Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]3[CH:18]=[CH:19][S:20][C:11]=23)=[CH:5][N:6]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH:1][C:2]2[S:3][C:4]([CH2:7][CH2:8][NH:9][C:10]3[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]4[CH:18]=[CH:19][S:20][C:11]=34)=[CH:5][N:6]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: N#Cc1cnc2ccsc2c1NCCc1cnc(N)s1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: ClCCl
Product: N#Cc1cnc2ccsc2c1NCCc1cnc(NC(=O)Nc2cccc(Cl)c2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.7 %

Procedure:
To a solution of 7-[2-(2-amino-thiazol-5-yl)-ethylamino]-thieno[3,2-b]pyridine-6-carbonitrile (27.1 mg, 0.09 mmol) in 2 ml of dichloromethane was added 3-chloro phenyl isocyanate (0.02 ml, 0.16 mmol). The resulting mixture was stirred at room temperature for 16 hr and filtered. Solids were washed with CH2Cl2, and the combined organics were concentrated. The residue was purified by chromatography on TLC plate with MeOH/CH2Cl2/NH3(aq)=1/20/0.1 to give 5.6 mg (14%) of a white solid. 1H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 8.06 (d, J=5.6 Hz, 1H), 7.62-7.66 (m, 1H), 7.43 (d, J=5.2 Hz, 1H), 7.25-7.31 (m, 2H), 7.16 (s, 1H), 7.00-7.07 (m, 1H), 4.06 (t, J=7.2 Hz, 2H), 3.20 (t, J=7.2 Hz, 2H). LC-MS (ESI) m/z 455.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH:13]([NH:15][CH3:16])[CH3:14])[N:9]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:8]2=[O:25].[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:15]([CH:13]([C:10]2[N:9]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C:8](=[O:25])[C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH3:14])[CH3:16])(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC(C)c1nc2c(OC)cccc2c(=O)n1-c1ccc(OC)cc1
Product: COc1ccc(-n2c(C(C)N(C)S(=O)(=O)c3ccc(C(C)(C)C)cc3)nc3c(OC)cccc3c2=O)cc1

Procedure:
In a similar manner as described above in Paragraph A, 8-methoxy-3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one, as prepared above in Example 5, was condensed with 4-tert-butylbenzenesulfonyl chloride to yield 4-tert-butyl-N-{1-[8-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide; MS (ESI) 536 (MH+).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]\[S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:7][CH:8]=1)([OH:3])=O.Cl.[C:32]([CH:34]1[CH2:37][NH:36][CH2:35]1)#[N:33]>>[C:32]([CH:34]1[CH2:37][N:36]([C:1]([C:4]2[N:5]=[C:6](/[CH:9]=[CH:10]\[S:11][C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:7][CH:8]=2)=[O:3])[CH2:35]1)#[N:33]
Reactant: O=C(O)c1csc(/C=C\SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N#CC1CNC1
Agent: Cl
Product: N#CC1CN(C(=O)c2csc(/C=C\SC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1
Yield: 66.2 %

Procedure:
In the same manner as in step c) in Example 3, 0.271 g of the title compound was prepared from 0.356 g of 4-carboxy-2-((Z)-2-tritylthioethen-1-yl)thiazole and 0.149 g of 3-cyanoazetidine hydrochloride.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:7][CH2:8][CH2:9][C:10]1[S:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:12][C:11]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[S:31][C:32]2[C:37]([N:38]=1)=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:22].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:15]1([C:13]2[S:14][C:10]([CH2:9][CH2:8][CH2:7][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:11]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[S:31][C:32]4[C:37]([N:38]=3)=[CH:36][CH:35]=[CH:34][N:33]=4)=[O:22])[N:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CCCc1sc(-c2ccccc2)nc1C(=O)Nc1ccccc1-c1nc2cccnc2s1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(Nc1ccccc1-c1nc2cccnc2s1)c1nc(-c2ccccc2)sc1CCCN1CCCC1
Reaction time: 1 h
Yield: 31.2 %

Procedure:
Pyrrolidine (88 μL, 1.06 mmol) was added to a solution of 5-(3-oxopropyl)-2-phenyl-N-(2-(thiazolo[5,4-b]pyridin-2-yl)phenyl)thiazole-4-carboxamide (250 mg, 0.53 mmol) and AcOH (127 mg, 2.1 mmol) in dichloroethane (DCE) (10 mL). The reaction mixture was stirred for 1 h. Sodium triacetoxyborohydride (449 mg, 2.1 mmol) was added and stirring continued for 16 h. The reaction mixture was poured into sat aq NaHCO3 and extracted with DCM. The combined organics were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by MPLC eluting with CH2Cl2/MeOH+1% TEA(0-10% gradient) to give the title compound (87 mg, 31% yield). MS Calcd for C29H27N5OS2: 525.17. Found (M+H)+ m/z=526.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH3:11])=[C:2]=[O:3].[NH2:12][C@H:13]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[CH3:31][CH:30]([CH3:32])[C:29]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][C@H:13]([NH:12][C:2]([NH:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:10][CH3:11])=[O:3])[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:21][CH2:20]2)[CH:23]=1)=[O:33]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: CSc1ccccc1N=C=O
Product: CSc1ccccc1NC(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure P and Scheme AB using 1-isocyanato-2-(methylsulfanyl)benzene and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 545.0 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[C].[Pd]>[F:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]([CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:17])=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: O=C(CCN1CCN(Cc2ccccc2)CC1)Nc1ccc(F)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(CCN1CCNCC1)Nc1ccc(F)cc1
Yield: 70.3 %

Procedure:
1-Benzyl-4-[2-(4-fluorophenylaminocarbonyl)ethyl]piperazine (2.9 g) was dissolved in acetic acid (100 ml), then 10% palladium carbon (7.2 g) was added thereto, and the mixture was stirred overnight in a hydrogen atmosphere. The 10% palladium carbon was filtered off, and the filtrate was evaporated, and water was added to the residue which was then basified by adding 1 N aqueous sodium hydroxide and subjected to extraction with chloroform, and the organic layer was washed with water, dried, and evaporated, whereby the title compound (1.5 g, 70%) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:4][CH2:3]1.[C:19]([NH:26][C:27](N)=[O:28])([C:21]1[S:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>N1C=CC=CC=1>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:27]([NH:26][C:19]([C:21]2[S:25][CH:24]=[CH:23][CH:22]=2)=[O:20])=[O:28])[CH2:7][CH2:6]1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: NC(=O)NC(=O)c1cccs1
Solvent: c1ccncc1
Product: O=C(NC(=O)c1cccs1)NC1CCN(Cc2ccc3ccccc3c2)CC1

Procedure:
4-Amino-1-(naphth-2-ylmethyl)piperidine (1.0 g, 0.0047 m) and 1-(then-2-oyl)urea (0.65 g, 0.0042 m) in pyridine (5 cm3) was refluxed for 9.5 hours. The solvent was evaporated, water added, and the precipitated title compound filtered and washed well with water. This was recrystallised from ethanol, converted to the hydrochloride salt in ethanol with ethanolic HCl, and recrystallised from ethanol, 0.5 g, at the hydrochloride, m.p. 217°-219° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[CH:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:20]([OH:21])[CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][CH2:23]2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(-c2ccccc2Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccc2-c2ccc(Cl)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (29.4 mL, 47.09 mmol) was added dropwise to a solution of 2-bromo-4′-chlorobiphenyl (INTERMEDIATE 9, 12 g, 44.85 mmol) in THF (220 ml) under nitrogen, at −78° C. The resulting colored mixture was stirred at −78° C. for 30 minutes and a solution of tert-butyl 4-formylpiperidine-1-carboxylate (10.04 g, 47.09 mmol) in THF (15 ml) was added. The reaction mixture was allowed to warm to 0° C. during 3 hours and then was quenched with a solution of saturated aq. NH4Cl. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic extracts and dried over MgSO4. The mixture was filtered and evaporation of the volatiles under reduced pressure gave a residue, which was purified by column chromatography (ISCO, 330 g silica gel column, eluting with 0→40% EtOAc/hexanes) to give tert-butyl 4-[(4′-chlorobiphenyl-2-yl)(hydroxy)methyl]piperidine-1-carboxylate as a mixture of enantiomers.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40]>CN(C=O)C.[Cu]I>[CH3:38][Si:39]([C:42]#[C:43][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2)([CH3:41])[CH3:40]
Reactant: C#C[Si](C)(C)C
Reactant: O=C1NCc2cccc(I)c21
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cccc2c1C(=O)NC2
Temperature: 100 °C
Yield: 49 %

Procedure:
To a nitrogen de-gassed solution of 7-iodoisoindolin-1-one (I59) (0.233 g, 0.899 mmol) in dry DMF (6 mL) were added triethylamine (0.501 mL, 3.598 mmol) followed by triphenylphosphine (0.035 g, 0.14 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.063 g, 0.090 mmol), CuI (0.026 g, 0.14 mmol) and finally (trimethylsilyl)acetylene (0.292 mL, 1.63 mmol). The reaction mixture was then heated under microwave irradiation at 100° C. for 30 then 10 minutes. The reaction mixture was concentrated in vacuo, then absorbed onto silica gel and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-46% EtOAc in dichloromethane) to give the title compound (I60) (0.120 g, 49% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 8.47 (s, 1H), 7.60-7.51 (m, 2H), 7.49 (dd, J=6.7, 2.0 Hz, 1H), 4.32 (s, 2H), 1.03 (t, J=7.9 Hz, 9H), 0.66 (q, J=7.9 Hz, 6H). LCMS Method C: rt 6.44 min; m/z 272.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:6][C:5](=[O:18])[C:4]=2[CH:3]=1
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1cc(-c2ccccc2)oc2ccc(OCCCCCl)cc12
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A mixture of 6-hydroxyflavone (5.0 g, 21 mmol), 1-bromo-4-chlorobutane (4.86 mL, 42 mmol), and potassium carbonate (12 g, 84 mmol) was refluxed in acetone for 24 hours. The solution was cooled to room temperature, filtered, and the solvent removed in vacuo. The residue was boiled with ether and filtered. Cooling gave 6.1 g (89%) of 6-(4-chlorobutoxy)-2-phenyl-4H-1-benzopyran-4-one as a white solid.
Reaction SMILES: C[C:2]1[CH:11]=[C:10](N)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:23]=[C:22]([NH:24][C:25]2[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=O)[CH:32]=3)[CH:28]=[CH:29][CH:30]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClC(Cl)C>[CH2:4]1[C:9]2[C:10](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:11][CH2:2][N:3]1[CH2:37][C:33]1[CH:32]=[C:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([NH:24][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:14]([CH3:13])[CH:23]=3)[CH:26]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cc(N)c2ccccc2n1
Reactant: Cc1cc(Nc2cccc(-c3cccc(C=O)c3)c2)c2ccccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cc(Nc2cccc(-c3cccc(CN4CCc5ccccc5C4)c3)c2)c2ccccc2n1
Reaction time: 19 h
Yield: 55 %

Procedure:
(3-Bromophenyl)-(2-methylquinolin-4-yl)amine (71). 71 is prepared from 70 by the procedure of Example 1 Step 3. Step 2. 3′-(2-Methylquinolin-4-ylamino)biphenyl-3-carbaldehyde (73). To a suspension of 71 (294 mg, 0.94 mmol) in toluene (9.6 mL) under N2 were sequentially added saturated NaHCO3 (aq. 3.8 mL), a solution of 72 (199 mg, 1.33 mmol) in EtOH (6.7 mL), and PdCl2(Ph3P)3 (32 mg, 0.046 mmol). The reaction was heated at 80° C. for 21 hours before it was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate (40 mL) and washed with water (15 mL), brine (15 mL). The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (dichloromethane to 20:1 dichloromethane/methanol) to give 73 as a yellow solid (219 mg, 68.9%). Step 3.3′-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-3-yl]-(2-methylquinolin-4-yl)amine. To a solution of 73 (102 mg, 0.301 mmol) in dichloroethane (3.0 mL) under N2 was added 40 (0.04 mL, 0.315 mmol). The reaction was stirred for 24 minutes before the sequential addition of NaBH(OAc)3 (94 mg, 0.444 mmol) and AcOH (0.02 mL, 0.349 mmol). The reaction was stirred for 19 hours and then extracted with ethyl acetate (2×30 mL). The ethyl acetate extracts were washed with 2 N NaOH (aq. 15 mL), brine (15 mL), dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (dichloromethane to 30:1 to 20:1dichloromethane/methanol) to give the desired product as a yellow solid (75 mg, 55%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([NH2:14])=[O:13])[CH:11]=1)[NH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[Cl:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([NH2:14])=[O:13])[CH:11]=1)[NH:8][N:7]=[C:6]2[CH:15]1[CH2:16][CH2:17][N:18]([S:25]([CH2:24][CH2:23][CH2:22][Cl:21])(=[O:27])=[O:26])[CH2:19][CH2:20]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)n[nH]c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Yield: 97.4 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-bromo-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (100 mg, 0.31 mmol) was reacted with 3-chloro-1-propanesulfonyl chloride (63 uL, 0.46 mmol) in the presence of diisopropylethylamine (0.24 mL, 1.38 mmol) in methylene chloride (5 mL) to give the crude title compound (140 mg, 98%), which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[N+:16]([O-])=O)C(OC)=O.Cl>C(O)(=O)C.[Fe]>[F:15][C:12]1[CH:11]=[C:10]2[C:9]([CH2:4][C:3](=[O:2])[NH:16]2)=[CH:14][CH:13]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: O=C1Cc2ccc(F)cc2N1
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a mixture of NaH (60%, 7 g, 0.16 mol) in dimethyl sulfoxide (150 mL) was added dropwise dimethyl malonate (20 mL, 0.16 mol). The mixture was heated to 100° C. for 10 min then cooled to room temperature, followed by the addition of 2,5-difluoronitrobenzene (14 g, 0.08 mol). After stirred at 90° C. for 2 h, the mixture was cooled and poured into 5% aq.HCl with ice cooling. EtOAc (50 mL) was added and the organic phase was separated, washed by water and dried with Na2SO4. The solvent was removed in vacuo to give 2-(4-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester (19.4 g). 2-(4-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester (6 g, 22 mmol) was dissolved in glacial acetic acid (30 mL), the aqueous HCl (6N, 30 mL) was added and the reaction mixture were heated ar refluxing for 4 h, Iron power (5 g, 88 mmol) was added portionwise to the mixture and the refluxing was allowed to continue for another 2 h. The solvent was removed in vacuo and the remaining residue was extracted by EtOAc. The organic phase washed with aqueous HCl (1N), brine and dried over Na2SO4. concentrated to give the titled compound as a yellow solid (3 g, 89%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][C:5]([C:13]#[CH:14])=[N:4]1)[CH3:2].Br[C:16]1[N:26]=[C:19]2[C:20]([CH3:25])=[N:21][CH:22]=[C:23]([CH3:24])[N:18]2[N:17]=1.C(N(CC)CC)C>O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:3]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][C:5]([C:13]#[C:14][C:16]2[N:26]=[C:19]3[C:20]([CH3:25])=[N:21][CH:22]=[C:23]([CH3:24])[N:18]3[N:17]=2)=[N:4]1)[CH3:2]
Reactant: C#Cc1nc(N2CCCC2)n(CC)n1
Reactant: Cc1ncc(C)n2nc(Br)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCn1nc(C#Cc2nc3c(C)ncc(C)n3n2)nc1N1CCCC1
Yield: 37.2 %

Procedure:
A mixture of 1-ethyl-3-ethynyl-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole (79 mg, 415 μmol, Eq: 1.00), 2-bromo-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (104 mg, 457 μmol, Eq: 1.1) and triethylamine (63.0 mg, 86.8 μl, 623 μmol, Eq: 1.5) in dioxane (2.11 ml) was purged with argon, then copper (I) iodide (1.58 mg, 8.31 μmol, Eq: 0.02), bis(triphenylphosphine)palladium(II) chloride (5.83 mg, 8.31 μmol, Eq: 0.02) and triphenylphosphine (2.18 mg, 8.31 μmol, Eq: 0.02) were added, the vessel was capped and heated for 18 hours to 110° C. The crude material was applied on silica gel and purified by flash chromatography over a 20 g silica gel column using ethyl acetate 100% as eluent affording 2-((1-ethyl-5-(pyrrolidin-1-yl)-1H-1,2,4-triazol-3-yl)ethynyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (52 mg, 37.2%) as an orange oil. MS: m/z=337.4 (M+H+)
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([CH3:25])[C:21](=[O:24])[NH:22][CH:23]=2)=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.[BrH:26]>C(O)(=O)C>[BrH:26].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:19]=[C:20]([CH3:25])[C:21](=[O:24])[NH:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: Cc1nc(-c2ccc(NC(=O)OCc3ccccc3)cc2)c[nH]c1=O
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc(-c2ccc(N)cc2)c[nH]c1=O

Procedure:
5-(4-Benzyloxycarbonylaminophenyl)-3-methyl-2(1H)pyrazinone (1.5 g) was treated with hydrogen bromide in acetic acid in a manner similar to that described in Example 20 to give the title compound as its hydrobromide salt (1.09 g) which on recrystallisation from ethanol/ether has m.p. >300° C.; ν(Nujol mull) 1632, 1640 cm-1.
Reaction SMILES: [SH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:46]([O:48][C:49](=[O:56])/[CH:50]=[C:51](\[CH3:55])/[CH2:52][CH2:53]O)[CH3:47]>C(OCC)(=O)C.C1COCC1>[CH2:46]([O:48][C:49](=[O:56])/[CH:50]=[C:51](\[CH3:55])/[CH2:52][CH2:53][S:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1)[CH3:47]
Reactant: CCOC(=O)/C=C(\C)CCO
Reactant: Sc1nnnn1-c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)CCSc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
This reaction was performed with reference to the literature (Mitsunobu, O., Synthesis, 1981, 1-28.). 5-Mercapto-1-phenyltetrazole (16.30 g, 91.20 mmol), triphenylphosphine (27.30 g, 104 mmol) and diisopropyl azodicarboxylate (95%, 21.10 g, 104 mmol) were added to a THF (410 ml) solution of ethyl-(2E)-5-hydroxy-3-methylpent-2-enoate (13.80 g, 86.90 mmol) while ice cooling. The reaction solution was warmed to room temperature and stirred for four hours. After the reaction solution was diluted with ethyl acetate, it was washed with distilled water and brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:ethyl acetate=5:1) to obtain the title compound (27.16 g) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]=[CH:16][C:17]1[C:30]2[C:31]3=[C:32]4[C:27](=[CH:28][CH:29]=2)[CH:26]=[CH:25][CH:24]=[C:23]4[CH:22]=[CH:21][C:20]3=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C1C=CC=CC=1>CO>[CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]1[C:30]2[C:31]3=[C:32]4[C:27](=[CH:28][CH:29]=2)[CH:26]=[CH:25][CH:24]=[C:23]4[CH:22]=[CH:21][C:20]3=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=NCCCCCCNCc1ccccc1)c1ccc2ccc3cccc4ccc1c2c34
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: c1ccc(CNCCCCCCNCc2ccc3ccc4cccc5ccc2c3c45)cc1

Procedure:
A solution of N-benzyl-N′-pyren-1-ylmethylene-hexane-1,6-diamine (420 mg, 1.00 mmol) and sodium borohydride (190 mg, 5.00 mmol) in methanol (10.0 ml) was stirred at room temperature for 3 hours under a nitrogen atmosphere. The solvent was removed under vacuum, and the residue was dissolved in chloroform and washed with water, and dried over magnesium sulphate. The solvent was removed and the residue was dried under vacuum to give a yellow oil (386/mg, 92%). 1H NMR (CDCl3) δ/ppm 1.32 (4H, m, (CH2)2), 1.45 (2H, m, BnNCCH2), 1.55 (2H, m, PyCNCCH2), 2.55 (2H, t, BnNCH2), 2.75 (2H, t, PyCNCH2), 3.75 (2H, s, PhCH2), 4.50 (2H, s, PyCH2), 7.15-7.25 (5H, m, Ph-H), 7.95-8.10, 8.15-8.22, 8.37 (4H, 4H, 1H respectively, m, m, d, Py-H). 13C NMR (CDCl3) δ/ppm 27.35, 30.16, 49.46, 50.02, 51.94, 54.13, 54.13, 123.19, 124.72, 125.00, 125.09, 125.89, 126.89, 127.03, 127.50, 127.64, 128.14, 128.40, 129.06, 131.34, 134.15; m/z (EI) 420 ([M])+, 7%).