Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])[CH2:2][C:3]#[CH:4].Br[C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:18]=1.CCN(CC)CC>CN(C=O)C.[Cu](I)I.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>[C:19]1([C:17]2[N:18]=[C:14]([C:4]#[C:3][CH2:2][CH2:1][C:5]3[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=3)[C:8]#[N:9])[S:15][CH:16]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C#CCCc1cccc(C#N)c1
Reactant: Brc1nc(-c2ccccc2)cs1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(CCC#Cc2nc(-c3ccccc3)cs2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.5 %

Procedure:
3-(But-3-yn-1-yl)benzonitrile (462 mg, 2.98 mmol) and 2-bromo-4-phenylthiazole (650 mg, 2.71 mmol) were taken in dry DMF (20 mL) and purged with nitrogen gas for 15 min. Et3N (1.9 mL, 13.5 mmol) was added to the reaction mixture, followed by a catalytic amount of copper iodide (51 mg, 0.27 mmol) and Pd(PPh3)4 (115 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 12 h and then quenched with water. The organic product was extracted with EtOAc, and the combined extracts were concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 15-20% EtOAc in petroleum ether) to get 3-(4-(4-phenylthiazol-2-yl)but-3-yn-1-yl)benzonitrile (430 mg, yield 50%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.92-7.90 (m, 2H), 7.59-7.52 (m, 3H), 7.47-7.33 (m, 5H), 3.04-2.99 (m, 2H), 2.83-2.78 (m, 2H). MS (ESI) m/z: Calculated for C20H14N2S: 314.09. found: 315.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:13]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)=[CH:5][CH:4]=2)=[O:15])=[CH:19][CH:18]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Cc1ccc2ccc(C(=O)O)c(O)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2ccc(C(=O)NCc3ccc(Cl)cc3)c(O)c2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a solution of 8-hydroxy-2-methylquinoline-7-carboxylic acid (0.305 g) of Preparation 5 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxy-benzotriazole monohydrate (0.217 g). The mixture is stirred overnight. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried to yield 0.337 g of the title product as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:19](=[N:21]O)[CH3:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:23])[C:11](=[O:24])[C:10]([CH3:26])([CH3:25])[N:9]=1.[H][H]>N.[Ni]>[NH2:21][CH:19]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:23])[C:11](=[O:24])[C:10]([CH3:25])([CH3:26])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1)[CH3:20]
Reactant: CC(=NO)c1ccc2c(c1)C(c1ccccc1F)=NC(C)(C)C(=O)N2C
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: CC(N)c1ccc2c(c1)C(c1ccccc1F)=NC(C)(C)C(=O)N2C

Procedure:
2.5 g of Raney-nickel paste are added to a solution of 2.22 g (6.28 mmol) of 5-(o-fluorophenyl)-1,3-dihydro-7-[1-(hydroxyimino)ethyl]-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one in 100 ml of 2 N methanolic ammonia and the mixture is stirred at room temperature for 24 hours in a hydrogen atmosphere. The catalyst is filtered off and the solvent is concentrated in vacuo. After filtration over 50 g of silica gel using chloroform as the elution agent, the residue gives 7-(1-aminoethyl)-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one as a foam of melting point 50°-51°.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:2]=1[CH:3]1[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH:4]1[CH2:5][O:6]2.[H-].[Na+].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.Cl>CN(C=O)C.O>[CH:1]1[CH:10]=[C:9]([O:11][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:8]=[C:7]2[C:2]=1[CH:3]1[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH:4]1[CH2:5][O:6]2
Reactant: Oc1ccc2c(c1)OCC1c3ccccc3OC21
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)OC1c3ccc(OCCN4CCCCC4)cc3OCC21
Yield: 69.1 %

Procedure:
Compound 6a,11a-dihydro-6H-benzo[4,5]furo[3,2-c]chromen-3-ol (100 mg, 0.42 mmol) was dissolved in DMF (5 ml) and NaH (10 mg, 0.42 mmol) was added to the solution at room temperature, followed by 1-(2-chloroethyl)piperidine hydrochloride (366 mg, 0.84 mmol). The reaction mixture was stirred at room temperature to 6 hours and poured into iced water and neutralized with 10% HCl to get the white precipitate. Precipitate were washed with water and purified by silica gel column chromatography using hexane-chloroform as the eluent to give 1-(2-(6a,11a-dihydro-6H-benzofuro[3,2-c]chromen-3-yloxy)ethyl)piperidine (102 mg, 70%) as white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:27][NH:28][O:29][CH3:30]>CN(C)C=O>[CH3:30][O:29][N:28]([CH3:27])[C:11]([C:8]1[CH:9]=[CH:10][C:5]2[N:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH:7]=1)=[O:13]
Reactant: Cn1nnc2ccc(C(=O)O)cc21
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2nnn(C)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.1 %

Procedure:
3-Methyl-3H-benzotriazole-5-carboxylic acid (1.67 g, 5.6 mmol) was suspended in 25 ml N,N-dimethylformamide. 1,1′-carbonyldiimidazole (1.0 g, 6.2 mmol) was added and the reaction stirred at room temperature for 90 minutes. Then, N,O-dimethylhydroxylamine hydrochloride (593 mg, 6.2 mmol) was added and the reaction stirred at room temperature overnight. The solvent was removed by rotary evaporation. The residue was dissolved in saturated aqueous ammonium chloride solution and extracted three times with chloroform. The combined organics were dried over sodium sulfate, filtered and concentrated to dryness. Crude material was purified on Biotage Flash 40S silica gel column using chloroform/methanol gradient system (100:0 to 97:3, respectively) as eluent to afford 3-methyl-3H-benzotriazole-5-carboxylic acid methoxy-methyl-amide (1.0 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-])=O.CO>[Fe].O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[NH2:12]
Reactant: COCSc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CO
Product: COCSc1ccc(N)c(N)c1

Procedure:
1.3 G. of 1-amino-2-nitro-4-methoxymethylthiobenzene is treated in 80 ml. methanol and 20 ml. water at reflux under nitrogen, with 0.7 g. ferrous sulfate and 2.8 g. iron (added in two portions) for four hours. The mixture is filtered, stripped under vacuum, and the residue recrystallized from cyclohexane. 1,2-Diamino-4-methoxymethylthiobenzene is thus obtained.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[S:3]Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.O.CCOCC>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[NH:15][C:16]([S:3][C:2]([F:6])([F:5])[F:1])=[CH:17][CH:18]=2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-c2ccc[nH]2)cc1
Reactant: FC(F)(F)SCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: FC(F)(F)Sc1ccc(-c2ccc(Cl)cc2)[nH]1
Reaction time: 0.5 h

Procedure:
Trifluoromethylsulfenyl chloride is bubbled into a solution of 2-(p-chlorophenyl)pyrrole (0.5 g, 0.00281 mol) and sodium carbonate (0.36 g, 0.00338 mol) in ether at -30° C. under nitrogen. The reaction mixture is stirred for 1/2 hour and diluted with a water/ether mixture. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a purple solid (0.78 g, mp 34°-39° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:5].[CH3:19][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]1)(=[O:5])[CH3:19]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of tert-butyl 3-(N-methoxy-N-methylcarbamoyl)pyrrolidine-1-carboxylate (6.30 g, 24.3 mmol) and MeMgCl (3.0 M, 40 mL) in THF (100 mL) was stirred at 0° C. for 3 h. Sat. NH4Cl was added to quench reaction. The resulting mixture was extracted with ethyl acetate (30 mL), washed with brine, dried over MgSO4, filtered, and evaporated to give tert-butyl 3-acetylpyrrolidine-1-carboxylate (3.6 g, 69% yield) as yellow oil. LCMS (ESI) m/z: 158.3 [M-56+H+].
Reaction SMILES: Br[C:2]1[N:3]([CH3:23])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:23][N:3]1[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=[C:2]1[N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1
Reactant: CN1CCNCC1
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Product: CN1CCN(c2nc(-c3ccccc3)c(-c3nc4c(N)ncnc4s3)n2C)CC1
Temperature: 195 °C
Yield: 48 %

Procedure:
A mixture of 2-(2-bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 26) (0.02 g) and N-methylpiperazine (1 mL) were heated under microwave conditions (CEM explorer, 195° C., 1 hour). The solvent was evaporated in vacuo and the residue dissolved in EtOAc (10 mL), washed with water (2×10 mL), dried and the solvent evaporated in vacuo to give the title compound as a yellow solid (10 mg, 48%)
Reaction SMILES: [OH-].[Li+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[C:11](=[O:13])[CH3:12].[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=O)=[CH:19][CH:18]=1)([O-:16])=[O:15].Cl>C1COCC1>[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21]2[O:3][C:4]3[C:5]([C:11](=[O:13])[CH:12]=2)=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=3)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CC(=O)c1c(O)cccc1O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc([N+](=O)[O-])cc2)oc2cccc(O)c12
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Dry, pulverulent lithium hydroxide (52.5 mmol, 4 equivalents) is added in one portion to a well-stirred solution of 2′,6′-dihydroxyacetophenone (13.1 mmol) in dry THF (40 ml) under an argon atmosphere at −78° C. The reaction mixture is stirred at −78° C. for one hour and subsequently at −10° C. for two hours. After the mixture has been re-cooled to −78° C., a solution of 4-nitrobenzoyl chloride (14.46 mmol) in THF (40 ml) is added in one portion. The mixture is stirred at −78° C. for one hour and at room temperature for 4 hours until the starting material has disappeared. The reaction mixture is emptied into a mixture of ice (400 g) and concentrated HCl (16 ml) and extracted with dichloromethane (3×50 ml). The solvents are removed from the dried extracts, and the residue is dried under reduced pressure for 24 hours. Glacial acetic acid (100 ml) and sulfuric acid (0.5 ml) are added to the residue, and the mixture is heated at 95–100° C. for from 30 minutes to one hour under an argon atmosphere. Approximately one third of the acetic acid is stripped off, and the residue is emptied into water. The precipitated product is filtered, washed and dried and recrystallised in methanol, giving 4′-nitro-5-hydroxyflavone. 1H NMR (250 MHz, CDCl3): δ=6.75–8.5 (m, 7H), 12.3 (s, 10H); EI-MS (70 eV) m/e (rel. abund.)=283.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:9][C:10]1[C:29](I)=[CH:28][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([Cl:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[O:15])=[CH:12][N:11]=1.[CH3:31][C:32]1[CH:33]=[N:34][N:35]([CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[C:36]=1B1OC(C)(C)C(C)(C)O1.O>C1(C)C=CC=CC=1.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:9][C:10]1[C:29]([C:36]2[N:35]([CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[N:34]=[CH:33][C:32]=2[CH3:31])=[CH:28][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([Cl:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[O:15])=[CH:12][N:11]=1
Reactant: Cc1cnn(C2CCCCO2)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnn(C2CCCCO2)c1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1Cl
Temperature: 110 °C

Procedure:
K3PO4 (191 mg, 0.9 mmol) and Pd(PPh3)4 (17.33 mg, 0.015 mmol) were added to a solution of 6-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 25.2, 138 mg, 0.3 mmol) and 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (131 mg, 0.45 mmol) in toluene (1.5 mL) under an argon atmosphere in a vial, which was sealed and heated at 110° C. for 18 h. The RM was poured into 20 mL water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 5 to 50% EtOAc) and crystallized from n-heptane to afford the title compound as an off-white powder. HPLC (Condition 4) tR=6.8 min, UPLC-MS (Condition 3) tR=1.26 min, m/z=495 [M−H]−.
Reaction SMILES: C(OC(=O)[N:7]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:19]3[N:23]=[N:22][NH:21][N:20]3[CH2:24][CH2:25][CH2:26][CH3:27])[CH:17]=2)[NH:12][C:11]=1[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=1)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:36]([NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:19]3[N:23]=[N:22][NH:21][N:20]3[CH2:24][CH2:25][CH2:26][CH3:27])[CH:17]=2)[NH:12][C:11]=1[C:28]1[CH:29]=[C:30]([CH3:35])[CH:31]=[C:32]([CH3:34])[CH:33]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCCCN1NN=NN1c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(Cc3ccccc3)C(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCN1NN=NN1c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCc3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of benzyl-{2-[5-(2-butylpentazol-1-yl)-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-ethyl}carbamic acid tert-butyl ester (57 mg in 3.5 mL methylene chloride) at 0° C. was added 0.12 mL anisole followed by 0.80 mL trifluoroacetic acid and the mixture stirred at 0° C. After 1.5 hours, the mixture was concentrated in vacuo and the residual acid removed by azeotrope with toluene to give the crude title compound in quantitative yield.
Reaction SMILES: [CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)(=[O:5])=[O:4].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1.[OH-].[K+]>CCOCC>[CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:21]1([OH:24])[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)/C=C/c1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CNS(=O)(=O)/C=C/c1ccc2[nH]cc(C3(O)CCN(C)CC3)c2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 62.5 %

Procedure:
A mixture of (E)-N-methyl-2-(1H-indole-5-yl)ethenesulphonamide (2.0 g), 1-methyl-4-piperidone (1.62 g) and potassium hydroxide (0.7 g) in IMS (20 mL) was stirred at ambient temperature for 22 hr. The reaction mixture was concentrated and the residue purified by column chromatography on silica gel. Eluting with dichloromethane/ethanol/ammonia (25:10:1) gave an oil which solidified on standing to a brown solid. Trituration with ether provided the product as a white powder (1.85 g, 64% of theory).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:14])[CH:6]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>>[C:1]([NH:4][C:5]1[C:13]([N+:20]([O-:22])=[O:21])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C(=O)O)c(F)c1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 83b from 4-acetylamino-2-fluoro-benzoic acid, conc. sulphuric acid and conc. nitric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:4][CH:3]=1
Reactant: BrCCc1ccncc1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(CCc4ccncc4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 4-(2-bromo-ethyl)-pyridine gave the title compound. ES-MS m/e (%): 504.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][CH:6]=1.[CH:10](Cl)([Cl:12])[Cl:11].CC(C)([O-])C.[K+].Cl>CN(C=O)C.C1COCC1>[Br:1][C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[C:5]([CH:10]([Cl:12])[Cl:11])[CH:6]=1
Reactant: ClC(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Br)s1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1sc(Br)cc1C(Cl)Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromo-5-nitrothiophene (29 g, 139 mmol) and chloroform (12.37 mL, 153 mmol) in DMF (110 mL) was added dropwise to a solution of potassium tert-butoxide (62.6 g, 558 mmol) in THF (225 mL)/DMF (180 mL). The internal temperature was monitored and maintained at <−60° C. during the addition. Upon complete addition, the reaction was stirred at −78° C. for 30 minutes. 2 N HCl was added and the products were extracted into EtOAc (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash silica gel column chromatography (0-10% EtOAc-hexanes) gave the title compound as a brown oil.
Reaction SMILES: P(Br)(Br)[Br:2].[N+:5]([C:8]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10]O)([O-:7])=[O:6].O>C(Cl)Cl>[N+:5]([C:8]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][Br:2])([O-:7])=[O:6]
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1c(CO)cccc1Oc1ccccc1Cl
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1c(CBr)cccc1Oc1ccccc1Cl
Temperature: 0 °C

Procedure:
A solution of Phosphorus tribromide (1.72 ml) in methylene chloride (15 ml) was added dropwise to a solution of 2-nitro-3-(2-chlorophenoxy)benzyl alcohol (9.6 g) in methylene chloride (80 ml) at -10° C., and the mixture was stirred at 0° C. for an hour. To the reaction mixture was added water (50 ml), and the methylene chloride layer was separated, washed with aqueous sodium bicarbonate and saline, dried and then evaporated in vacuo. The oily residue was subjected to column chromatography on silica gel (110 g) and eluted with a mixture of n-hexane and benzene (2:1). The eluate was evaporated in vacuo, and the residue was recrystallized from a mixture of benzene and n-hexane to give 2-nitro-3-(2-chlorophenoxy)benzyl bromide (2.7 g). mp 68°-70° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][C:26]([C@@H:29]([NH:31][C:32](=[O:34])[CH3:33])[CH3:30])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[N:15][CH:16]=1)=O>CC(O)=O>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][C:26]([C@@H:29]([NH:31][C:32](=[O:34])[CH3:33])[CH3:30])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[N:15][CH:16]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(C(=O)Nc4ccccc4N)cn3)CC2)cc1
Solvent: CC(=O)O
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(-c4nc5ccccc5[nH]4)cn3)CC2)cc1
Temperature: 110 °C

Procedure:
A mixture of 92 mg (S)-2-{4-[4-(1-acetylamino-ethyl)-phenyl]-piperidin-1-yl}-pyrimidine-5-carboxylic acid (2-amino-phenyl)-amide in 2 mL HOAc is refluxed for 12 h at 110° C. After concentration in vacuo water is added and the precipitate is collected by filtration to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:17]#[N:18].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:21]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=4[F:13])[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: N#Cc1ccc(N2CCNCC2)c(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(F)c1
Temperature: 77.5 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
A mixture of 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, step 1, 0.857 g), 3-fluoro-4-(piperazin-1-yl)benzonitrile (1.039 g), triethylamine (0.75 mL), and THF (6 mL) is stirred for 3 h at 75-80° C. The mixture is then concentrated under reduced pressure and the residue is partitioned between dichloromethane and saturated sodium bicarbonate. The combined organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96). The appropriate fractions are combined and concentrated. Ethyl ether is added to the residue and the resulting solid is collected, washed with additional ethyl ether, and dried under reduced pressure to give 1.25 g of the title compound. A portion of this material is recrystallized from ethyl acetate; mp 132-133° C. ; IR (mineral oil) 1255, 1513, 1246, 801, 1504 cm-1 ; 1H NMR (CDCl3) δ2.74, 3.26, 3.77, 6.90, 7.13, 7.25, 7.34, 7.53, 8.13.