Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl.O>[C:9]([O:8][C:7]([NH:6][C@@H:3]1[CH2:4][CH2:5][N:1]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:2]1)=[O:13])([CH3:10])([CH3:12])[CH3:11]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
A solution of tert-Butyl (3S)-pyrrolidin-3-ylcarbamate (10.0 g, 53.7 mmol) in DCM (40 ml) was treated with TEA (14.9ml, 107 mmol) and cooled to 0° C. Benzyl chloroformate (7.6 ml, 53.7 mmol) was added dropwise and the resulting suspension was allowed to warm gradually to room temperature over a period of 18 hours. The reaction mixture was diluted with water (100 ml) and the organic phase separated. The aqueous phase was extracted with further DCM (2×50 ml) and the combined organic extracts dried (sodium sulphate) and concentrated in vacuo to give a pale yellow solid (14.6 g, 85%)
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: OB(O)c1cccnc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2cccnc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (50 mg, 69%), MS (ISN) m/z=289.4 [(M+H)+], mp 272.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available pyridin-3-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>N1C=CC=CC=1>[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([CH:2]([NH2:1])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][O:11][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: NCCc1ccccc1CO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: NC(Cc1ccccc1COC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
1-Amino-2-(2-hydroxymethylphenyl)ethane (10.2 g) was dissolved in 40 ml of pyridine, and with stirring under ice cooling, 25 g of 4-nitrobenzoyl chloride was added gradually. The mixture was stirred at room temperature for 4 hours and then at 50° C. for 1 hour, and poured into ice water. The crystals precipitated were washed in water, dried, and recrystallized from tetrahydrofuran-benzene to afford 24.3 g of 1-(4-nitrobenzoyl)-amino-2-[2-(4-nitrobenzoyloxymethyl)phenyl]ethane having a melting point of 168.2° to 169.7° C.
Reaction SMILES: [Cl:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14]>C1(C)C=CC=CC=1>[Cl:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:19])=[O:4]
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)C(Cl)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)CNC(=O)C(Cl)c1ccccc1
Yield: 85.8 %

Procedure:
21.0 g (0.11 m) α-chlorophenylacetyl chloride and 14.0 g (0.10 m) glycine ethyl ester hydrochloride are suspended in 500 ml toluene and the mixture is heated to reflux overnight. The reaction mixture is filtered, and after the solvent is removed, the residual solid is recrystallized from cyclohexane to give 22 g (86% yield) of the title compound, which has a melting point of 88°-9° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.[H-].[Na+].Cl[C:26]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]=[C:28]([N:38]2[C:50]3[CH:49]=[CH:48][C:47]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[CH:46][C:45]=3[C:44]3[C:39]2=[CH:40][CH:41]=[C:42]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:43]=3)[N:27]=1>CN(C)C=O>[C:57]1([C:42]2[CH:41]=[CH:40][C:39]3[N:38]([C:28]4[N:29]=[C:30]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:31]=[C:26]([N:13]5[C:12]6[CH:11]=[C:10]7[C:2]([CH3:22])([CH3:1])[C:3]8[C:8]([C:9]7=[CH:21][C:20]=6[C:19]6[C:14]5=[CH:15][CH:16]=[CH:17][CH:18]=6)=[CH:7][CH:6]=[CH:5][CH:4]=8)[N:27]=4)[C:50]4[C:45]([C:44]=3[CH:43]=2)=[CH:46][C:47]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:48][CH:49]=4)[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Reactant: Clc1nc(-c2ccccc2)nc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4nc(-c5ccccc5)nc(-n5c6ccc(-c7ccccc7)cc6c6cc(-c7ccccc7)ccc65)n4)c3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18.7 g (66.3 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]-fluorene are dissolved in 200 ml of dimethylformamide under a protective-gas atmosphere, and 5.3 g of 60% NaH in mineral oil (73 mmol) are added. After 1 h at room temperature, a solution of 9-(4-chloro-6-phenyl-1,3,5-triazin-2-yl)-3,6-diphenyl-9H-carbazole (40.5 g, 79.5 mmol) in 150 ml of dimethylformamide is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene, recrystallised from dichloromethane/isopropanol and finally sublimed in a high vacuum, the purity is 99.9%. The yield is 21.4 g (28 mmol, 42%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[O:17])[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>C(#N)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][N:10]3[CH2:11][CH2:12][CH:13]([C:16](=[O:17])[C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[F:25])[CH2:14][CH2:15]3)[CH2:4][CH2:3]2)=[O:35])=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3F)CC2)CC1
Solvent: CC#N
Product: O=C(Nc1ccc(Cl)cc1)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3F)CC2)CC1

