired product.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([SH:17])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>C(O)C>[CH2:22]([S:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)[CH:21]=[CH2:20]
Reactant: Sc1nnc(-c2ccccc2)c2ccccc12
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCSc1nnc(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 4-phenylphthalazine-1-thiol (Example 1B) (238 mg, 1 mmol) in ethanol (40 ml) is added aqueous KOH (1 molar, 1 ml). After 10 minutes, allylbromide (0.1 ml, 1 mmol) is added, and the mixture is stirred at room temperature for 4 days. After the solvent is evaporated, the residue is extracted with CH2Cl2. The organic phase is evaporated and the residue is stirred with isopropyl ether. Filtration gives the pure title compound, which is recrystallized from ethanol (130 mg). (R1=vinyl, R2=phenyl, A=benzene, Y1=CH2, m=0, n=1, p=0, q=0).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6].Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1>>[CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:6][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: CNCC[C@H](O)c1ccccc1
Product: CNCC[C@H](Oc1ccc(C(F)(F)F)cc1)c1ccccc1

Procedure:
A process according to claim 4 comprising the additional step, following all preceding steps, of reacting (S)-3-(methylamino)-1-phenylpropanol with a strong base followed by 4-chlorobenzotrifluoride to provide (S)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine.
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:11].[CH3:12][Si:13]([CH2:16][CH2:17][O:18][CH2:19]Cl)([CH3:15])[CH3:14].[H-].[Na+]>CN(C=O)C>[I:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:19][O:18][CH2:17][CH2:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:11]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1ccc2[nH]cnc2c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(ncn2COCC[Si](C)(C)C)c1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of 4-Iodo-5-methyl-1H-benzoimidazole (100 mg, 0.39 mmol, Example 287: step a) and SEMCl (71 mg 0.43 mmol) in 2 mL of DMF under Ar was added NaH (11 mg, 0.43 mmol). The mixture was stirred at RT for 4 h and purified directly by PTLC (25% EtOAc/hexane) to give 122 mg (81%) of product as a colorless oil: 1H-NMR (CDCl3; 400 MHz) δ 7.95 (s, 1H), 7.37 (d, 1H, J=8.4 Hz), 7.21 (d, 1H, J=8.4 Hz), 5.48 (s, 2H), 3.47 (t, 2H, J=8.3 Hz), 2.59 (s, 3H), 0.89 (t, 2H, J=8.3 Hz), −0.06 (s, 91H). Mass spectrum (ESI, m/z): Calcd. for C14H21IN2OSi, 389.1 (M+H), found 389.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([C:14]([CH3:16])=[CH2:15])[C:10]=1[C:17]#[N:18].[H][H]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([CH:14]([CH3:16])[CH3:15])[C:10]=1[C:17]#[N:18]
Reactant: [H][H]
Reactant: C=C(C)c1nsc(-c2ccc(C)cc2F)c1C#N
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2snc(C(C)C)c2C#N)c(F)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Into a 25-mL 3-necked round-bottom flask, was placed 5-(2-fluoro-4-methylphenyl)-3-(prop-1-en-2-yl)-1,2-thiazole-4-carbonitrile (140 mg, 0.54 mmol, 1.00 equiv), ethyl acetate (10 mL), Pd(no water)/C (140 mg). To the above hydrogen gas was introduced. The resulting solution was stirred for 2 h at 20° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 130 mg (crude) of 5-(2-fluoro-4-methylphenyl)-3-(propan-2-yl)-1,2-thiazole-4-carbonitrile as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([OH:23])[CH2:21][OH:22])=[CH:15][C:14]=2[CH3:24])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8].[CH3:25][C:26]([CH3:28])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]3[CH2:21][O:22][C:26]([CH3:28])([CH3:25])[O:23]3)=[CH:15][C:14]=2[CH3:24])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(CC(O)CO)ccc1OCCNc1ncnc(C)c1Cl
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(CC2COC(C)(C)O2)ccc1OCCNc1ncnc(C)c1Cl

Procedure:
6.0 g of 5-chloro-4-{2-[4-(2,3-dihydroxypropyl)-2-methylphenoxy]ethylamino}-6-methylpyrimidine and 50 ml of acetone were dissolved in 200 ml of toluene and a small amount of p-toluenesulfonic acid was added to the solution. The mixture was then heated under reflux for 6 hours. At the end of this time, the reaction mixture was adjusted to weakly alkaline by the addition of a dilute aqueous solution of sodium hydroxide. Then the reaction mixture was washed with water and dried over anhydrous sodium sulfate. Toluene was removed by distillation under reduced pressure. The oily product thus obtained was subjected to column chromatography (Wakogel C-200, eluted with a 2:1 by volume mixture of toluene and ethyl acetate) to isolate the product and give 4.8 g of the title compound as a pale yellow oily liquid, n25.0 =1.5516.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.Br[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9]>>[C:10]1([CH:8]([N:4]2[CH:5]=[N:6][C:2]([NH2:1])=[N:3]2)[CH3:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(Br)c1ccccc1
Reactant: Nc1nc[nH]n1
Product: CC(c1ccccc1)n1cnc(N)n1

Procedure:
Prepared in analogy to example 3a) starting with 3-amino-1,2,4-triazole and (1-bromoethyl)benzene. The title compound was obtained as a colorless solid (Yield=10%). MS ISP (m/e): 189.2.0 (100) [(M+H)+].
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[CH3:13][O:14][C:15](=[O:35])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:35])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:25]3[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc([N+](=O)[O-])sc3n2)cc1
Reactant: NCCc1ccc2c(c1)OCO2
Product: COC(=O)c1ccc(-c2nc(NCCc3ccc4c(c3)OCO4)c3cc([N+](=O)[O-])sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxyphenethylamine is reacted with 4-(4-chloro-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][C:7]#[N:8])[CH3:3].[Cl:9][CH2:10][CH2:11][CH2:12]I>>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([CH2:12][CH2:11][CH2:10][Cl:9])[C:7]#[N:8])[CH3:3]
Reactant: CN(C)CCCC#N
Reactant: ClCCCI
Product: CN(C)CCC(C#N)CCCCl

Procedure:
The amine of formula III, when n is equal to 3, p equal to 2 and q equal to zero, is prepared from 4-(N,N-dimethylamino)butyronitrile. This compound is condensed with 3-chloro-l-iodopropane to form 2-[2-(N,N-dimethylamino) ethyl]-5-chloropentanenitrile which, after cyclization, gives 4-cyano-l-methylperhydroazepine. From this compound and using conventional methods, the expected amine is obtained.
Reaction SMILES: FC(F)(F)C(O)=[O:4].C([C@@H]1C(OC)=[N:15][C@@H:14]([CH2:19][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH3:22])[C:13]([O:29][CH3:30])=N1)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(#N)C>[CH3:30][O:29][C:13](=[O:4])[C@@H:14]([NH2:15])[CH2:19][C@@H:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][CH3:22]
Reactant: CC[C@@H](C[C@@H]1N=C(OC)[C@@H](C(C)C)N=C1OC)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC[C@@H](C[C@H](N)C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of trifluoroacetic acid (3.4 ml) in water (440 ml) was added dropwise over 15 min a solution of (2R,5S)-2-isopropyl-3,6-dimethoxy-5-((S)-2-phenyl-butyl)-2,5-dihydro-pyrazine (4.69 g, 14.8 mmol) in acetonitrile (75 ml). The mixture was stirred overnight at room temperature then made basic by addition of saturated aqueous sodium carbonate solution and the mixture was extracted with ethyl acetate. The phases were separated and the organic phase was washed sequentially with water and with saturated brine, then dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, EtOAc/heptane) to yield a yellow oil (2.78 g, 85%); MS (ISP): 222.1 ([M+H]+).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1>N1C=CC=CC=1.C(Cl)Cl.C(Cl)Cl>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cccnc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (0.733 mL, 5.84 mmol) is suspended in pyridine/DCM (3 mL, 2:1). The solution is stirred at 0° C., and 3-aminopyridine (500 mg, 5.31 mmol) dissolved in DCM (1 mL) is added dropwise. The reaction mixture is at 0° C. for 1 hour. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate. This organic portion is washed with 0.1 M HCl and then concentrated in vacuo to afford the titled compound. (MH+215)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33](=[O:35])[CH3:34])=[N:31][CH:32]=2)=[CH:23][CH:22]=1>C1COCC1>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)([OH:35])[CH3:34])=[N:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: Ic1ccncc1
Reactant: COc1ccc(-c2ccc(C(C)=O)nc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(C)(O)c3ccncc3)nc2)cc1
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To cooled (−78° C.) 4-iodopyridine (270 mg, 1.3 mmol) [Albrecht, et al., US Patent Application Publication No. 2009/0318436] in THF (15 mL) was added slowly 1.6 M n-BuLi in hexane (1.65 mL, 2.6 mmol). Stirring was continued for an additional 30 minutes at the same temperature, followed by the addition of a THF (5 mL) solution of 1-(5-(4-methoxyphenyl)pyridin-2-yl)ethanone (300 mg, 1.3 mmol). After stirring for 2 hours at the same temperature, the reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL). The aqueous layer was extracted with ethylacetate (2×150 mL). The combined organic layers were washed with brine (20 mL). Finally, the organic phase was dried over Na2SO4 and concentrated under reduced pressure to give crude product. The crude product was purified by flash chromatography (silica gel 60-120μ) using 20% ethyl acetate and hexane as eluent to afford racemic 1-(5-(4-methoxyphenyl)pyridin-2-yl)-1-(pyridin-4-yl)ethanol as an off-white solid (135 mg, 33% yield) in 99.6% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.74 (d, 1H), 8.45 (dd, 2H), 7.98 (dd, 1H), 7.68 (d, 1H), 7.62 (d, 2H), 7.48 (dd, 2H), 7.02 (d, 2H), 6.15 (s, 1H), 3.78 (s, 3H), 1.88 (s, 3H); LC-MS m/z calculated for [M+H]+307.14. found 307.3.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:3].Br[CH2:16][C:17](=O)[C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19]>>[CH2:21]([O:20][C:18]([C:17]1[C:6]2[NH:7][C:8]3[CH:9]=[C:10]([F:14])[CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4][CH:2]([CH3:1])[NH:3][CH:16]=1)=[O:19])[CH2:22][CH3:23]
Reactant: CC(N)Cc1c[nH]c2cc(F)ccc12
Reactant: CCCOC(=O)C(=O)CBr
Product: CCCOC(=O)C1=CNC(C)Cc2c1[nH]c1cc(F)ccc21

Procedure:
2-Methyl-8-fluoro-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid n-propyl ester was prepared in a manner similar to that described in Example 1A by using α-methyl-6-fluorotryptamine and n-propyl 3-bromopyruvate; MS (ESI): 303 (MH+).
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][O:11][CH2:12][CH2:13][NH2:14]>O1CCCC1>[CH3:10][O:11][CH2:12][CH2:13][NH:14][C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COCCN
Reactant: CCOC(=O)CC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)NCCOC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.0 g (13.3 mmol) Ethyl 3-chloro-3-oxopropanoate are dissolved in 50 ml tetrahydrofuran and 2.99 g (39.85 mmol) 2-methoxyethylamine are added at 0° C. The reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the product is isolated by column chromatography (silica, eluent dichloromethane/methanol 50:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]1[C:6]([CH:7]=[CH:8][CH:9]=[C:10]1[C:16]([OH:18])=O)=[N:5]2.[NH2:19][CH2:20][CH2:21][N:22]([CH2:33][CH3:34])[CH2:23][CH2:24][O:25][C:26]1[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=1>S(Cl)(Cl)=O.ClCCl>[CH2:33]([N:22]([CH2:21][CH2:20][NH:19][C:16]([C:10]1[C:11]2[C:6](=[N:5][C:4]3[C:13]([N:12]=2)=[CH:14][CH:15]=[C:2]([Br:1])[CH:3]=3)[CH:7]=[CH:8][CH:9]=1)=[O:18])[CH2:23][CH2:24][O:25][C:26]1[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=1)[CH3:34]
Reactant: CCN(CCN)CCOc1cccnc1F
Reactant: O=C(O)c1cccc2nc3cc(Br)ccc3nc12
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CCNC(=O)c1cccc2nc3cc(Br)ccc3nc12)CCOc1cccnc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.5 %

Procedure:
A solution of 7-bromophenazine-1-carboxylic acid (81) (333 mg, 1.10 mmol) (Madelmont, J. C.; Chezal, J. M.: Moins, N.; Teulade, J. C.; Chavignon, O. Labelled analogues of halobenzamides as radiopharmaceuticals, WO 2008/012782A3) in thionyl chloride (8 mL) was refluxed, under argon, for 1 h. After cooling to room temperature, the solvent was evaporated under reduce pressure and the residue was dissolved in anhydrous toluene (5 mL). The solvent was evaporated under vacuum and the residue was dissolved in anhydrous dichloromethane (11 mL). A solution of compound 5 (300 mg, 1.32 mmol) in anhydrous dichloromethane (5 mL) was added, at 0° C. and the mixture was then stirred at room temperature for 24 h. The solvent was evaporated under reduce pressure and the residue was chromatographed (Al2O3, AcOEt) to give compound 82 (537 mg, 1.05 mmol) as a yellow oil. Yield 95%; Rf (Al2O3, AcOEt) 0.69; IR (CCl4) ν 1190, 1249, 1283, 1466, 1517, 1663, 2800-3000, 3250-3350 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.09 (t, 3H, J=7.1 Hz), 2.80 (q, 2H, J=7.1 Hz), 2.86 (t, 2H, J=6.0 Hz), 3.00 (t, 2H, J=5.5 Hz), 3.70 (q, 2H, J=6.0 Hz), 4.04 (t, 2H, J=5.5 Hz), 6.75 (ddd, 1H, 5JH-F=0.8 Hz, J=4.8, 7.9 Hz), 6.93 (ddd, 1H, 4JH-F=10.1 Hz, J=1.5, 7.9 Hz), 7.45 (td, 1H, 4JH-F=1.5 Hz, J=1.5, 4.8 Hz), 7.71 (dd, 1H, J=2.0, 9.2 Hz), 7.82 (dd, 1H, J=7.1, 8.7 Hz), 7.89 (d, 1H, J=9.2 Hz), 8.15 (dd, 1H, J=1.5, 8.7 Hz), 8.23 (d, 1H, J=2.0 Hz), 8.84 (dd, 1H, J=1.5, 7.1 Hz), 10.79 (m, 1H); ESI-MS m/z 512.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[C:12]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH3:11])[C:8]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 98 was prepared from 2,2-diphenylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 1H), 7.37–7.22 (m, 13H), 6.91 (d, 1H, J=7.2 Hz), 6.24 (br s, 1H), 3.37 (dd, 2H, J=5.6, 11.6 Hz), 2.88 (d, 2H, J=11.6 Hz), 2.42 (m, 1H), 2.32 (m, 4H), 2.01 (s, 3H), 1.93 (t, 2H, J=11.6 Hz), 1.81–1.52 (m, 8H), 1.01 (t, 3H, J=6.8 Hz); ESMS m/e: 512.3 (M+H)+.
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:20])=[N:8][CH:9]=[C:10](/[CH:11]=[CH:12]/[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[C:5]=2[S:4][CH:3]=1.[O:21]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])/[CH:12]=[CH:11]/[C:10]1[C:5]2[S:4][CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:29][CH:30]=3)[C:6]=2[C:7]([NH2:20])=[N:8][CH:9]=1)[CH3:16]
Reactant: CCOC(/C=C/c1cnc(N)c2c(Br)csc12)OCC
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12)OCC
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A mixture of Example 176A (250 mg, 0.70 mmol), 4-phenoxyphenylboronic acid (180 mg, 0.84 mmol), Pd(PPh3)4 (50 mg, 0.04 mmol), and sodium carbonate (150 mg, 1.4 mmol) in 1,2-dimethoxyethane (8 mL) and water (4 mL) was heated to reflux for 15 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was extracted with dichloromethane and the extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to provide the desired product (170 mg, 55%). 1H NMR (DMSO-d6, 400 MHz) δ 8.00 (s, 1H), 7.56 (s, 1H), 7.47 (m, 4H), 7.20 (t, 1H), 7.13 (m, 4H), 6.81 (d, 1H), 6.17 (dd, 1H), 5.67 (br s, 2H), 5.13 (d, 1H), 3.57 (m, 4H), 1.18 (t, 6H); MS m/e 447.3 (M+H)+.