Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20].[CH3:22][N:23]([CH3:34])[CH2:24][CH2:25][CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH2:27]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[S:15][C:14]([C:16]([NH:27][CH:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:25][CH2:24][N:23]([CH3:34])[CH3:22])=[O:18])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2nc3ccccc3s2)s1
Reactant: CN(C)CCC(N)c1ccccc1
Product: CN(C)CCC(NC(=O)c1cc([N+](=O)[O-])c(Sc2nc3ccccc3s2)s1)c1ccccc1

Procedure:
Prepared according to the procedure described for example 44 from 5-(1,3-benzothiazol-2-ylsulfanyl)-4-nitro-thiophene-2-carboxylic acid as in step A of example 256 (34 mg, 0.1 mmol) and N′,N′-dimethyl-1-phenyl-propane-1,3-diamine (21.3 mg, 0.12 mmol). The title compound was obtained as a solid (6.5 mg, 13% yield). MS m/z: 499.08, 501.07 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:29]S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:12][NH:13][C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[N:24][CH:23]=[CH:22]4)[CH:15]=2)=[CH:2]1.N1CCCN2CCCCCC=12.SCCO>CN(C=O)C>[NH2:29][C@@H:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:12][NH:13][C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[N:24][CH:23]=[CH:22]3)[CH:15]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N[C@H](CNc2cc(-c3ccc4cnccc4c3)no2)Cc2c[nH]c3ccccc23)cc1
Agent: OCCS
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: N[C@H](CNc1cc(-c2ccc3cnccc3c2)no1)Cc1c[nH]c2ccccc12
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To 25 mL of round-bottom flask was added N-((S)-3-(1H-indol-3-yl)-1-(3-(isoquinolin-6-yl)isoxazol-5-ylamino)propan-2-yl)-4-nitrobenzenesulfonamide (75 mg, 132 μmol), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (20 mg, 132 μmol) (commercially available from Aldrich), 2-mercaptoethanol (10 mg, 132 μmol) and 2 mL of DMF. After 2 hours, the reaction mixture was directly purified by preparative LC to give N-((S)-2-amino-3-(1H-indol-3-yl)propyl)-3-(isoquinolin-6-yl)isoxazol-5-amine (38 mg, 75% yield). MS m/z: 384 (M+1); 1H NMR (400 MHz, CD3OD) δ ppm 9.69 (s, 1H), 8.61 (d, J=6.26 Hz, 1H), 8.48 (d, J=8.61 Hz, 1H), 8.37-8.42 (m, 2H), 8.18 (dd, J=8.71, 1.27 Hz, 1H), 7.63 (d, J=7.82 Hz, 1H), 7.46 (d, J=8.22 Hz, 1H), 7.29 (s, 1H), 7.20 (t, J=7.53 Hz, 1H), 7.08 (t, J=7.43 Hz, 1H), 3.81-3.83 (m, 1H), 3.60-3.63 (m, 1H), 3.46-3.54 (m, 1H), 3.20 (d, J=7.24 Hz, 2H),
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[N:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10]1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[N:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:10]1
Reactant: COc1ccccc1-n1cnc(-c2ccccc2)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1-n1cnc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1,1 g of 1-(2-methoxyphenyl)-3-phenyl-1,2,4-triazole (cf. Example 2) are dissolved in 40 ml of dichloromethane and a solution of 1 ml of BBr3 in 10 ml of dichloromethane is added dropwise. After 3-4 hours stirring at ambient temperature the mixture is poured onto ice water and the organic phase is separated off. The remaining aqueous phase is again extracted with dichloromethane. After the collected dichloromethane phases have been dried over Na2SO4 the solvent is distilled off. 1 g (96%) of the title compound are left (melting point: 148-154° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N+]=[N-]>>[CH2:24]([O:23][C:21]([C:20]1[NH:17][C:12]2[CH:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[O:16][C:13]=2[CH:14]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Product: CCOC(=O)c1cc2oc(-c3ccc([N+](=O)[O-])cc3)cc2[nH]1

Procedure:
2-(4-Nitro-phenyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid ethyl ester is prepared from commercially available 5-(4-nitro-phenyl)furfural and ethyl azidoacetate as described hereinabove.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:17][CH:16]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1cccc2ccccc12