Procedure:
The title compound was synthesized from Trans-{1-[2-(4-Amino-cyclohexyl)-ethyl]-piperidin-4-yl}-(2,4-difluoro-phenyl)-methanone (example 58, intermediate F) and 4-Chloro phenyl isocyanate in acetonitrile according to the procedure described for example 38. MS (m/e): 504.3 (M+H+).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]1([C:17](=[N:24][CH2:25][CH:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]([O:29][CH3:30])=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:37]I>C1COCC1>[C:11]1([C:17](=[N:24][CH2:25][C:26]([CH3:37])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]([O:29][CH3:30])=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CI
Reactant: COC(=O)C(CN=C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(CN=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of LiHMDS in THF cooled to −78° C. was added a solution of methyl 3-(diphenylmethyleneamino)-2-phenylpropanoate (E320) in THF also cooled to approximately −78° C. This solution stirred for 30 min at −78° C., then methyl iodide was added directly and the solution was warmed to 0° C. After 3 h the solution was poured into NH4Cl(sat) and extracted with EtOAc. The combined organics were dried (Na2SO4) filtered, and evaporated. Column chromatography (SiO2, 0-15% EtOAc/Hexanes) gave pure methyl 3-(diphenylmethyleneamino)-2-methyl-2-phenylpropanoate (E321).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([OH:17])=[C:11]([CH3:18])[C:10]=2[CH3:19])[CH:6]=[CH:7][CH:8]=1.CC1C=CC(S(O[CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:19][C:10]1[C:11]([CH3:18])=[C:12]([O:17][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: Cc1c(C)c(-c2cccc(CO)c2)c(C)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)c(-c2cccc(CO)c2)c(C)c(C)c1OCCCS(C)(=O)=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 63.9 %

Procedure:
To a solution of 3′-(hydroxymethyl)-2,3,5,6-tetramethylbiphenyl-4-ol (0.616 g, 2.40 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (1.05 g, 3.60 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (0.597 g, 4.32 mmol), and the mixture was stirred at 90° C. for 12 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.577 g, yield 85%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:18])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:19]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1)#[N:21].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>[CH3:11][C@H:9]1[O:8][C@@:7]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:19]=[C:2]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=3)[C:20]#[N:21])[CH:3]=[CH:4][C:5]=2[NH:10]1
Reactant: CC1Nc2ccc(Br)cc2C(C)(c2ccccc2)O1
Reactant: N#Cc1cc(F)cc(B(O)O)c1
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: C[C@@H]1Nc2ccc(-c3cc(F)cc(C#N)c3)cc2[C@](C)(c2ccccc2)O1
Temperature: 85 °C
Yield: 13.2 %

