Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:11][C:10]2=[O:29])=[CH:6][CH:5]=1)([OH:3])=O.[NH:32]1[CH2:36][CH:35]=[CH:34][CH2:33]1.C(N(CC)CC)C>ClCCl>[N:32]1([C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[CH2:13][N:12]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[CH2:11][C:10]3=[O:29])=[CH:30][CH:31]=2)=[O:3])[CH2:36][CH:35]=[CH:34][CH2:33]1
Reactant: O=C(O)c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1
Reactant: C1=CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1)N1CC=CC1
Reaction time: 8 h

Procedure:
23 mg (0.053 mmol) of 1-(4-carboxybenzyl)-4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of dichloromethane. 6 mg (0.079 mmol) of 3-pyrroline, 13 mg (0.079 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.022 ml (0.159 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [C:1]1([CH:7]([CH2:10][CH3:11])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=[C:15]([C:19]([O:21]O)=O)[CH:14]=1>>[CH2:10]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:14][CH:15]1[CH2:19][O:21]1)[C:8]#[N:9])[CH3:11]
Reactant: CCC(C#N)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCC(C#N)(CC1CO1)c1ccccc1

Procedure:
The title compound was prepared by the methods described in Examples 2 and 3 except that 2-phenylbutyronitrile was used instead of methyl 2-phenylbutyrate and complete epoxidation required adding a second quantity of m-chloroperbenzoic acid. The resultant light-yellow oil was used in subsequent reactions without furher purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH2:11]([N:13](CC)[CH2:14]C)C.Cl.CNC>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([CH3:14])[CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: CNC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
6-Chloronicotinoyl chloride (500 mg, 2.76 mmol) and triethylamine (0.576 ml, 4.13 mmol) were taken-up in THF (13.8 ml) under argon and cooled to 0° C. Dimethylamine hydrochloride (337 mg, 4.13 mmol) was dissolved in THF (2 ml) and added dropwise to the reaction mixture over 15 minutes. The mixture was maintained at 0° C. for 1 hour, warmed to room temperature, and stirred for 15 minutes. The reaction was then diluted with ethyl acetate and washed twice with brine. The aqueous layers were combined and back-extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:12][CH:13]([N:15]1[C:28]2[CH:27]=[C:26]([C:29]#[N:30])[CH:25]=[CH:24][C:23]=2[S:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])(=O)=O>C1(C)C(C)=CC=CC=1>[N:1]1([CH2:14][CH:13]([N:15]2[C:28]3[CH:27]=[C:26]([C:29]#[N:30])[CH:25]=[CH:24][C:23]=3[S:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: C1CCNCC1
Solvent: Cc1ccccc1C
Product: CC(CN1CCCCC1)N1c2ccccc2Sc2ccc(C#N)cc21

Procedure:
Piperidine (19.8 cc) is added to a suspension of 2-(2-cyano-10-phenothiazinyl)-1-propyl methane-sulphonate (36.05 g) in xylene (360 cc). The mixture is brought to reflux for 19 hours. After cooling, the mixture is washed with distilled water (6×150 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa). The residue is purified by chromatography on a column (height: 96 cm; diameter: 4.8 cm) of silica gel (0.06-0.2 mm), eluting with 90:10, 85:15, 80:20 and 75:25 (by volume) mixtures (4 liters, 4 liters and 4 liters, respectively) of cyclohexane and ethyl acetate and collecting 500- cc fractions. The first 9 liters are discarded and fractions 8 to 13 are combined and concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give 10 -[(2RS)-1-piperidino-2-propyl]-2-phenothiazinecarbonitrile (13.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[C:35]([CH3:41])[C:34]=1[S:42](Cl)(=[O:44])=[O:43]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:42]([C:34]4[C:35]([CH3:41])=[C:36]([CH3:40])[CH:37]=[C:38]([CH3:39])[C:33]=4[CH3:32])(=[O:44])=[O:43])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: Cc1cc(C)c(C)c(S(=O)(=O)Cl)c1C
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(C)c(C)cc(C)c4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,3,5,6-tetramethyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=617.7)=80%.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14](Cl)=[C:15]([F:20])[CH:16]=2)[N:11]([CH:22]2[CH2:24][CH2:23]2)[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C=O)C.Cl>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:15]([F:20])[CH:16]=2)[N:11]([CH:22]2[CH2:24][CH2:23]2)[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2cc(F)c(Cl)cc2n(C2CC2)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Agent: Cl
Solvent: CN(C)C=O
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(C2CC2)c(=O)n1OCc1ccccc1
Temperature: 70 °C

Procedure:
A solution of 3-benzyloxy-7-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione (Example E-3, 0.15 g, 0.42 mmol) in DMF (4.0 mL) was reacted with pyrrolidine (1.0 mL) and heated to 70° C. overnight. The mixture was then cooled, diluted with 0.25 M HCl, and extracted with ethyl acetate. The organic layers were combined, dried with sodium sulfate, and concentrated. The residue was then purified by column chromatography (silica gel, 1:1 hexanes/ethyl acetate) to provide 0.15 g of the title compound as a solid.
Reaction SMILES: CC[O-].CC[O-].[Mg+2].[C:8]([O:12][C:13](=[O:18])[CH2:14][C:15]([CH3:17])=[O:16])([CH3:11])([CH3:10])[CH3:9].[Cl:19][C:20]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=[C:25]([Cl:33])[C:21]=1[C:22](Cl)=[O:23].Cl>C1(C)C=CC=CC=1>[C:8]([O:12][C:13](=[O:18])[CH:14]([C:22](=[O:23])[C:21]1[C:25]([Cl:33])=[CH:26][CH:27]=[C:28]([C:29]([O:31][CH3:32])=[O:30])[C:20]=1[Cl:19])[C:15]([CH3:17])=[O:16])([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)c1ccc(Cl)c(C(=O)Cl)c1Cl
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c(C(=O)C(C(C)=O)C(=O)OC(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A suspension of 1.65 g of magnesium ethylate in 30 ml of toluene was kept at 60-70° C. and 2.28 g of acetoacetic tert-butyl ester was added dropwise thereto. After the dropwise addition was completed, the resultant mixture was refluxed for two hours. Then, the reaction solution was cooled to room temperature and 3.85 g of 2,6-dichloro-3-methoxycarbonyl benzoic acid chloride was added dropwise thereto. The reaction mixture was stirred at room temperature for two hours and at 50-100° C. for three hours, then cooled to room temperature, treated with dilute hydrochloric acid, and extracted from ethyl acetate. Then, the organic layer was alkali extracted from an aqueous 5% sodium carbonate solution. The water layer was mixed with chloroform, educed with dilute hydrochloric acid, and extracted again. The organic layer was washed with saturated saline solution and dried over magnesium sulfate. The solution was distilled under a reduced pressure to expel the solvent and obtain 2.80 g of 2-(2,6-dichloro-3-methoxycarbonyl benzoyl) acetoacetic tert-butyl ester. A solution of this ester in 45 ml of toluene and 0.2 g of p-toluene sulfonic acid hydrate added thereto were refluxed together for six hours. The reaction solution was cooled, mixed with 200 ml of ethyl acetate, washed twice with 200 ml of water, further washed with saturated saline solution, and dried over magnesium sulfate. The solution was distilled under a reduced pressure to expel the solvent and obtain 2.10 g of 2,6-dichloro-3-methoxycarbonyl benzoyl acetone. nD22 1.5759.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][NH:21][CH2:22]3)[CH2:18]2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:5][CH:4]=1)#[N:2].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][N:21]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH2:22]3)[CH2:18]2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:26][CH:27]=1)#[N:2]
Reactant: CS(=O)(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CNCC(C1)O2
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CS(=O)(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CN(Cc3ccc(F)cc3)CC(C1)O2
Temperature: 160 °C
Yield: 62.7 %

Procedure:
N-[2-(4-Cyanophenoxy)ethyl]-N-[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]methanesulfonamide (0.079 g, 0.2 mmol; see step (ii) above) and 1-bromomethyl-4-fluorobenzene (0.040 g, 0.21 mmol) and K2CO3 (0.041 g, 0.3 mmol) were was mixed in a microwave vessel and then heated in the microwave reactor for 15 min at 160° C. The mixture was filtered and put on a SCX-II plug. The plug was washed with DCM, acetonitrile, DCM/MeOH (80:20), after which the product was eluted with DCM:MeOH(NH3-satd.), 80:20. The product was purified on a 9 g Horizon prep. chromatography column (A:DCM(1% MeOH), B:DCM/MeOH(NH3-satd.), 80:20. Gradient 0-25% B, 270 mL (9 mL fractions)), which gave 63 mg (62.7%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Cl[CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: Cc1nc(CCl)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(Cn2c3c(c(=O)n2-c2ccc(F)cc2F)[C@H]2CC[C@]3(C)C2(C)C)cs1
Temperature: 100 °C
Yield: 43 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol), tetrabutylammonium iodide (120 mg, 0.32 mmol) and 4-(chloromethyl)-2-methylthiazole (Maybridge plc, Tintagel, Cornwall, UK; 197 mg, 1.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. overnight. Dichloromethane (50 mL) was added and the solution was washed with 1:1 water/brine (2×25 mL) and the combined aqueous washes were back-extracted with dichloromethane (50 mL). The combined organic extracts were washed with saturated aqueous sodium thiosulfate (50 mL), and brine (50 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 50-70% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-(2-methyl-thiazol-4-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (59 mg, 43%) as a light tan solid. APCI(+)-MS (M+H) 416.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[NH:7][CH:6]=1.C=O.[C:17](O)(=O)C>C(O)C>[ClH:1].[CH2:17]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: CC(=O)O
Agent: C=O
Agent: Cl
Solvent: CCO
Product: Oc1ccc2[nH]c3c(c2c1)CCNC3
Temperature: 25 °C

Procedure:
To a solution of 3-(2-amino-ethyl)-1H-indol-5-ol hydrochloride (10.0 g) in 450 mL of absolute ethanol was added 1.6 g of paraformaldehyde and 5.4 mL of glacial acetic acid. The mixture was heated to reflux for 1.5 h then allowed to cool to rt. The white precipitate so formed was collected by filtration and dried under vacuum to yield 5.9 g of 2,3,4,9-tetrahydro-1H-β-carbolin-6-ol hydrochloride.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:25])=[C:7]([C:16]([I:24])=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[C:18]=1[I:19])[C:8]([N:10]([CH2:12][C:13]([OH:15])=[O:14])[CH3:11])=[O:9])(=[O:3])[CH3:2].[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1O)([O-:28])=[O:27].O1CCCC1>CN(C)C=O>[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:14][C:13](=[O:15])[CH2:12][N:10]([C:8](=[O:9])[C:7]1[C:6]([I:25])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:18]([I:19])=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[C:16]=1[I:24])[CH3:11])([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)N(C)CC(=O)O)c1I
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)N(C)CC(=O)Oc2ccccc2[N+](=O)[O-])c1I
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6.85 g (10 mMol) N-(3,5-diacetamido-2,4,6-triiodobenzoyl)-sarcosine and 1.7 g (12.2 mMol) o-nitrophenol are dissolved in 15 ml N,N-dimethylformamide. 60 ml tetrahydrofuran is added to this solution which is then cooled down to 0° C. 2,5 g (12 mMol) N,N-dicyclohexylcarbodiimide is added. The reaction runs for 2 hours at 0° C. and overnight at room temperature. The precipitate (N,N'-dicyclohexylurea) is filtered off, washed with 10 ml N,N-dimethylformamide, the tetrahydrofuran is distilled, the solution kept in the refrigerator overnight and then the dicyclohexylurea is again filtered off. The organic solution is added dropwise to 250 ml ether, the precipitate is decantered, dissolved with 25 ml N,N-dimethylformamide and added to water dropwise. The precipitate is filtered, washed with saturated sodium bicarbonate solution and water and dried. Yield: 5.4 g (67%).
Reaction SMILES: [CH:1]1([CH2:11][C:12](=O)[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[NH2:15][CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[OH:18].[BH4-].[Na+]>CO>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([CH:17]([OH:18])[CH2:16][NH:15][CH:12]([CH3:13])[CH2:11][CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][O:2]2)=[CH:24][CH:23]=1
Reactant: CC(=O)CC1OCCc2ccccc21
Reactant: NCC(O)c1ccc(O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(CC1OCCc2ccccc21)NCC(O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
In 15 ml of anhydrous methanol were dissolved 2.93 g (15.5 mmol) of (isochroman-1-yl)acetone [Chem. Pharm. Bull., 36, 1758 (1988)] and 1.57 g (10.3 mmol) of 2-amino-1-(4-hydroxyphenyl)ethanol [U.S. Pat. No. 2,585,988 (1952)], and the resulting solution was stirred for 3 hours at room temperature. Methanol was evaporated, and anhydrous benzene was added to the mixture, and water formed was removed off by azeotropic distillation. To the resulting mixture was added 15 ml of anhydrous methanol. Subsequently, 567 mg (15 mmol) of sodium borohydride was gradually added under ice cooling, and the resulting mixture was stirred for 3 hours at room temperature. The methanol was evaporated off, and then 10% sulfuric acid aqueous solution was added to the residue, and the mixture was washed with ether. The resulting mixture was rendered basic with the addition of saturated aqueous potassium hydrogencarbonate and then extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated off, and the residue was subjected to silica gel column chromatography (ethyl acetate :triethylamine=20:1) to give 2.8 g (83%) of crystals of Compound 1.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C.C(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: Fc1ccc2c(C3CCN(CCN4CCOCC4)CC3)noc2c1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 2-chloroethyl morpholine hydrochloride (4.46 g, 29.7 mmol) and K2O3 (7.3 g, 2.2 eq) in acetonitrile (60 ml) was heated at reflux for 24 hours. The crude mixture was diluted with DCM and filtered. The solvent was concentrated to an oil (~7.1 g). Purification on a silica gel column (55 g, SiO2, eluted with MeOH:DCM) yielded a solid product weighing 4 g. Recrystallization from hot ethanol yielded 2.1 g (48%), m.p.=131-132° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[I-].[Mg+2].[I-].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:23][CH3:24])=[C:14]([CH:16]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]2=[O:22])[CH:15]=1>ClCCl.CO>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:23][CH3:24])=[C:14]([CH:16]2[C:20](=[O:21])[CH:19]3[CH:18]([CH:5]4[O:1][CH:2]3[CH:3]=[CH:4]4)[C:17]2=[O:22])[CH:15]=1
Reactant: c1ccoc1
Reactant: CCc1ccc(Br)cc1C1C(=O)C=CC1=O
Agent: [I-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc(Br)cc1C1C(=O)C2C3C=CC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Furan (4.0 ml, 55.0 mmol) and magnesium iodide (1.00 g, 3.6 mmol) are added to a solution of 2-(5-bromo-2-ethylphenyl)cyclopent-4-ene-1,3-dione (5.0 g, 17.9 mmol) in dichloromethane (20 ml) and the mixture is stirred at room temperature for 3 days. A further quantity of furan (1.3 ml, 17.8 mmol) is added and stirring continued for 18 hours, and then a further quantity of furan (1.3 ml, 17.8 mmol) is added and the mixture is stirred for 48 hours, and then allowed to stand at room temperature for 5 days. The reaction mixture is dissolved in methanol and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(5-bromo-2-ethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-8-en-3,5-dione.
Reaction SMILES: CO[C:3](=[O:29])[C:4]1[C:5](=[CH:10][C:11]([N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:6]([O:8]C)=O.[NH3:30]>C(O)CO>[CH3:28][N:21]([C:11]1[CH:10]=[C:5]2[C:6](=[O:8])[NH:30][C:3](=[O:29])[C:4]2=[CH:13][C:12]=1[NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cc(Nc2ccccc2)c(N(C)c2ccccc2)cc1C(=O)OC
Reactant: N
Solvent: OCCO
Product: CN(c1ccccc1)c1cc2c(cc1Nc1ccccc1)C(=O)NC2=O

Procedure:
Analogously to Example 1, 160 mg (0.41 mmol) of 4-(N-methyl-N-phenylamino)-5-anilinophthalic acid dimethyl ester in 12 ml of ethylene glycol are heated at 120° and, with stirring, ammonia gas is passed through the mixture for 18 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodiumchloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel withhexane/ethyl acetate 1:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of slightly yellow crystals, FAB-MS: 344 [M+ +H], 1H-NMR (CDCl3): 3.28 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(#N)C.C(OCC)(=O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:3]([CH3:11])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)cc1C
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A suspension of 1-(4-hydroxy-3-methylphenyl)ethanone (20.1 g) in acetonitrile (200 ml) was added to a suspension of cesium carbonate (86.6 g) in acetonitrile (400 ml) and the mixture stirred under nitrogen at room temperature for 2 minutes. ethyl 2-bromo-2-methylpropanoate (33 g) was added and the mixture stirred for 25 hours, further ethyl 2-bromo-2-methylpropanoate (33 g) was added and the mixture stirred for a further 16 hours. The mixture was filtered and the filtrate concentrated to give an orange oil, the oil was dissolved in ethyl acetate and the solution washed thrice with 1M sodium hydroxide and brine. The organic layer was separated, dried over sodium sulfate, filtered and the filtrate concentrated; the resulting oil was purified by Biotage® chromatography eluting with cyclohexane:ethyl acetate (9:1) to give the title compound as a clear oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)#[N:13]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
A suspension of 4-chloro-6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (100 mg, 0.26 mmol), (prepared as described for the starting material in Example 1), 5-hydroxyindole (42 mg, 0.32 mmol) and cesium carbonate (129 mg, 0.39 mmol) in DMF (1 ml) was stirred for 10 minutes at ambient temperature followed by 1.5 hours at 70° C. After cooling, water (5 ml) was added. The precipitate was filtered, washed with water and dried under vacuum. The solid was purified by column chromatography, eluting with methanol/methylene chloride/ethyl acetate (5/45/50) to give 6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-yloxy)quinoline (28 mg, 22%).