Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[C:17](=[N:19]/[N:20]=[C:21]([NH2:23])[NH2:22])/[CH3:18])[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.CCO.[Cl:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[CH:32][CH:31]=1.Cl>O>[ClH:29].[ClH:1].[NH2:22][C:21](=[N:20]/[N:19]=[C:17](/[C:13]1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([NH:3][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=1)\[CH3:18])[NH2:23]
Reactant: Clc1ccnc2ccccc12
Reactant: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc(N)cc2)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc(Nc3ccnc4ccccc34)cc2)c1

Procedure:
To a solution of triamine F5 (0.35 g, 0.91 mmol) in 1:2 EtOH:H2O (30 mL) were sequentially added 4-chloroquinoline (0.64 g, 3.90 mmol) and c.HCl (0.25 mL, 8.24 mmol), and the resulting solution was refluxed for 20 h (reaction progress followed by TLC, eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:acetic acid; product Rf=0.51, yellow spot after staining with KMnO4). After this time, solvent was removed under reduced pressure, and the residue dried via two MeOH-azeotrope cycles. The residue was re-precipitated from MeOH:EtOAc to give Cpd. JJ2 (91 mg, 20%) as a pale yellow amorphous solid; mp 240-244° C. (powder-glue), 264-268° C. (glue-liquid); 1H NMR (400 MHz, DMSO): δ 14.67 (br s, 1H, quinolinyl-N+—H), 11.19 (s, 1H, hydrazonyl-N+—H), 11.07 (s, 1H, ArC(O)NHAr), 10.48 (s, 1H, ArNHAr), 8.72 (d, J=8.52 Hz, 1H, ArH), 8.61 (d, J=6.90 Hz, 1H, ArH), 8.24 (m, 3H, ArH), 8.08 (m, 2H, ArH), 7.95 (d, J=8.10 Hz, 1H, ArH), 7.82 (m, 6H, ArH & ═C(NH2)2), 7.68 (d, J=8.38 Hz, 2H, ArH), 7.43 (t, J=7.97 Hz, 1H, ArH), 7.01 (d, J=6.90 Hz, 1H, ArH), 2.37 (s, 3H, Ar(CH3)2═N—); LCMS (APCI+): 438 (100%); HPLC: 96.4%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]([NH:17][C:18]([C:20]1([Br:27])[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][NH:21]1)=[O:19])([CH3:16])[CH3:15].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>C1COCC1>[CH3:16][C:14]([NH:17][C:18]([C:20]1([Br:27])[C:25]([CH2:26][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([Cl:28])[CH:30]=2)=[CH:24][CH:23]=[CH:22][NH:21]1)=[O:19])([CH3:13])[CH3:15]
Reactant: CC1=CC=CNC1(Br)C(=O)NC(C)(C)C
Reactant: Clc1cccc(CBr)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)NC(=O)C1(Br)NC=CC=C1CCc1cccc(Cl)c1
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
Cool diisopropylamine dissolved in THF (60 mL) to 0-5° C. Add n-butyl lithium(39 mL, 97.99 mmol.) and stir the reaction at that temperature for 30 min. Canulate this reaction mixture to a cooled solution of N-(1,1-dimethylethyl)-2-bromo-3-methyl pyridine carboxamide (9.91 g, 97.99 mmol) in dry THF (250 mL) (−70° C.). Stir for 0.5 h then add 3-chlorobenzyl bromide(11.4 g, 55.31 mmol) dissolved in 50 mL of THF. Stir the reaction mixture for 0.5 h. Quench the reaction with water and extract the products twice with EtOAc. Dry the organic phase over Na2SO4, filter and chromatograph on silica gel column eluting with 3% MeOH solution in CH2Cl2 to give the title compound (15 g, Yield 60%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].ClC1C=CC(C2CC(=O)C(=CN(C)C)C(=O)C2)=CC=1>>[CH3:16][N:17]([CH:19]=[C:9]1[C:10](=[O:12])[CH2:11][CH:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:7][C:8]1=[O:13])[CH3:18]
Reactant: O=C1CC(=O)CC(c2cccs2)C1
Reactant: COC(OC)N(C)C
Agent: CN(C)C=C1C(=O)CC(c2ccc(Cl)cc2)CC1=O
Product: CN(C)C=C1C(=O)CC(c2cccs2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared from 5-thien-2-yl-cyclohexane-1,3-dione (388 mg, 2.0 mmol) and N,N-dimethylformamide dimethylacetal (2 ml), following the procedure described for 5-(4-chloro-phenyl)-2-dimethylaminomethylene-cyclohexane-1,3-dione (example 2/a stage 1) except that the reaction mixture was stirred at ambient temperature for 30 min.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]1[N:19]=[CH:20][N:21]([CH3:30])[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1>>[C:1]1([NH:7][C:8]([C:20]2[N:21]([CH3:30])[C:22]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[C:18]([C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[Cl:10])[N:19]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=C=Nc1ccccc1
Product: Cn1c(C(=O)Nc2ccccc2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Using essentially the same procedure as Example 36, Method A, but using phenyl isocyanate (0.023 mL, 0.21 mmol), 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole (35 mg, 0.10 mmol) was converted to the title compound after purification by Prep TLC (25% ethyl acetate in hexanes).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14](C)[CH:13]=2)[CH2:8]1>CO.C(Cl)Cl.[Pd]>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:8]1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC1CCCN1C1CCN(c2ccc(N)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′]bipyrrolidinyl (Intermediate (iii) obtained above, 2.23 g, 7.7 mmol) in MeOH was de-aerated and nitrogen was introduced. To this solution was added Pd—C (10%). This mixture was stirred under H2 atmosphere at r.t. for 8 h. TLC (10% MeOH in DCM) and LC/MS showed the reaction was complete. The mixture was passed through a Celite pad, rinsed with methanol. The filtrate was concentrated to dryness, and further dried under high vacuum to yield a reddish brown liquid after drying under high vacuum to obtain the title compound as a gummy black liquid, 1.73 g (86%). This material was used in the next step without further purification and storage. MS: 260 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:8]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Yield: 67.8 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.94 g, 3.8 mmol), sodium hydride (60% in oil, 0.148 g, 3.7 mmol) and cyclopentyl-bromide (0.43 mL, 4.0 mmol) to give the title compound (0.80 g) as a white solid,
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:22])[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[O:7]1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[N+](C)([O-])=O.C(OCC)C>[C:23]([C:19]1[CH:20]=[CH:21][C:8]2[O:7][C:6]([CH3:22])([CH3:5])[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:9]=2[CH:18]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccccc3)ccc2O1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 27.6 %