Procedure:
A mixture of 6-bromo-2,4-dimethyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazine (0.6 g, 1.9 mmol), 3-cyano-5-fluorobenzene boronic acid (0.45 g, 2.7 mmol), tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.17 mmol), sodium carbonate (0.6 g, 5.7 mmol) in a mixture of DME and water (20/5 mL) was subject to a positive nitrogen flow to remove oxygen and then heated to 85° C. under a blanket of nitrogen for 2 hours. The mixture was allowed to cool to ambient temperature. Brine (30 mL) and ethyl acetate (100 mL) were added. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (MgSO4), and evaporated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate/4:1) to afford the title compound as off-white solid (0.09 g, 13%): mp 128-129° C.; 1H-NMR (DMSO-d6) δ 8.08 (s, 1H), 7.91 (dt, 1H, J=10.7, 1.9 Hz), 7.71 (d, 1H, J=2.0 Hz), 7.65 (m, 1H), 7.57 (dd, 1H, J=8.8, 2.4 Hz), 7.32-7.36 (m, 2H), 7.24-7.29 (m, 3H), 6.71 (d, 1H, J=1.6 Hz), 6.69 (d, 1H, J=8.3 Hz), 4.33 (m, 1H), 1.84 (s, 3H), 1.24 (d, 3H, J=5.5 Hz); MS (ESI) m/z 357 [M−H]−.
Reaction SMILES: [CH2:1]([C:3]([C:8]1[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:16].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[CH2:1]([C:3]([C:8]1[C:9]([CH2:14][OH:16])=[N:10][CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(OC)c1cccnc1C
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCC(CC)(OC)c1cccnc1CO
Reaction time: 24 h
Yield: 60 %

Procedure:
To a solution of 3-(1-ethyl-1-methoxy-propyl)-2-methyl-pyridine (0.185 g, 0.884 mmol) in CH2Cl2 (3 mL) was added TFAA (1 mL). The mixture was stirred for 24 h. K2CO3 (0.60 g, 4.3 mmol) in water (10 mL) was added. The aqueous mixture was extracted with CH2Cl2 (4×25 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (3:1 Et2O/CH2Cl2), affording [3-(1-ethyl-1-methoxy-propyl)-pyridin-2-yl]-methanol as a yellow oil (0.111 g, 60%). 1H NMR (CDCl3) δ 0.70 (t, 6H, J=7.5 Hz), 1.76-1.88 (m, 2H), 1.89-2.01 (m, 2H), 3.06 (s, 3H), 4.93 (s, 2H), 7.21 (dd, 1H, J=7.8, 4.8 Hz), 7.56 (dd, 1H, J=7.8, 1.5 Hz), 8.47 (dd, 1H, J=4.8, 1.5 Hz).
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])O.[Na+].Cl[CH2:35][O:36][CH2:37][CH3:38].O>C(#N)C>[C:1]1([CH:7]2[O:12][C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]([CH2:35][O:36][CH2:37][CH3:38])[S:22]([C:25]([F:26])([F:27])[F:28])(=[O:23])=[O:24])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCCl
Reactant: O=C1OC(c2ccccc2)CCN1Cc1ccccc1NS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOCN(c1ccccc1CN1CCC(c2ccccc2)OC1=O)S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 75 %

Procedure:
6-Phenyl-3-[2-(trifluoromethanesulfonylamino)benzyl]-[1,3]-oxazinan-2-one (0.20 g, 0.48 mmol) and sodium hydrogen carbonate (0.08 g, 0.85 mmol) were suspended in acetonitrile (10 ml), added with chloromethylethyl ether (0.07 g, 0.83 mmol) and heated to reflux for three hours. After cooling to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 6-phenyl-3-{2-[N-(ethoxymethyl)-N-(trifluoromethanesulfonyl)amino]benzyl)-[1,3]-oxazinan-2-one (0.17 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)#[N:20]>>[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:16][C:11]2[C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=3)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:26])=[CH:23][CH:22]=1)#[N:20]
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(C#N)cc2)cc1

Procedure:
Using a procedure similar to Example 1B except starting with N1-(4-methoxybenzoyl)-1,2-benzenediamine and 4-cyanobenzoyl chloride, the title compound was obtained as a solid (59%); MS(FD): 371.0.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[N:12]1([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[NH2:8][C:6]1[CH:7]=[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:27])[F:29])=[O:19])[CH2:17][CH2:16]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Nc1cc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 79 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (3.000 g, 17.38 mmol), piperazin-1-yl-(2-trifluoromethylphenyl)methanone (5.360 g, 20.80 mmol) and cesium carbonate (11.32 g, 34.76 mmol) was heated at 140° C. in anhydrous DMSO (15 mL) for 12 h. The mixture was cooled and poured over ice water. The solid product obtained was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulphate, concentrated in vacuo. The residue was purified by column chromatography to obtain the product, [4-(3-amino-4-nitrophenyl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone, in 79% yield (6.800 g). 1H NMR (300 MHz, CDCl3) δ 8.01 (d, 1H, J=9.6 Hz), 7.72 (d, 1H, J=7.9 Hz), 7.62 (t, 1H, J=7.1 Hz), 7.54 (t, 1H, J=7.4 Hz), 7.34 (d, 1H, J=7.3 Hz), 6.22 (dd, 1H, J=2.6,9.7 Hz), 6.15 (br. s, 2H), 5.94 (d, 1H, J=2.6 Hz), 4.05-3.93 (m, 1H), 3.90-3.80 (m, 1H), 3.50-3.40 (m, 2H), 3.35-3.20 (m, 4H). MS (ES+) m/z 395.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[N:6]([CH2:18][CH3:19])[C:7]3[N:15]=[C:14]([Cl:16])[CH:13]=[C:12]([CH3:17])[C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH2:24]>CN(C=O)C.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>[Cl:16][C:14]1[CH:13]=[C:12]([CH3:17])[C:8]2[NH:9][C:10](=[O:11])[C:4]3[CH:3]=[C:2]([CH2:24][CH:23]=[CH2:22])[CH:21]=[N:20][C:5]=3[N:6]([CH2:18][CH3:19])[C:7]=2[N:15]=1
Reactant: CCN1c2ncc(Br)cc2C(=O)Nc2c(C)cc(Cl)nc21
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cnc2c(c1)C(=O)Nc1c(C)cc(Cl)nc1N2CC
Temperature: 100 °C
Yield: 71.3 %

Procedure:
A solution of 8-bromo-2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (12.6 g, 34.3 mmol) in DMF (25-0 mL) was degassed under reduced pressure for 20 min. Pd(PPh3)4 (775 mg, 0.7 mmol) was then added followed by allyltributyltin (12.5 mL, 41.1 mmol). After degassing under reduced pressure for 10 min, the mixture was heated to 100° C. for 7 h. The mixture was then concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 19:1) to give the title compound (8.04 g, 71% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]([F:16])([F:15])[C:3]([Cl:14])([F:13])[C:4]([F:12])([F:11])[C:5]([F:10])([F:9])[CH2:6][CH2:7]I.C(O)C.[OH-].[K+]>O>[Cl:14][C:3]([F:13])([C:2]([Cl:1])([F:15])[F:16])[C:4]([F:11])([F:12])[C:5]([F:10])([F:9])[CH:6]=[CH2:7]
Reactant: FC(F)(Cl)C(F)(Cl)C(F)(F)C(F)(F)CCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CC(F)(F)C(F)(F)C(F)(Cl)C(F)(F)Cl
Yield: 92 %

Procedure:
To a stirred solution of 1,2-dichloro-1,1,2,3,3,4,4,-heptafluoro-6-iodohexane (370.0 g) and ethanol (400 mL) was added dropwise a solution of potassium hydroxide (56.0 g), ethanol (300 mL) and water (20 mL) at 80°-90° C. over 40 minutes. After the addition was complete, the reaction mixture was refluxed for 1 hour and then poured into water. Lower layer was separated and washed with water to give desired product (233.5 g). 19F NMR: -63.9 (m, 2F), -111.9 (m, 2F), -116.2 (m, 2F), -130.5 (m, 1F); 1H NMR: 5.72 to 6.10 (m). IR: 1651 (m), 1422 (s), 1180 (s), 1055 (s), 1019 (s), 1002 (s), 980 (s).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:4]3[CH:3]=[C:2]([NH:38][C:35]4[CH:36]=[CH:37][C:32]([C:31]([F:30])([F:39])[F:40])=[CH:33][CH:34]=4)[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(C(F)(F)F)cc4)cc3n2C(=O)OC(C)(C)C)cn1
Yield: 63 %

Procedure:
The title compound was prepared in 63% yield from compound (10) and 4-trifluoromethyl phenylamine using the method described for Preparation 35. 1H-NMR (CDCl3, 500 MHz): δ 1.53 (m, 9H), 1.70 (m, 9H), 6.61 (d, J=0.95 Hz, 1H), 6.81 (br s, 1H), 7.47 (d, J=8.51 Hz, 2H), 7.57 (d, J=8.20 Hz, 2H), 7.73 (m, 1H), 7.83 (d, J=0.63 Hz, 1H), 8.23 (d, J=0.63 Hz, 1H), 8.52 (d, J=0.95 Hz, 1H). 19F-NMR (CDCl3): δ −61.73.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:15](OCC)(OCC)OCC>>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[CH:6]=[CH:5][N:4]2[CH:15]=[N:2][N:1]=[C:3]2[CH:8]=1
Reactant: NNc1cc(-c2ccccn2)ccn1
Reactant: CCOC(OCC)OCC
Product: c1ccc(-c2ccn3cnnc3c2)nc1

Procedure:
A mixture of 2.0 g of 2'-hydrazino-2,4'-bipyridine and 50 ml of triethyl orthoformate was heated on a steam bath for 18 hours then chilled and filtered. The crystals were dissolved in methylene chloride, treated with activated carbon, filtered and the filtrate concentrated. Chilling and filtration gave 1.5 g of the desired product as cream colored crystals, mp 144-°145° C.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16]([OH:19])=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:24][N:12]1[C:13]2[C:14]([C:20]([F:21])([F:23])[F:22])=[CH:15][C:16]([O:19][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:17][C:18]=2[C@@H:10]2[CH2:9][NH:8][CH2:26][CH2:25][C@H:11]12
Reactant: BrCc1ccccn1
Reactant: CN1c2c(cc(O)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1c2c(cc(OCc3ccccn3)cc2C(F)(F)F)[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general method as a yellow solid (60 mg, 61%) from (4aS,9bR)-8-hydroxy-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 71, 100 mg, 0.27 mmol), 2-bromomethyl-pyridine (141 mg, 0.56 mmol) and K2CO3 (156 mg, 1.12 mmol). MS (ESI): 364 (base, M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.CC(C)=O.[CH2:16]1[S:20](=[O:22])(=[O:21])[O:19][CH2:18][CH2:17]1>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:18][CH2:17][CH2:16][S:20]([OH:22])(=[O:21])=[O:19])[CH2:7][CH2:6][CH2:5]2
Reactant: O=S1(=O)CCCO1
Reactant: Brc1ccc2c(c1)CCCN2
Solvent: CO
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CCCc2cc(Br)ccc21

Procedure:
4.2 g of the 6-bromo-1,2,3,4-tetra-hydroquinoline obtained according to a) above were dissolved in 0 ml. acetone and, while stirring at 50° C., 2.44 g. molten propane-1,3-sultone, dissolved in 20 ml. acetone, were added dropwise within the course of 30 minutes. After boiling under reflux for 24 hours, a further 2.44 g. molten propanesultone, dissolved in 20 ml. acetone, were added dropwise under the same conditions. After boiling under reflux for 48 hours, the reaction mixture was subjected to column chromatography (silica gel; elution agent chloroform/methanol=1/1 v/v; 25 ml. fractions); fractions 6-10 were evaporated in a vacuum at 35° C., the 1.8 g. of red-brown residue obtained was stirred with about 20 ml. methanol and 1.05 g of sand-coloured crystals were obtained; m.p. 217° C. (decomp.).