Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[CH:11][C:10]([C:13]([O:15]C)=O)=[CH:9][N:8]=1.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:13]([C:10]4[CH:11]=[N:12][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:17])=[N:8][CH:9]=4)=[O:15])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: COC(=O)c1cnc(N2CCCS2(=O)=O)nc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3CCCS3(=O)=O)nc2)CC1
Yield: 6.8 %

Procedure:
Using methyl 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)pyrimidine-5-carboxylate (85 mg) described in Preparation Example 231 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (72 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (10 mg) was obtained.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21].ClCCl>CN(C=O)C>[N:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=3)[CH2:18][CH2:19]2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCN(c2ccncc2)CC1
Temperature: 4 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
Triethylamine (3.48 ml) was added to a stirred suspension of 1-(4-pyridyl)piperazine (4.08 g) in DMF (50 ml). The mixture was cooled to 4° C., and 4-nitrobenzoylchloride (4.64 g) added. The mixture was stirred for 1 hour at 4° C. and then for 16 hours at ambient temperature. Dichloromethane (250 ml) was then added and the mixture washed with water (3×30 ml), saturated brine (1×30 ml), then dried (MgSO4) and the solvents evaporated. The residual oil was purified by flash chromatography on silica gel using 5% v/v methanol/dichloromethane and then with 10% v/v methanol/dichloromethane as eluant to give 1-(4pyridyl)-4-(4-nitrobenzoyl)piperazine (5.09 g) as a yellow solid. m.p. 158-160° C.; microanalysis. found: C, 61.3; H, 5.3; N, 17.6%; C16H16N4O3 requires: C, 61.5; H, 5.2; N, 17.9%: NMR: 3.42(6H+H2O,m), 3.87(2H,bs), 6.93(2H,d), 7.84(2H,d), 8.30(2H,d), 8.41(2H,d): MS: m/z 313 (MH)+.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH:10]([C:17]([NH2:19])=O)[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>N1C=CC=CC=1>[C:17]([CH:10]1[C:9]2[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)#[N:19]
Reactant: NC(=O)C1CCCc2ccc(-c3ccccc3)nc21
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: N#CC1CCCc2ccc(-c3ccccc3)nc21
Yield: 16.2 %

Procedure:
2-Phenyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (8 g.) was dissolved in pyridine (20 ml.), treated with P2S5 (5.2 g.) and the mixture heated at reflux temperature for 30 minutes. The solvent was removed in vacuo and the residual oil dissolved in dilute HCl, washed with ether (2 × 50 ml.) and the washings discarded. The aqueous solution was made basic, extracted into chloroform (3 × 50 ml.) and the combined extracts dried and evaporated to dryness. The residual oil was chromatographed on silica gel by elution with chloroform giving 8-cyano-2-phenyl-5,6,7,8-tetrahydroquinoline (1.2 g.) as colourless needles from ether mpt. 100° C. Found: C, 82.0; H, 6.2; N, 11.7% C16H14N2 requires: C, 82.0; H, 6.0; N, 11.9%. Further elution with chloroform gave the title compound (1.1 g.) as colourless needles from ether mpt. 154° C. Found: C, 71.8; H, 6.1; N, 10.2%, C 16 H16N2S requires: C, 71.6; H, 6.0; N, 10.4%.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.[N:49]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57]C=2N=N1.[C:69](O)([C:71](F)(F)F)=[O:70]>CN1C(=O)CCC1>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([C:69](=[O:70])[CH2:71][N:49]4[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]4)[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(Nc2ccc(C3CCN(C(=O)CN4CCCCC4)CC3)cc2)cc1NCc1cccc(F)c1F
Temperature: 25 °C