Procedure:
264 mg of aluminum chloride were added to an ice-cooled solution of 237 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran in 6 ml of nitromethane. The mixture was stirred for 5 minutes, 349 mg of benzoyl chloride were added and the stirring was continued at 0° C. for 30 minutes and at room temperature for 16 hours. The o reaction mixture was diluted with diethyl ether and washed with sodium hydroxide solution. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (2:3) for the elution to give 94 mg of 6-benzoyl-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][N:12]([C:36](=[O:38])[CH3:37])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1
Reactant: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ncccc3F)CC2)C1
Reaction time: 20 h

Procedure:
To a solution of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol) and triethylamine (0.035 ml, 0.25 mmol) in dichloromethane (0.6 ml) was added acetyl chloride (0.18 ml, 0.251 mmol) at room temperature. Stirring for 20 h was followed by partitioning between a water-brine mixture (1:1) (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with two 5 ml-portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (7 mg, 12%) as off-white solid. MS m/e: 440 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:58]1[CH:63]=[CH:62][CH:61]=[C:60]([CH2:64][NH2:65])[CH:59]=1>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:65][CH2:64][C:60]3[CH:59]=[N:58][CH:63]=[CH:62][CH:61]=3)=[O:13])=[CH:14][CH:15]=2)=[N:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)(=[O:18])=[O:19]
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 39.2 %