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: Cc1ccccc1
Product: Brc1ccc(-c2cccc3ccccc23)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
Under an argon gas atmosphere, 200.0 g (1.163 mol) of 1-naphthaleneboronic acid, 329.0 g (1.163 mol) of 4-bromoiodobenzene, 26.9 g (23.3 mmol) of tetrakis(triphenylphosphine)palladium(0), 3.7 L of toluene and 1.74 L of aqueous solution of 2M sodium carbonate were added together, and stirred at 90 degrees C. for 24 hours. After the reaction was over, the mixture experienced filtration, through which aqueous phase thereof was eliminated. After organic phase thereof was washed by water and dried with magnesium sulfate, the toluene was distilled away under reduced pressure. Residue thereof was refined by silica-gel column chromatography, such that 268 g of 1-(4-bromophenyl)naphthalene was obtained at an yield of 81%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:19]([OH:25])=[O:20].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(Br)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1C[C@H]1c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of racemic trans-1,1-dimethylethyl [2-(4-bromophenyl)cyclopropyl]carbamate (Intermediate 4) (1.25 g) in 71.5 mL of DCM was cooled to 0° C. TFA (17 mL) was added dropwise and the solution was stirred at this temperature for 1 h. Then the mixture was evaporated in vacuo to obtain 1.83 g of title material as a yellow solid which was used without further purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[N:11][C:10]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN>CN(C=O)C>[CH3:17][NH:18][C:14]([C:10]1[N:11]=[N:12][S:13][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1snnc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1nnsc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 5-tert-butoxycarbonylamino-[1,2,3]thiadiazole-4-carboxylic acid (0.66 g, 2.7 mmol) in DMF (10 ml) was treated with TBTU (1.16 g, 3.5 mmol), N,N-diisopropyl ethyl amine (2.29 ml, 13.5 mmol) and methylamine (1.75 ml, 2M THF solution) and stirred at ambient temperature for 5 h. The reaction mixture was partitioned between potassium hydrogen sulfate (30 ml, 10% aqueous solution) and ethyl acetate (60 ml) and extracted. The organic layer was washed with water and brine, and the aqueous phases were back-extracted with ethyl acetate. The combined organic phases were dried and the solvent was evaporated. The residue was suspended in dichloromethane, sucked off, and the filtrate was evaporated. The product was obtained after purification of the crude material by silica gel chromatography using a heptane/ethyl acetate gradient as colorless solid (0.23 g, 33%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:24](Cl)(=[O:26])[CH3:25]>>[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CC(=O)Nc1ccc2[nH]cc(C3CCNCC3)c2n1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.004 mL (0.062 mMol) acetyl chloride, the title compound was prepared.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:34]=[CH:33]2.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CS(C)=O>[C:23]1([C:19]2[CH:18]=[C:17]([C:10]3[N:9]=[C:8]([NH:29][C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[N:34]=[CH:33]5)[C:7]4[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:50]5[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]5)[CH:6]=4)[N:11]=3)[CH:22]=[CH:21][CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN1CCN(C)CC1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.30 g, 0.44 mmole) in DMSO (2 mL) was added 1-methylpiperazine (0.903 g, 1.00 mL, 9.02 mmole) and the reaction was stirred at 85° C. for 3 h. The mixture was poured onto ice-water (100 mL) and the crude product was filtered. The product was then dissolved in a mixture of CH2Cl2 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (SiO2, 10% CH2Cl2 CH3OH—with 0.1% NH4OH) to give tert-butyl 5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate which was taken on to the next step. HPLC retention time 6.00 mins.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]#[N:20].[I:25]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[F:16][C:17]1[C:24]([I:25])=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: N#Cc1ccccc1F
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cccc(I)c1F
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
n-Butyl lithium (2.5 M in hexanes, 16.8 mL, 42 mmol) was added dropwise to a stirred solution of 2,2,6,6-tetramethylpiperidine (6.90 mL, 141 mmol) in tetrahydrofuran (60 mL) at −78° C. The mixture was stirred for 30 minutes at −50° C. then 2-fluorobenzonitrile (4.4 g, 37 mmol) in tetrahydrofuran (25 mL) was added dropwise to the mixture at −78° C. The reaction was warmed to −50° C. over a 30 minute period and then recooled to −78° C. and a solution of iodine (10.20 g, 40 mmol) in tetrahydrofuran (25 mL) was added. Then the mixture was warmed to ambient temperature. After 1 hour, saturated aqueous sodium thiosulphate solution was added to the reaction and the mixture was extracted with diethyl ether. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (20:1 hexanes/ethyl acetate) gave the title compound (7.86 g, 87%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]([F:39])([F:38])[C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[NH2:30]>>[F:25][C:26]([F:38])([F:39])[C:27]1[CH:28]=[C:29]([NH:30][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:15][C@@H:10]4[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][C@@H:11]4[CH2:13]3)[CH:17]=[N:18][CH:19]=2)=[O:22])[CH:31]=[C:32]([C:34]([F:35])([F:37])[F:36])[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)Nc4cc(C(F)(F)F)cc(C(F)(F)F)c4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 3,5-bis(trifluoromethyl)aniline were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 545 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[C:12](Cl)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cu](C#N)[C:19]#[N:20]>CN(P(N(C)C)(N(C)C)=O)C>[CH:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:19]#[N:20])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1cccc2c(C3CCCCC3)nccc12
Reactant: N#C[Cu]C#N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1cccc2c(C3CCCCC3)nccc12

Procedure:
1-Cyclohexyl-5-chloroisoquinoline, copper cyanide and hexamethylphosphotriamide were reacted in the same way as in step (d) of Example 13 to afford 1-cyclohexyl-5-cyanoisoquinoline having a melting point of 94.7° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[N:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1.[CH2:28]([O:31][C:32]1[CH:43]=[C:42]([O:44][CH2:45][CH2:46][CH3:47])[CH:41]=[CH:40][C:33]=1[C:34](N(OC)C)=[O:35])[CH2:29][CH3:30]>C1COCC1>[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:34]([C:33]2[CH:40]=[CH:41][C:42]([O:44][CH2:45][CH2:46][CH3:47])=[CH:43][C:32]=2[O:31][CH2:28][CH2:29][CH3:30])=[O:35])=[CH:23][CH:22]=1
Reactant: CCCOc1ccc(C(=O)N(C)OC)c(OCCC)c1
Reactant: Cc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCOc1ccc(C(=O)Cc2ccncc2)c(OCCC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a cooled solution of lithium diisopropylamide (generated from diisopropylamine (109 mg, 1.07 mmol) and a solution of n-butyllithium in hexanes (0.49 mL of a 2.5M solution, 1.22 mmol)) in THF (0.5 mL) at -78° C. was added 4-picoline (95 μL, 0.98 mmol). Stirred -78° to 0° C. for 1 h. The reaction mixture was cooled to -78° C. and a solution of 2,4-di-n-propyloxy-N-methoxy-N-methyl-benzamide from Step B (274 mg, 0.98 mmol) in THF (0.5 mL) was added dropwise. The reaction was stirred <0° C. for 4 h and then quenched by the addition of a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (2 times). The combined extracts were successively washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The solution was filtered and the solvents removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 0-50% ethyl acetate in hexanes to yield the title compound (147 mg, 48% yield), mass spectrum (CI) m/e=314 (M+1)+.
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[CH2:7]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][Cl:25])[CH2:18][CH2:17]1)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:25].[ClH:5].[CH2:7]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][SH:3])[CH2:18][CH2:17]1)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(N)=S
Reactant: ClCCCN1CCN(CC=Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: SCCCN1CCN(CC=Cc2ccccc2)CC1
Yield: 49 %

Procedure:
The procedure described in Example 1(b) was followed, using 3.1 g of thiourea, 7.4 g of 1-cinnamyl-4-(3-chloropropyl)piperazine dihydrochloride, 4,1 g of triethylamine and 100 ml of reagent ethanol. The hydrolysis was effected with 3.0 g of sodium hydroxide in 30 ml of water. Work-up, as described above, gave 3.6 g (52% of theory) of 3-(4-cinnamylpiperazin-1-yl)propanethiol dihydrochloride as a white crystalline solid, M.p. 249°-252° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][S:10][C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:6]2=[C:5]([C:16]([O:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[O:17])[CH:4]=[C:3]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.[Cl:31]C1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl>[ClH:31].[O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][S:10](=[O:39])[C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:6]2=[C:5]([C:16]([O:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[O:17])[CH:4]=[C:3]1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)CCOC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1SCC2
Agent: Cl
Solvent: ClCCl
Product: CN(C)CCOC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1S(=O)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.8 g of 2-(dimethylamino)ethyl 5,6-dihydro-8-oxo-9-phenyl-8H-pyrido [1,2-d]thieno[2,3-f][1,4]thiazepine-11-carboxylate in 90 ml of methylene chloride were treated with 9 ml of 3N ethanolic hydrochloric acid, whereupon the mixture was cooled to -10°. The mixture was treated dropwise with 1.72 g of about 90 percent m-chloroperbenzoic acid in 45 ml of methylene chloride. After warming to room temperature, the mixture was washed with 100 ml of 5 percent sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by chromatography on silica gel and then dissolved in 34 ml of methylene chloride. After the addition of 3N ethanolic hydrochloric acid until an acidic reaction was obtained, the mixture was stirred at room temperature for an additional 15 minutes. After removal of the solvent in vacuo and recrystallization from methanol, there was obtained 2-(dimethylamino)ethyl 5,6-dihydro-8-oxo-9-phenyl-8H -pyrido[1,2-d]thieno[2,3-f][1,4]thiazepine-11-carboxylate 4-oxide hydrochloride as yellow crystals of m.p. 148°-152° (dec.).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:34]([O:36][CH3:37])=[O:35])=[CH:12][C:13]=3[N:14]3[CH2:21][C:20](=O)[N:19]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:18][C:17]4[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:34]([O:36][CH3:37])=[O:35])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])[CH2:18][C:17]4[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)N(CCN(C)C)Cc1cc(OC)ccc1-3
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)C)Cc1cc(OC)ccc1-3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate (prepared in an analogous fashion to that described in Example 1) in THF (0.06 M), BH3Me2S (20 eq, 2 M solution in THF) was dropwise and the solution stirred at RT for 3 h. MeOH was added carefully to the mixture until effervescence ceased, then the volatiles were removed in vacuo. The crude residue was not isolated and directly used in the next step; MS (ES+) m/z 490 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:13])[CH:6]=[CH:5][CH:4]=1.Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C.O>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:13][CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1cccc2cccnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)Oc1cccc2cccnc12
Reaction time: 0.08 h
Yield: 59.1 %

Procedure:
To a solution of compound NaH (100 mg, 4.14 mmol) in DMF (3 mL) was added quinolin-8-ol (200 mg, 1.38 mmol) at 26° C. After stirred for 5 minutes, ethyl 2-bromopropanoate (300 mg, 1.65 mmol) was added and the reaction mixture stirred for 16 h at 26° C. The mixture was then diluted with water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated to give ethyl 2-(quinolin-8-yloxy)propanoate (200 mg, 59.2%) as colorless oil which was used in next step without further purification. (304 mg, Yield 90%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][O:28][CH2:29][CH:30]([NH:32][C:33]1[NH:37][C:36]([CH3:38])=[N:35][N:34]=1)[CH3:31]>>[CH3:27][O:28][CH2:29][CH:30]([N:32]1[C:17](=[O:18])[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:10][CH:11]=2)=[C:22]([CH2:23][CH2:24][CH3:25])[N:34]2[N:35]=[C:36]([CH3:38])[N:37]=[C:33]12)[CH3:31]
Reactant: COCC(C)Nc1nnc(C)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)COC)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 58.8 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.84 g) and N-(2-methoxy-1-methylethyl)-5-methyl-4H-1,2,4-triazol-3-amine (0.4 g) was stirred at 250° C. for 15 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 52%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([C:2]3[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)[N:3]=3)[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: COc1ccc(-c2nc(C)cc(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(C)cc(N3CCN(C(c4ccccc4)c4ccccc4)CC3)n2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
1.17 g of 4-chloro-2-(4-methoxyphenyl)-6-methylpyrimidine and 1.38 g of 1-diphenylmethylpiperazine were dissolved in 20 ml of N,N-dimethylformamide. After the addition of 1 g of potassium carbonate, the mixture was stirred for 6 hours at 80° to 85° C. The reaction mixture was poured into ice-water, then the resulting crystals were filtered off, washed with water and dried. Whereby 2.2 g of crystals were obtained. 1.85 g of the crystals were obtained by recrystallizing with ethanol. Melting point is 147° to 149° C.