Procedure:
The mixture of 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (80 mg, 0.17 mmol), 4-morphonlineacetic acid (100 mg, 0.68 mmol), DIEA (240 μL, 1.36 mmol) in 4 mL NMP was stirred at RT. To it was added BOP (260 mg, 0.68 mmol). The mixture was stirred at RT for overnight. To it was added TFA (0.5 mL). The mixture was subjected to reverse phase preparative HPLC to isolate the title compound (70 mg). MS found for C31H36F2N6O2 as (M+H)+ 563.5. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.18 (1H, s), 7.34-7.11 (7H, m), 5.80 (1H, s), 4.55 (2H, s), 4.35-4.26 (4H, m), 3.83 (2H, m), 3.60 (2H, m), 3.05 (2H, m), 2.89 (1H, m), 1.95-1.57 (10H, m) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C1(C)C=CC=CC=1.[C:23](#[N:26])[CH:24]=[CH2:25]>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:25][CH2:24][C:23]#[N:26])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=CC#N
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)c1c(n2CCC#N)CCN(C)C1
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.5 g, 7.5 mmol) was taken in 20 ml of benzene: toluene mixture (1:1) along with acrylonitrile (1 ml, 15 mmol), cooled to 0° C., followed by addition of triton base (0.3 ml). The contents were stirred for 15 min. Acrylonitrile and triton base (same amount) were added and stirred at RT for 1 h. The reaction was monitored by TLC and LCMS. On completion of the reaction, reaction mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain solid material, which was crystallized using diethyl ether to yield 3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanenitrile (yield: 1 g). 1H NMR (CDCl3) 7.25 (s, 1H), 7.18-7.15 (d, 1H), 7.08-7.03 (d, 1H), 4.38-4.32 (t, 2H), 3.70-3.65 (m, 2H), 2.95-2.90 (m, 4H), 2.78-2.70 (t, 2H), 2.58 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH2:16]([O:23][C:24]([N:26]([CH2:47][C:48]([N:50]1[CH2:54][C@@H:53]([F:55])[CH2:52][C@H:51]1[C:56]#[N:57])=[O:49])[C:27]12[CH2:34][CH2:33][C:30]([C:35](ON3C4C=CC=CC=4N=N3)=[O:36])([CH2:31][CH2:32]1)[CH2:29][CH2:28]2)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.ClCCl>[CH2:16]([O:23][C:24]([N:26]([CH2:47][C:48]([N:50]1[CH2:54][C@@H:53]([F:55])[CH2:52][C@H:51]1[C:56]#[N:57])=[O:49])[C:27]12[CH2:34][CH2:33][C:30]([C:35]([N:6]3[CH2:7][CH2:8][CH:3]([F:2])[CH2:4][CH2:5]3)=[O:36])([CH2:31][CH2:32]1)[CH2:29][CH2:28]2)=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: FC1CCNCC1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCC(F)CC3)(CC1)CC2
Reaction time: 0.58 h
Yield: 78.4 %