Procedure:
A solution of 4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoic acid (420 mg, 0.99 mmol, 1.00 equiv), EDCI (230 mg, 1.20 mmol, 1.22 equiv), HOBt (170 mg, 1.26 mmol, 1.27 equiv), triethylamine (300 mg, 2.97 mmol, 3.01 equiv) and pyridin-3-ylmethanamine (140 mg, 1.30 mmol, 1.31 equiv) in N,N-dimethylformamide (20 mL) was stirred overnight at room temperature. The product was precipitated by the addition 60 mL of water/ice. The solid was collected by filtration, washed with 2×20 mL of water and dried in a vacuum oven to give 0.20 g (39%) of 4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS: (ES, m/z): 557 [M+CH3CN+H]+, 516 [M+H]+, 102. 1HNMR (400 MHz, CDCl3, ppm) δ 9.22 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 8.06-7.89 (m, 6H), 7.82 (d, J=8.0 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.38-7.36 (m, 1H), 4.84 (s, 2H), 4.51 (d, J=5.2 Hz, 2H), 2.24 (s, 3H).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36](=[O:38])[CH3:37])=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=O)=CC=1)([O-])=O.[OH-].[Li+]>C1COCC1.C(OCC)(=O)C>[C:36]([C:28]1[C:27]2[C:32](=[CH:33][C:24]([CH2:23][N:21]3[CH:22]=[C:18]([C@:11]([OH:10])([C:14]([F:15])([F:16])[F:17])[CH2:12][CH3:13])[N:19]=[N:20]3)=[CH:25][CH:26]=2)[N:31]=[C:30]([C:34]#[N:35])[CH:29]=1)(=[O:38])[CH3:37]
Reactant: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(C(C)=O)cc(C#N)nc3c2)nn1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@](O)(c1cn(Cc2ccc3c(C(C)=O)cc(C#N)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-{1-[(4-acetyl-2-cyanoquinolin-7-yl)methyl]-1H-1,2,3-triazol-4-yl}-1-(trifluoromethyl)propyl 4-nitrobenzoate (obtained as described in Example 52, step 4) (47 mg, 0.085 mmol) in THF (2 mL) was added lithium hydroxide 2M (210 uL, 0.42 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with an ammonium chloride sln., brine, dried over MgSO4, filtered and concentrated to yield the title compound. The crude residue was purified by flash chromatography (10% acetone-90% dichloromethane) to give the desired product. 1H NMR (400 MHz, acetone-d6): δ 8.55 (d, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 8.85 (d, 1H), 6.02 (s, 2H), 2.85 (s, 3H), 2.35 (m, 1H), 2.05 (m, 1H), 0.86 (t, 3H).
Reaction SMILES: CN([CH:4]=[C:5]([C:11](=O)[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[C:15]([NH2:18])(=[NH:17])[CH3:16].CC[O-].[Na+]>CCO>[CH3:16][C:15]1[N:18]=[C:11]([CH3:12])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:17]=1
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C)nc1C
Yield: 42.6 %

Procedure:
Intermediate 51 (17.6 g, 95 mmol) and acetamidine hydrochloride (17.6 g, 95 mmol), were dissolved in EtOH and added NaOEt (6.5 g, 95 mmol). This mixture was refluxed for 4 h. After that, ethanol removed on rotavapour followed by work-up (AcOEt/H2O) to obtain the crude. Crude was purified by column chromatography using 60-120 mesh silicagel and AcOEt and Petether (25:75) as eluent to obtain the title compound (7.3 g).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([CH3:15])[C:9]2=[O:16])=[N:6][CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[CH:18].C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][N:10]1[C:11]([CH3:14])([CH3:13])[CH2:12][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:18]#[C:17][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:7][N:6]=2)[C:9]1=[O:16]
Reactant: C#Cc1ccccc1
Reactant: CN1C(=O)C(c2ccc(I)cn2)CC1(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1C(=O)C(c2ccc(C#Cc3ccccc3)cn2)CC1(C)C
Temperature: 60 °C
Yield: 80.6 %

Procedure:
A solution of (RS)-3-(5-iodopyridin-2-yl)-1,5,5-trimethylpyrrolidin-2-one (140 mg, 0.42 mmol), ethynylbenzene (65.0 mg, 69.9 μl, 0.64 mmol), triethylamine (129 mg, 177 μl, 1.27 mmol), bis(triphenylphosphine)palladium (II) chloride (17.9 mg, 25.4 μmol) and triphenylphosphine (3.34 mg, 12.7 μmol) in 4 ml of THF was purged with argon. Then copper (I) iodide (2.42 mg, 12.7 μmol) was added and the reaction was heated for 3 h at 60° C. After extraction with ethyl acetate/water, drying over sodium sulfate and concentration; the residue was taken up in ethyl acetate, adsorbed onto 3 g of silicagel which was loaded onto a 20 g prepacked flash chromato-graphy column. After elution with a 0% to 65% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 103 mg (72%) of the title compound as an amorphous yellow solid, MS: m/e=305.2 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]>C(O)C.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccc(F)cc2)c(NC(C)=O)c2ccc(Cl)cc21
Solvent: CCO
Solvent: CCCCCC
Product: CC(=O)Nc1c(C(=O)c2ccc(F)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-6-chloro-1-ethoxycarbonyl-2-(4-fluorobenzoyl)indole (step 1). m.p.: 205-207° C. (ethanol/hexane)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19]([OH:21])=O)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.C(Cl)(=O)C([Cl:25])=O>ClCCl.CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19]([Cl:25])=[O:21])[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1(CCCCBr)c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
23 g (0.067 mol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid are dissolved in 40 ml dichloromethane and combined with three drops of dimethylformamide and 6.96 ml (0.081 mol) of oxalyl chloride, dissolved in 10 ml dichloromethane, under nitrogen at 0° C. The mixture is stirred for 3 hours at ambient temperature. Then the solvent is removed and the crude product is further reacted without any more purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[O:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[O:35][CH2:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:31][CH2:32][CH:33]2[O:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[O:35][CH2:34]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3O2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCN(CCC2COc3ccccc3O2)C1
Reaction time: 16 h
Yield: 96.6 %

Procedure:
First 1.96 g (12.5 mmol) of piperidine-3-carboxylic acid ethyl ester and then 2.58 g (20 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.34 g 10 mmol) of 2-[2-(p-toluenesulphonyloxy)ethyl]-benzo-1,4-dioxan in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.82 g (100%) of crude product are obtained which are filtered over 190 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 3.70 g (96.6%) of 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester are then obtained in the form of a pale yellow oil. The 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 162°-165°.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH2:26].C(N(C(C)C)CC)(C)C>C(#N)C>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH:26][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: NCc1cccs1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCc2cccs2)S/C1=C\c1ccc2ncccc2c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 67.7 %

Procedure:
The suspension of 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one (example 1a, 3.0 g, 10.5 mmol), thiophene methyl amine (2.4 g, 21.0 mmol) and diisopropylethylamine (DIEA) (3.66 mL, 21.0 mmol) in acetonitrile (30 mL) was stirred under at 80° C. for 12 h. After cooling to room temperature, the solid was collected by filtration, washed with a little bit of acetonitrile and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-10% methanol in methylene chloride in 30 min) afforded 2-[(thiophen-2-ylmethyl)-amino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one (2.5 g, 67%) as a light yellow solid: LC-MS m/e 352 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16][OH:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C)C=O>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(CO)ccc2[nH]1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To a solution of 0.3 g of 2-butyl-6-(hydroxymethyl)-4(1H)-quinazolinone in 3.5 ml of dry N,N-dimethylformamide is added 1.7 g of pyridinium dichromate. The reaction mixture is stirred at room temperature for 16 hours and then poured into 125 ml of water. The resulting precipitate is removed by filtration and the filtrate extracted with 9:1 chloroform-methanol. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated in vacuo and combined with the precipitate above. The combined solids are purified by flash chromatography on silica gel by eluting with 1:1 ethyl acetate-hexanes to give 0.27 g of the desired product. CI MASS SPEC 231(M+H).
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10][C:9]([Br:16])=[CH:8][N:7]=1>S(=O)(=O)(O)O>[CH3:15][O:14][C:12]([C:11]1[C:6](=[O:2])[NH:7][CH:8]=[C:9]([Br:16])[N:10]=1)=[O:13]
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1nc(Br)c[nH]c1=O
Temperature: 3.5 °C

Procedure:
Concentrated sulphuric acid (5 ml) was stirred and cooled to 2-5° C. and sodium nitrite (0.7 g) added batchwise such that the reaction exotherm did not exceed 10° C. The reaction mixture was allowed to reach room temperature and then warmed to 40° for 2-3 minutes to give a homogeneous solution. The stirred reaction mixture was then cooled to 2°-5° C. and a cooled (2°-5° C.) solution of 2-amino-3-methoxycarbonyl-5-bromopyrazine (JACS, 1949, 71, 2798; 2.32 g) in concentrated sulphuric acid added dropwise so that the reaction temperature did not exceed 5° C. After the addition was complete, the reaction mixture was allowed to warm to 15° C. over three hours and then added dropwise to crushed ice (200 g). The resulting mixture was extracted with ethyl acetate. The organic phase washed with brine, dried with sodium sulphate and evaporated under reduced pressure to give the crude product as a yellow solid. The crude product was used in further experiments without further purification. A portion of the crude product was recrystallised from acetonepetroleum ether (boiling range 60°-80° C.) to give 3-methoxycarbonyl-5-bromopyrazine-2-one as a yellow solid: