Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:4]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]([CH2:29][C@H:30]([OH:35])[C:31]([F:34])([F:33])[F:32])[C:25](=[O:28])[NH:26][N:27]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]([CH2:29][C@H:30]([OH:35])[C:31]([F:33])([F:34])[F:32])[C:25](=[O:28])[N:26]([CH2:2][C:3]3[CH:8]=[CH:7][N:6]=[C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[Cl:15])[N:4]=3)[N:27]=2)=[CH:19][CH:18]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Clc1ccccc1-c1nccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1n(Cc2ccnc(-c3ccccc3Cl)n2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 60 °C
Reaction time: 96 h

Procedure:
259 mg (0.18 mmol) of the compound from Example 81A (purity about 20%) were dissolved in 2 ml of acetonitrile, and 62 mg (0.21 mmol) of the compound from Example 5A and 89 mg (0.27 mmol) of cesium carbonate were added. The mixture was stirred at 60° C. for 2.5 h and at RT for a further 96 h. The solid was then filtered off and rinsed with a little acetonitrile. The filtrate was concentrated under reduced pressure and directly purified chromatographically [Method 19]. This gave 31 mg of the target compound, which were subjected to a further chromatographic purification on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3, then 1:1). This gave 23 mg (22% of theory) of the target compound.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:23]=[C:22]([C:34]([F:37])([F:36])[F:35])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:33][C:28]1[CH:27]=[C:26]([C:24]2[CH:23]=[C:22]([C:34]([F:35])([F:36])[F:37])[N:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=3)[N:25]=2)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)ccn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 30.7 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.29 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.08 g, 24%). MS (ISP) 499.1 [(M+H)+]; mp 281° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[CH2:38](Br)[CH:39]=[CH2:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:40][CH:39]=[CH2:38])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: C=CCBr
Product: C=CCOc1cc2c(cc1OC)CCN(CC(=O)NC1CCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with allyl bromide
Reaction SMILES: [NH2:1][C@:2]1([CH2:9][C:10]#[C:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[CH:21]=[CH:20][C:19]=3[F:27])[CH:15]=[C:14]([CH3:28])[N:13]=2)[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8]>CC#N.CCOC(C)=O.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:25]([O:24][C:22]1[CH:21]=[CH:20][C:19]([F:27])=[C:18]([C:16]2[CH:15]=[C:14]([CH3:28])[N:13]=[C:12]([C:11]3[CH2:10][CH2:9][C@:2]4([CH2:6][CH2:5][N:4]([CH3:7])[C:3]4=[O:8])[N:1]=3)[N:17]=2)[CH:23]=1)[CH3:26]
Reactant: CCOc1ccc(F)c(-c2cc(C)nc(C#CC[C@@]3(N)CCN(C)C3=O)n2)c1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1ccc(F)c(-c2cc(C)nc(C3=N[C@]4(CC3)CCN(C)C4=O)n2)c1
Temperature: 40 °C
Reaction time: 66 h
Yield: 74.9 %

Procedure:
Silver trifluoromethanesulphonate (60.06 mg, 0.23 mmol) was added to a solution of (3R)-3-amino-3-[3-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]prop-2-ynyl]-1-methyl-pyrrolidin-2-one (which may be prepared as described in Description 19) (447 mg, 1.17 mmol) in MeCN (20 mL) at 20° C. and the reaction was stirred for 66 hrs. An additional 10 mol % AgOTf was added, stirring was continued for an additional 3 days then the mixture was heated to 40° C. until no starting material remained. The solvent was evaporated and the residue was partitioned between water and EtOAc. The organic layer was dried (Na2SO4) and the solvent was evaporated to afford a brown oil. This was purified using a Biotage Isolera with a 25 g SNAP cartridge, eluting with a 0 to 50% mixture (9% MeOH; 89% EtOAc and 2% 880 NH3) in EtOAc affording the (5R)-2-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (D20) (335 mg, 0.876 mmol, 74.9% yield) as a light brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]2[N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:10]=[CH:11][C:3]=12.[C:18]([NH:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:21])[CH:19]=[CH2:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:6]1[N:5]=[C:4]2[N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:10]=[CH:11][C:3]2=[C:2]([C:25]2[CH:24]=[C:23]([NH:22][C:18](=[O:21])[CH:19]=[CH2:20])[CH:28]=[CH:27][CH:26]=2)[N:7]=1
Reactant: C=CC(=O)Nc1cccc(B(O)O)c1
Reactant: Clc1nc(Cl)c2cnn(C3CCCCO3)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: C=CC(=O)Nc1cccc(-c2nc(Cl)nc3c2cnn3C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
4,6-Dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.366 mmol), (3-acrylamidophenyl)boronic acid (70 mg, 0.366 mmol) and triphenylphosphine (4 mg, 0.015 mmol) were dissolved in a mixture of toluene (7 mL) and 1 M sodium carbonate (39 mg, 0.367 mmol), after which palladium(II) acetate (2.0 mg, 0.009 mmol) was added and the reaction mixture was stirred for 36 h at 80° C. The reaction was allowed to cool to room temperature, and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (20 mL) and washed with water (10 mL). The organic layer was separated, the aqueous layer was extracted with ethyl acetate (20 mL), the combined organic layers were washed with brine (20 mL), and dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography (20% ethyl acetate/hexane) to yield the title compound. 1H NMR (400 MHz, CDCl3): δ 8.45 (m, 2H), 7.88 (d, 1H, J=8.0 Hz), 7.85 (d, 1H, J=8.0 Hz), 7.68 (s, 1H), 7.49 (t, 1H, J=8.0 Hz), 6.46 (m, 1H), 6.27 (m, 1H), 6.06 (d, 1H, J=10.4 Hz), 5.79 (d, 1H, J=10.0 Hz), 4.12 (m, 1H), 3.82 (t, 1H, J=10.0 Hz), 2.58 (m, 1H), 2.14 (m, 1H), 1.95 (m, 1H), 1.78 (m, 2H), 1.62 (m, 1H); ESI-MS: 384.10 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[C:4]([C:15]#[C:16][Si](C)(C)C)[C:3]=1[C:21]([F:24])([F:23])[F:22].[C:25]([Cu])#[N:26].[OH-].[NH4+]>CN1C(=O)CCC1>[F:24][C:21]([F:22])([F:23])[C:3]1[C:2]([C:25]#[N:26])=[CH:7][CH:6]=[C:5]2[C:4]=1[CH:15]=[CH:16][NH:8]2
Reactant: N#C[Cu]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1C#C[Si](C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Temperature: 250 °C

Procedure:
An NMP solution (15 mL) of N-{4-chloro-3-(trifluoromethyl)-2-[(trimethylsilyl)ethynyl]phenyl}-2,2-dimethylpropanamide (1.04 g, 2.77 mmol) was treated with CuCN (1.04 g, 11.01 mmol) and the resulting mixture was heated at 250° C. in a microwave for 5.5 h. The dark brown reaction mixture was poured into crushed ice (250 mL) containing conc. ammonium hydroxide (30 mL). The resulting slurry was filtered and rinsed with Et2O. The filtrate was diluted with Et2O (50 mL) and partitioned. The aqueous portion was extracted with Et2O (2×25 mL). The combined organic portions were washed with H2O (25 mL) and brine (25 mL). Drying (Na2SO4) and filtration were followed by concentration to a brown/yellow solid (0.723 g) that was used for the next reaction without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:27]I>O1CCCC1>[CH:1]1([N:4]([CH3:27])[C:5]2[C:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1
Reactant: CI
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(NC3CC3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(cyclopropylamino)-2-phenylquinoxaline-6-carboxylate (182.4 mg, 0.56 mmol, 1.00 equiv, 98%) in tetrahydrofuran (17 mL). Sodium hydride (274.5 mg, 11.44 mmol, 20.00 equiv) was added. The resulting solution was stirred for 1 h at room temperature. This was followed by the dropwise addition of CH3I (809.4 mg, 5.70 mmol, 10.00 equiv) with stirring at 0° C. The resulting solution was allowed to react, with stirring, overnight at room temperature. The resulting mixture was concentrated under vacuum and diluted with 10 ml of water. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solid was collected by filtration and washed with water and methanol. This resulted in 66.5 mg (36%) of 3-(cyclopropyl(methyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[K+].Cl>O.C(O)C>[CH2:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
12.7 Grams (0.0917 mol) of p-hydroxybenzoic acid, 28.5 g of n-nonyl bromide and 10.2 g of potassium hydroxide were added to a mixture composed of 1,500 ml (milliliter) of ethanol and 200 ml of water, and the mixture was allowed to react under reflux for 10 hours. Further, 500 ml of water was added thereto, and the mixture was stirred for 3 hours. After the completion of the reaction, a concentrated hydrochloric acid was added to acidify the reaction mixture. Thereafter, the solvent was distilled off, and the remaining product was cooled to room temperature and then filtered to give a colorless solid. The solid was fully washed with water and re-crystallized from chloroform to give an intended product (yield 75%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][CH2:11][C@@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:13]1.Cl[CH:26](Cl)[C:27](=[N:29][NH:30]S(C1C=CC(C)=CC=1)(=O)=O)[CH3:28]>CO>[F:24][C:20]1[CH:19]=[C:18]([N:14]2[CH2:13][C@H:12]([CH2:11][N:10]3[CH:26]=[C:27]([CH3:28])[N:29]=[N:30]3)[O:16][C:15]2=[O:17])[CH:23]=[CH:22][CH:21]=1
Reactant: NC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Reactant: CC(=NNS(=O)(=O)c1ccc(C)cc1)C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cn(C[C@H]2CN(c3cccc(F)c3)C(=O)O2)nn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
N,N-Diisopropylethylamine (3.20 mL, 18.35 mM) was added to a solution of (5S)-5-(aminomethyl)-3-(3-fluorophenyl)-1,3-oxazolidin-2-one (0.77 g, 3.57 mM; see Dong Pharmaceuticals WO 0194342) in anhydrous methanol (25 mL). The solution was cooled to 0° C., and N′-[2,2-dichloro-1-methylethylidene]-4-methylbenzenesulfonohydrazide (1.28 g, 4.58 mM) was added. The solution was warmed to room temperature and stirred overnight. The reaction mixture was then concentrated under vacuum and chromatographed on silica gel using 2% methanol/dichloromethane to give 0.71 g of the title product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][CH2:10][CH2:11][OH:12]>O>[CH3:8][N:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:10][CH2:11][OH:12]
Reactant: CNCCO
Reactant: Clc1ccccn1
Solvent: O
Product: CN(CCO)c1ccccn1
Temperature: 25 °C

Procedure:
2-chloropyridine (12 g) and 2-(methylamino)ethanol (100 ml) are stirred under nitrogen at 120° C. for 18 hours. Cool to room temperature and then pour into iced water (250 ml). Extract with ethyl acetate (2×200 ml). Dry over sodium sulfate. Filter. Evaporate to dryness. The crude product is distilled in vacuo to give 10.3 g of N-methyl-N-(2-pyridinyl)-2-aminoethanol, boiling at 110° C./1.0 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=5)[CH2:21][CH2:20]4)=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4ccc(Cl)cc4)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-chloro-4-iodobenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 486.2 (M+H)+.
Reaction SMILES: CN([C:4]([O:8]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl[C:24]1[CH:41]=[CH:40][C:27]([C:28]([NH:30][C:31]2C=C(C=CC=2)C(O)=O)=[O:29])=[C:26](OC)[CH:25]=1.Cl.CNOC.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:4][O:8][N:30]([CH3:31])[C:28](=[O:29])[C:27]1[CH:26]=[CH:25][CH:24]=[CH:41][CH:40]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1cc(Cl)ccc1C(=O)Nc1cccc(C(=O)O)c1
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccccc1
Reaction time: 2.5 h

Procedure:
TBTU (4.73 g, 14.7 mmol) was added to a solution of 3-{(4-chloro-2-methoxybenzoyl)amino}benzoic acid (4.50 g, 14.7 mmol), N,O-dimethylhydroxylamine hydrochloride (1.72 g, 17.7 mmol) and i-Pr2NEt (7.60 g, 58.9 mmol) in DMF (29 mL) at 25°. The reaction mixture was stirred at 25° for 2.5 h. The mixture was diluted with EtOAc (200 mL). The resulting solution was successively washed with aqueous 1 N HCl (2×75 mL), water (2×75 mL), aqueous saturated NaHCO3 (2×75 mL) and brine (75 mL), then dried (MgSO4), filtered and concentrated under reduced pressure to give the corresponding N-methoxy-N-methylbenzamide of formula 6 (4.32 g, 84% yield) as a white solid:
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:7][C:8]=1[C:9]1[NH:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2.C(#N)C.O.C(O)=O>C(O)C.[OH-].[Na+]>[C:18]1([C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:8]2[C:3](=[O:2])[NH:4][N:5]=[C:6]([C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[CH:7]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1nnc(-c2ccncc2)cc1-c1[nH]c2ccccc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: CC#N
Product: O=c1[nH]nc(-c2ccncc2)cc1-c1[nH]c2ccccc2c1-c1ccccc1
Temperature: 150 °C

Procedure:
63 mg 2-(3-Methoxy-6-pyridin-4-yl-pyridazin-4-yl)-3-phenyl-1H-indole is dissolved in 0.75 ml ethanol and 0.75 ml 1N aqueous NaOH solution. The reaction mixture is stirred at 150° C. in microwave apparatus (200 W). The reaction mixture is directly applied to HPLC chromatography to isolate the product (RP18 column, acetonitrile/water, 0.05% HCOOH)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:15]=1.C([O-])(=O)C.[Na+]>CN(C)C(=O)C.C(OCC)(=O)C.O.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>[C:26]([O:25][C:23]([NH:22][CH2:21][CH2:20][C:16]1[CH:15]=[C:14]2[C:19]([C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[CH2:12][O:13]2)=[CH:18][CH:17]=1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)c1ccc(Br)c(COc2cccc(CCNC(=O)OC(C)(C)C)c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)COc1cc(CCNC(=O)OC(C)(C)C)ccc1-2
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 56.1 %

Procedure:
To a solution of methyl 4-bromo-3-[[3-[2-[(tert-butoxycarbonyl)amino]ethyl]phenoxy]methyl]benzoate (410 mg) in N,N-dimethylacetamide (4.0 ml) was added dichlorobis(triphenylphosphine)palladium(II) (124 mg) and sodium acetate (362 mg), and the mixture was stirred at 130° C. for 1.5 hours under nitrogen. The mixture was cooled to room temperature, diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 3-[2-[(tert-butoxycarbonyl)amino]ethyl]-6H-benzo[c]chromene-8-carboxylate (190 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[NH:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH2:20]([N:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[S:9]1(=[O:12])=[O:11])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCI
Reactant: O=S1(=O)NCc2cccc(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCN1Cc2cccc(Cl)c2S1(=O)=O

Procedure:
A suspension of 10.2 g of 7-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide, 8.3 g of potassium carbonate and 7.7 ml of 1-iodopentane was refluxed in 50 ml of ethanol for 28 hours, cooled, concentrated and added to 200 ml of water. The mixture was extracted with n-BuCl, the extract washed with water and brine, dried over MgSO4 and concentrated to give 13.3 g of an amber oil which was triturated with hexane to give 11.4 g of the title compound as a tan powder, m.p. 46°-48° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:15]=2)=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH3:40])[CH2:35][CH2:34]2)=[N:31][CH:32]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:39]([N:36]1[CH2:35][CH2:34][N:33]([C:30]2[N:31]=[CH:32][C:27]([NH:26][C:4](=[O:5])[C:3]3[CH:7]=[C:8]([NH:11][C:12]([C:14]4[CH:19]=[CH:18][N:17]=[C:16]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)[CH:15]=4)=[O:13])[CH:9]=[CH:10][C:2]=3[Cl:1])=[CH:28][CH:29]=2)[CH2:38][CH2:37]1)[CH3:40]
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1ccnc(N2CCOCC2)c1
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc(NC(=O)c3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.8 %

Procedure:
2-Chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzoic acid (0.162 g) was added to a stirred mixture of 5-amino-2-(4-ethylpiperazin-1-yl)pyridine (0.093 g), diisopropylethylamine (0.232 g), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.176 g) and DMF (10 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and evaporated. The residue was triturated under a mixture of isohexane and ethyl acetate. The resultant solid was isolated and dried under vacuum at 40° C. to give the title compound (0.071 g); NMR Spectrum: (DMSOd6) 1.02 (t, 3H), 2.34 (m, 2H), 2.4-2.46 (m, 4H), 3.38-3.42 (m, 4H), 3.5-3.53 (m, 4H), 3.69-3.71 (m, 4H), 6.82 (d, 1H), 7.08 (d, 2H), 7.22 (s, 1H), 7.62 (d, 1H), 7.82-7.98 (m, 3H), 8.28 (d, 1H), 8.39 (s, 1H); Mass Spectrum: M+H+ 550 and 552.
Reaction SMILES: C(=O)([O-])O.[K+].Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([O:25][CH3:26])=[CH:13][C:14]2[O:19][C:18](=[O:20])[C:17]3[CH2:21][CH2:22][CH2:23][C:16]=3[C:15]=2[CH:24]=1.Cl.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[N:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)C.C(Cl)(Cl)Cl>[CH3:26][O:25][C:12]1[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:38]2[CH2:39][CH2:40][N:35]([C:30]3[N:29]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:36][CH2:37]2)=[CH:24][C:15]2[C:16]3[CH2:23][CH2:22][CH2:21][C:17]=3[C:18](=[O:20])[O:19][C:14]=2[CH:13]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)[O-]
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2ncccn2)CC1)CCC3
Yield: 54 %

Procedure:
Method B (60 h at 50° C.; 4 equivalents of potassium hydrogencarbonate); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(2-pyrimidinyl)piperazine dihydrochloride; yield 54%; fusion point 184°-186° C. (from chloroform and ethanol). Fumarate: method E; yield 77%; fusion point 226°-228° C. (from acetone).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.[CH:10]([C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)([CH3:12])[CH3:11]>C1COCC1>[NH:1]1[CH:5]=[C:4]([S:6]([N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:10]([CH3:12])[CH3:11])(=[O:8])=[O:7])[N:3]=[CH:2]1
Reactant: CC(C)c1ncc[nH]1
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)c1nccn1S(=O)(=O)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A round bottom flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 8.35 g of imidazole-4-sulfonylchloride and 150 ml of THF. This solution was treated with 11.10 g of 2-isopropylimidazole in one portion and the solution stirred 24 hours at room temperature. The solution was concentrated to a clear oil and partitioned between ethylacetate and water. The organic layer was washed with water and the water washes back extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to a foam. The foam was dissolved in acetone and chromatographed on activity III alumina to separate 1-(4-imidazolylsulfonyl)-2-isopropylimidazole, mp 118°-120°.