Procedure:
4-Fluoropiperidine hydrochloride (18.2 mg) was suspended in tetrahydrofuran (0.87 mL). While this suspension was chilled in an ice bath, triethylamine (18.2 μL) was added and the mixture was stirred at the same temperature for 35 minutes. Subsequently, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed sequentially with 0.1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluant:ethyl acetate:methanol=20:1) to give (2S,4S)-1-[[N-benzyloxycarbonyl-[4-(4-fluoropiperidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (37.0 mg).
Reaction SMILES: C(O[CH:5]1[O:14][C@@H:13]([CH3:15])[C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C@@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[F:23])(=O)C.C(O[C@@H]1O[C@@H](C)[C@@H](NC(=O)C(F)(F)F)[C@@H](OC(=O)C)[C@H]1F)(=O)C.O[C@H]1O[C@@H](CO)[C@@H](O)[C@@H](O)[C@H]1O.[BrH:59]>C(O)(=O)C>[C:9]([O:8][C@@H:7]1[C@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C@H:13]([CH3:15])[O:14][C@@H:5]([Br:59])[C@@H:6]1[F:23])(=[O:11])[CH3:10]
Reactant: CC(=O)OC1O[C@@H](C)[C@@H](NC(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@H]1F
Reactant: Br
Agent: CC(=O)O[C@@H]1O[C@@H](C)[C@@H](NC(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@H]1F
Agent: OC[C@@H]1O[C@H](O)[C@H](O)[C@H](O)[C@@H]1O
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1[C@@H](F)[C@H](Br)O[C@@H](C)[C@H]1NC(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
1,3-Di-O-acetyl-2,4,6-trideoxy-2-fluoro-4-(trifluoroacetamido)-L-talopyranose [the mixture of Compounds (11) and (12)] (335 mg) obtained in Example 1-(8) above was dissolved in 3.4 ml of a solution of 30% hydrogen bromide in acetic acid. The resultant solution was allowed to stand at room temperature for 1 hour to effect the bromination reaction.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](Br)[S:4][C:3]=1[C:8]1[S:9][C:10](Br)=[CH:11][C:12]=1[Br:13].C(O)C.O>[Zn].C(O)(=O)C>[Br:13][C:12]1[CH:11]=[CH:10][S:9][C:8]=1[C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Br:1]
Reactant: Brc1cc(Br)c(-c2sc(Br)cc2Br)s1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Brc1ccsc1-c1sccc1Br
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of 3,3′,5,5′-tetrabromo-2,2′-bithiophene (25 g, 52.3 mmol), ethanol (50 ml), water (50 ml) and glacial acetic acid (100 ml) was heated to reflux. Then the heating oil bath was removed, and zinc powder (13.1 g, 200 mmol) was added in portions at such a rate that the mixture continued to reflux. After the addition was complete, heating was continued, the mixture was refluxed for another 5 h and cooled down to room temperature. The unreacted zinc powder was filtered off and the filtrate was collected, diluted with diethyl ether and then washed twice with water. The ether solution was dried with anhydrous MgSO4 and the solvent was evaporated under reduced pressure. The crude product was recrystallized from hexane to afford a greenish crystal in the yield of 91% (15.3 g). 1H-NMR (CDCl3, ppm): δ7.40 (d, 2H, J=5 Hz), 7.11 (d, 2H, J=5 Hz).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[C:15]([OH:16])=[C:14]2[C:10]([CH2:11][CH2:12][C:13]2=O)=[C:9]([CH3:18])[CH:8]=1)=[O:4].Cl.[NH2:20][OH:21].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C>O>[Cl-:1].[OH:16][C:15]1[C:7]([CH2:6][NH:5][C:3]([CH2:2][N+:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:4])=[CH:8][C:9]([CH3:18])=[C:10]2[C:14]=1[C:13](=[N:20][OH:21])[CH2:12][CH2:11]2
Reactant: c1ccncc1
Reactant: Cc1cc(CNC(=O)CCl)c(O)c2c1CCC2=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(CNC(=O)C[n+]2ccccc2)c(O)c2c1CCC2=NO
Product: [Cl-]

Procedure:
200 Grams of 6-chloroacetylaminomethyl-2,3-dihydro-7-hydroxy-4-methyl-1H-indene-1-one, 77.9 g of hydroxylamine hydrochloride, 300 ml of pyridine and 1,800 ml of ethanol were refluxed for 3 hours. After the reaction was completed, the solvent was removed by evaporation under a reduced pressure, then to the residue thus obtained was added 2 liters of water and the mixture was stirred vigorously, cooled and crystallized. The crystals were collected by filtration, washed with water, and recrystallized from water to obtain 167 g of (2,3-dihydro-7-hydroxy-1-hydroxyimino-4-methyl-1H-indene-6-yl)methylaminocarbonylmethylpyridinium chloride. Colorless flake-like crystals. Melting point: 279° C. (Decomposed).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.[CH2:10]([Mg]Br)[CH:11]=[CH2:12]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:12][CH:11]=[CH2:10])[CH:3]=1
Reactant: BrCc1cccc(Br)c1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A mixture of 1-bromo-3-(bromomethyl)benzene (1 g, 4.00 mmol) in THF (15 mL) was added allylmagnesium bromide (4.80 mL, 4.80 mmol) and stirred at rt for 1 h, then refluxed for 2 h. It was then quenched with NH4Cl, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil. It was then purified by 5% EtOAc/hexane to isolate 1-bromo-3-(but-3-en-1-yl)benzene (0.7 g, 3.32 mmol, 83% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.41-7.31 (m, 2H), 7.21-7.12 (m, 2H), 5.85 (ddt, J=17.1, 10.3, 6.6 Hz, 1H), 5.14-4.94 (m, 2H), 2.75-2.64 (m, 2H), 2.45-2.31 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([O:6][CH3:7])[C:4]=1[Cl:11].[CH3:12][O:13]C(Cl)Cl.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:11][C:4]1[C:3]([O:2][CH3:1])=[C:10]([CH:9]=[CH:8][C:5]=1[O:6][CH3:7])[CH:12]=[O:13]
Reactant: COC(Cl)Cl
Reactant: COc1cccc(OC)c1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C=O)c(OC)c1Cl

Procedure:
2-chlororesorcinol dimethyl ether (3.4 g) is dissolved in 20 ml of CH2Cl2 and TiCl4 (4.3 ml) is added. To this solution is added dichloromethyl methyl ether (2.3 g). After 30 minutes the reaction mixture is poured into H2O and extracted with ether. Drying and evaporation gives 3-chloro-2,4-dimethoxybenzaldehyde, mp 107°-108° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21]([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Br)c2)n(-c2ccnc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Br)c3)n(-c3ccnc(Cl)c3)n2)CCN1

Procedure:
50 mg (0.13 mmol) of the compound of Example 33A is reacted analogously to the synthesis of the compound of Example 4 with 14 mg (0.14 mmol) of 2-oxopiperazine. 49 mg (81% of theory) of the title compound is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:20]#[N:21].[Cl:22][C:23]1[C:29]([O:30][CH3:31])=[CH:28][C:26]([NH2:27])=[C:25]([CH3:32])[CH:24]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:22][C:23]1[C:29]([O:30][CH3:31])=[CH:28][C:26]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:20]#[N:21])=[C:25]([CH3:32])[CH:24]=1
Reactant: COc1cc(N)c(C)cc1Cl
Reactant: COc1cc2cc3ncc(C#N)c(Cl)c3cc2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OC)c(OC)cc4cc23)c(C)cc1Cl
Yield: 81.8 %

Procedure:
Following the procedure of Example 11, a mixture of 75.8 mg (0.25 mmol) of 4-chloro-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile, 51.5 mg (0.30 mmol) of 4-chloro-5-methoxy-2-methylaniline and 28.9 mg (0.25 mmol) of pyridine hydrochloride in 5.0 mL of 2-ethoxyethanol is heated at 120–130° C. for 2 hours to yield the crude product. Purification of the crude product on preparative TLC (developing solvent: 95:5 methylene chloride/methanol) yields 88.7 mg (82.1%) of the pure product as a yellow solid, mp 171–173° C.
Reaction SMILES: Br[C:2]1[C:3]([NH2:11])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[C:12]1(B(O)O)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1>>[C:12]1([C:2]2[C:3]([NH2:11])=[CH:4][C:5]3[O:9][CH2:8][O:7][C:6]=3[CH:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: Nc1cc2c(cc1Br)OCO2
Reactant: OB(O)C1=CCCCC1
Product: Nc1cc2c(cc1C1=CCCCC1)OCO2

Procedure:
The title compound was prepared by Suzuki coupling of 6-bromo-benzo[1,3]dioxol-5-ylamine (Bioorganic & Medicinal Chemistry (2002), 10(11), 3395-3400) and cyclohexen-1-ylboronic acid according the procedure Example 44, step (g). Mass spectrum (ESI, m/z): Calcd. for C13H15NO2, 218.1 (M+H), found 218.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH2:13][CH3:14].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18][N:30]1[CH2:29][CH2:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)[CH2:32][CH2:31]1)[CH2:13][CH3:14]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCC1(CCCCCl)C(=O)Nc2cc(F)c(Cl)cc21
Product: CCC1(CCCCN2CCN(c3cccc(Cl)c3)CC2)C(=O)Nc2cc(F)c(Cl)cc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 starting from 5-chloro-3-(4-chlorobutyl)-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1-(3-chlorophenyl)-piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][CH:16]=[CH:15][CH2:14][N:13]2[C:19]([OH:21])=[O:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:29][N:30]1[CH:34]=[C:33]([S:35](Cl)(=[O:37])=[O:36])[N:32]=[CH:31]1.Cl>O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][C:16]([S:35]([C:33]3[N:32]=[CH:31][N:30]([CH3:29])[CH:34]=3)(=[O:37])=[O:36])=[CH:15][CH2:14][N:13]2[C:19]([OH:21])=[O:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(S(=O)(=O)N2C=CC=CCN2C(=O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(S(=O)(=O)N2C=CC(S(=O)(=O)c3cn(C)cn3)=CCN2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 1-[(4-methoxyphenyl)sulfonyl]-diazepine-2-carboxylic acid (0.150 g, 0.48 mmol) is dissolved in water (10 mL) and p-dioxane (10 mL). The triethyl amine (0.27 mL, 1.9 mmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride (0.104 g, 0.58 mmol) are next added. The reaction mixture is stirred overnight at room temperature and then the solution is acidified with 1N HCl to pH~1, poured into water, and extracted with methylene chloride. The organic extracts are dried (Na2SO4) and concentrated down to an oil. The oil is purified by HPLC with a reverse phase column using 70% (95% water, 5% acetonitrile, 0.1% formic acid) and 30% (80% acetonitrile, 20% water) as the eluent.
Reaction SMILES: Cl.C(N(CC)CC)C.[C:9]([C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[CH2:14][CH2:15][O:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])#[N:10].[N-:29]=[N+:30]=[N-:31].[Na+].Cl>O.C(O)(C)(C)C>[N:10]1[NH:29][N:30]=[N:31][C:9]=1[C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[CH2:14][CH2:15][O:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(C#N)c1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)CCOCCc1cccc(-c2nn[nH]n2)c1
Temperature: 140 °C

Procedure:
Triethylamine hydrochloride (2.09 g) was added in one portion to a mixture of tert-butyl 3-(3-cyanophenethoxy)propanoate [Example 7, Step i)] (1.74 g), sodium azide (0.99 g) and tert-butanol (12.64 mL), and sealed into a microwave tube. The reaction was heated to 140° C., over a period of 2 h in the microwave reactor. The reaction mixture was diluted with water and acidified with 2M hydrochloric acid (5 mL). The mixture was extracted with DCM and the organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20-100% ethyl acetate in isohexane, then elution gradient 0-10% methanol in DCM to afford the subtitled compound (1.77 g). 1H NMR (300 MHz, CDCl3) δ 8.11 (d, J=7.8 Hz, 1H), 8.06 (s, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 3.79 (t, J=5.3 Hz, 2H), 3.75 (t, J=5.6 Hz, 2H), 2.96 (t, J=5.2 Hz, 2H), 2.63 (t, J=5.3 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[N:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:19][C:20]1[N:25]=[C:24]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:9]=[CH:10][C:11]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:13]=3)[CH2:2][CH2:3]2)[CH:23]=[CH:22][N:21]=1.[Cl:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:9]=[CH:10][C:11]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:13]=3)[CH2:2][CH2:3]2)[N:25]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(=O)NCc1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3ccnc(Cl)n3)CC2)cc1
Product: CC(=O)NCc1ccc(CN2CCN(c3nccc(Cl)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of N-(4-((piperazin-1-yl)methyl)-phenylmethyl)acetamide (1.0 g) obtained in Example 78(2) and 2,4-dichloropyrimidine (0.60 g) in acetonitrile (20 ml) was added potassium carbonate (0.84 9) and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (100 ml). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:methanol=20:1-10:1) to give N-(4-((4-(2-chloropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide (0.61 g) as white crystals and N-(4-((4-(4-chloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide (10 mg) as white crystals. N-(4-((4-(2-chloropyrimidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide.