Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C([O:11][C:12](=O)[CH2:13][C:14](=O)/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C>C(O)(=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]1[C:12]([OH:11])=[CH:13][C:14]([CH:15]=[CH:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:2]1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)CC(=O)/C=C/c1ccccc1
Solvent: CC(=O)O
Product: Oc1cc(C=Cc2ccccc2)nn1-c1ccccn1
Temperature: 60 °C
Yield: 68 %

Procedure:
2-hydrazinopyridine (161 mg, 1.477 mmol) was added to a solution of (E)-ethyl-5-phenyl-3-oxopent-4-enoate (8a, 355 mg, 1.62 mmol) prepared in Example C-1 in acetic acid (3 mL), followed by stirring under reflux at 60° C. for 30 minutes. Then, the reaction solution was concentrated by distillation under reduced pressure, and ethyl acetate (5 mL) and water (5 mL) were added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and separated by column chromatography (n-Hex/EtOAc=10/1 (v/v)) to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([SH:36])[NH:26][C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:19][CH:18]=1.[H-].[Na+]>CN(C)C=O>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]2[N:26]=[C:25]([S:36][C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[NH:24][C:23]=2[C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(Sc3ccc(C(F)(F)F)cc3[N+](=O)[O-])[nH]c2-c2ccc(OC)cc2)cc1
Reaction time: 0.33 h
Yield: 94.1 %

Procedure:
Under agitation and a layer of argon, a solution of 4.52 g of 4-chloro-3-nitrotrifluoromethylbenzene in 25 ml of dimethylformamide is added dropwise to a solution of 6.25 g of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole and 0.6 g of sodium hydride (80% strength in white oil) in 200 ml of dimethylformamide. The solution is further stirred for 20 minutes, concentrated under vacuum, and the residue distributed between water and ethyl acetate. The organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized from hexane/acetone, thus obtaining 9.44 g of 4,5-bis(4-methoxyphenyl)-2-(2-nitro-4-trifluoromethylphenylthio)imidazole in yellow needles, mp 264°-266°.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[Br:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH:15]=O)[CH:10]=1>CO>[Br:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](/[CH:15]=[N:1]/[CH:2]2[CH2:6][CH2:5][NH:4][C:3]2=[O:7])[CH:10]=1
Reactant: NC1CCNC1=O
Reactant: O=Cc1cc(Br)ccn1
Solvent: CO
Product: O=C1NCCC1/N=C/c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.9 %

Procedure:
To a suspension of 3-aminopyrrolidin-2-one (2.83 g, 28.22 mmol) in methanol (100 mL) was added 4-bromopicolinaldehyde (5 g, 26.88 mmol) and 4 A molecular sieves (20 g, 26.88 mmol). The reaction mixture was stirred for 16 hours at room temperature and then filtered through a pad of Celite. The filtrate was concentrated to give 3-[(E)-(4-bromo-2-pyridyl)methyleneamino]pyrrolidin-2-one as a brown gum (3.09 g, 11.53 mmol). This was dissolved in THF (120 mL) and treated with phenyl vinyl sulfone (1.94 g, 11.53 mmol), silver acetate (1.92 g, 0.59 mL, 11.53 mmol) and DBU (1.72 mL, 11.53 mmol). The reaction mixture was stirred for 3 hours at room temperature and then filtered through a pad of Celite and washed with dichloromethane. The filtrate was concentrated at reduced pressure to give a brown foam (9.53 g). This was dissolved in THF (120 mL) at 0° C. and treated with 1.7 M potassium tert-butoxide in THF (51.93 mL, 88.28 mmol) dropwise over 5 minutes. The reaction mixture was stirred at 0° C. for 1.5 hours. The reaction was quenched by the addition of acetic acid (5.04 mL, 88.28 mmol) and then filtered, washed with dichloromethane and the filtrate concentrated at reduced pressure to give a brown gum. The product was purified by silica gel chromatography eluting with 0-10% methanol in ethyl acetate to give 2-(4-bromo-2-pyridyl)-1,7-diazaspiro[4.4]non-1-en-6-one as an orange solid (830 mg);
Reaction SMILES: [F:1][C:2]1([F:43])[CH2:6][C@H:5]([O:7][C:8]2[CH:13]=[C:12]([F:14])[C:11]([S:15]([N:18](CC3C=CC(OC)=CC=3OC)[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:10]([F:36])[CH:9]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:43][C:2]1([F:1])[CH2:6][C@H:5]([O:7][C:8]2[CH:13]=[C:12]([F:14])[C:11]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:16])=[O:17])=[C:10]([F:36])[CH:9]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CC(F)(F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 72.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (98 mg, 0.158 mmol) prepared in Example 135a, triethylsilane (0.30 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield the title compound (54 mg, 73%) as a colorless solid.
Reaction SMILES: [CH:1]1([C:6](=O)[CH:7]([C:13]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.Cl.[NH2:23]O>CCO>[CH:1]1([C:6]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:13]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[O:14][N:23]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: CCOC(=O)C(C(=O)C1CCCC1)C(=O)C1CCCC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(C2CCCC2)noc1C1CCCC1

Procedure:
A solution of ethyl 3-cyclopentyl-2-(cyclopentylcarbonyl)-3-oxopropanoate (2.20 g, 7.84 mmol) in EtOH (6.4 mL) was stirred as water (1.2 mL) followed by hydroxylamine hydrochloride (1.02 g, 14.7 mmol) was added. The solution was then heated to reflux for 3 hours. The solution was concentrated and the residue was partitioned between ether and saturated aqueous NaHCO3 solution. The organic layer was washed with brine, dried with MgSO4, filtered and concentrated to yield ethyl 3,5-dicyclopentyl-4-isoxazolecarboxylate as a yellow oil (1.58 g, crude yield 73%). 1H NMR (400 MHz, DMSO-d6): δ 4.23 (q, J=7 Hz, 2H), 3.78-3.72 (m, 1H), 3.45-3.37 (m, 1H), 2.00-1.92 (m, 4H), 1.83-1.49 (m, 12H), 1.26 (t, J=7 Hz, 3H). ESI-LCMS m/z 278 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[O:3]1.[CH3:17][O:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1.C(OC(C)C)(C)C>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH:24]2[CH2:25][CH2:26][N:27]([C:13](=[O:15])[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[O:1])[O:3][C:4]=4[CH:10]=3)=[O:16])[CH2:28][CH2:29]2)=[CH:30][CH:31]=1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)oc2c1
Reactant: COc1ccc(CC2CCNCC2)cc1
Solvent: CC(C)OC(C)C
Product: COc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)oc4c3)CC2)cc1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-oxalamic acid (Example 43e) and 4-(4-methoxy-benzyl)-piperidine according to the method described in Example 1c. Melting Point: 193-197° C. (diisopropylether)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[CH2:11]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 66.3 %

Procedure:
4′-Hydroxyacetophenone (13.62 g, 100 mmol), benzylbromide (17.1 g, 100 mmol), and cesium carbonate (35.83 g, 100 mmol) were added to tetrahydrofuran at room temperature and stirred overnight. The product was concentrated to dryness and recrystallized from ether and hexane to yield 15 g of 4′-benzyloxyacetophenone which appeared as a white powder. An Rf of 0.42 was observed when resolved by thin layer chromatography using methylene chloride. 1H nmr (δ, ppm, CDCl3), 7.94 (2H, δ, 8.8 Hz, O—Ar—C(O)), 7.42 (5H, m, Ar′CH2O—), 7.01 (2H, δ, 8.8 Hz, O—Ar—C(O)), 5.14 (2H, s, Ar′CH2O—), 2.56 (3H, S, CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[C:5]2[C:18]1[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=1.Cl[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH:12]1[C:11]([N:7]2[C:8]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]([CH:18]3[CH2:19][CH2:20][N:21]([CH2:25][CH2:26][N:27]4[C:28](=[O:32])[NH:29][CH2:30][CH2:31]4)[CH2:22][CH2:23]3)=[CH:6]2)=[CH:16][CH:15]=[C:14]([F:17])[CH:13]=1
Reactant: O=C1NCCN1CCCl
Reactant: Fc1ccc(-n2cc(C3=CCNCC3)c3cc(Cl)ccc32)cc1
Product: O=C1NCCN1CCN1CCC(c2cn(-c3ccc(F)cc3)c3ccc(Cl)cc23)CC1

Procedure:
The intermediate may be worked up in a conventional manner. The further process leading to sertindole comprises cyclization of N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine to the corresponding 3-acetoxy-indole using eg. acetic anhydride in the presence of alkalimetal acetate such as sodium acetate. 5-chloro-1-(4-fluoro)indole is then obtained from the 3-acetoxy-indole by reduction and subsequent elimination of H2O. The resulting 5-chloro-1-(4-fluorophenyl)indole is reacted with 4-piperidone according to the above procedure, the resulting 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole is reduced in order to obtain 5-chloro-1-(4-fluorophenyl)-3-(piperidin-4-yl)indole which in turn is reacted with 1-(2-chloroethyl)-2-imidazolidinon to obtain sertindole. Alternatively, the 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole may first be reacted with 1-(2-chloroethyl)-2-imidazolidinon followed by reduction, thereby obtaining sertindole, which may be isolated as an acid addition salt, e.g. the tartrate, or as the free base.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][CH:11]=3)=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:26][CH2:25]1
Reactant: Cc1nc(/C=C/c2conc2-c2ccc(F)cn2)sc1C(=O)O
Reactant: NC1CC1
Product: Cc1nc(/C=C/c2conc2-c2ccc(F)cn2)sc1C(=O)NC1CC1
Yield: 48 %

Procedure:
As described for example 90 g, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (99 mg, 0.3 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (53 mg, 48%) which was obtained as a yellow solid. MS: m/e=371.1 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10]CC)=O)[N:5]=[N:4][N:3]=1.[CH3:13][NH2:14]>C(O)C>[CH3:13][NH:14][C:8](=[O:10])[CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: CCOC(=O)Cn1nnnc1S
Reactant: CN
Solvent: CCO
Product: CNC(=O)Cn1nnnc1S
Reaction time: 8 h

Procedure:
Ethyl 5-mercapto-1H-tetrazol-1-ylacetate (2.0 g) was dissolved in 33% methylamine in ethanol (20 ml) and stood overnight at R.T. The solution was evaporated to dryness in vacuo, the residue dissolved in water (20 ml), adicified and ether extracted (6×50 ml). The extracts were dried and evaporated to give a crystalline solid which was crystallised from ethyl acetate, 0.59 g (32.0%) m.p. 167°-168°; δ[(CD3)2CO] 2.88 (3H,d, J 5 Hz, --NHCH3), 5.15 (2H,s, --CH2CO--), 6.70 (1H,m, --NH--), 12.9 (1H,bs, --SH). Found: C, 27.53; H, 4.17; N, 40.07; S, 18138. C4H7N5OS requires: C, 27.74; H, 4.07; N, 40.44; S, 18.51%.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCOCC1.O>[CH:1]1([CH2:6][CH2:7][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: NCCCN1CCCC1
Solvent: C1COCCO1
Solvent: O
Product: O=C(CCC1CCCC1)NCCCN1CCCC1
Reaction time: 4 h

Procedure:
3-Cyclopentyl propionylchloride (5 mmol) in 10 ml of dioxane was added dropwise to a solution of 10 mmol of 1-(3-aminopropyl)pyrrolidine in water. After stirring for 4 hours the solvent was evaporated under reduced pressure and the residue purified by column chromatography on silica gel (eluent: methylene chloride/methanol/aqueous ammonia (90/10/1)). The solvent was removed under reduced pressure and the residue was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:21])([C:14]2[S:15][C:16]([CH2:19]O)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.CS([Cl:32])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[S:15][C:16]([CH2:19][Cl:32])=[CH:17][N:18]=2)([F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(CO)s2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(CCl)s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-fluoro-4-(5-hydroxymethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.34 g, 4.24 mmol) and pyridine (426 mg, 1.3 eq.) in CH2Cl2 (30 mL) at 0° C. was added MsCl (631 mg, 1.3 eq.). The mixture was warmed to room temperature and stirred overnight. The reaction mixture was washed with saturated NaHCO3 solution and dried over Na2SO4. Removal of the solvent afforded the desired product, which was used directly in the following reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=S.[NH2:15][C:16]1[CH:17]=[C:18]([CH:37]=[CH:38][C:39]=1[NH:40][CH3:41])[O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:36])[CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH:30]2[CH2:34][OH:35])[CH:21]=1.NC(N)=S>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:40]([CH3:41])[C:39]2[CH:38]=[CH:37][C:18]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:36])[CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][C@H:30]4[CH2:34][OH:35])[CH:21]=3)=[CH:17][C:16]=2[N:15]=1
Reactant: CNc1ccc(Oc2ccnc(NC(=O)CN3CCCC3CO)c2)cc1N
Reactant: Fc1ccc(C(F)(F)F)cc1N=C=S
Agent: NC(N)=S
Solvent: CO
Product: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(Oc3ccnc(NC(=O)CN4CCC[C@H]4CO)c3)ccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Fluoro-5-(trifluoromethyl)phenyl isothiocyanate was added to a solution of N-[4-(3-Amino-4-methylamino-phenoxy)-pyridin-2-yl]-2-(2-hydroxymethyl-pyrrolidin-1-yl)-acetamide in methanol. Reaction was stirred at room temperature for 15 hours. Thiourea formation was confirmed by LC/MS. Ferric chloride was added and the resulting mixture was stirred at room temperature for 4 hours. After cyclization was complete by LC/MS the reaction mixture was concentrated and aqueous sodium carbonate was added until basic pH. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water then brine, and dried over magnesium sulfate and concentrated. The crude product was purified by reverse phase HPLC. MS: MH+=559.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C2C=CC=CC=2)=[C:4]([F:15])[C:3]=1[C:16]([F:19])([F:18])[F:17].[N:20]([O-])=O.[Na+].[ClH:24]>O>[ClH:24].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:20])=[C:4]([F:15])[C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: Fc1c(Nc2ccccc2)ccc(Br)c1C(F)(F)F
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Br)c(C(F)(F)F)c1F
Reaction time: 0.5 h

Procedure:
A sample of 4-bromo-2-fluoro-3-trifluoromethyl-phenyl aniline (4 g, 15.5 mmol) is suspended in concentrated HCl (36 mL) and cooled in an ice/salt bath. The reaction is then treated dropwise with a solution of NaNO2 (1.12 g, 16.3 mmol) in water (36 mL). The reaction is allowed to stir for 30 minutes and then treated with a solution of SnCl2 dihydrate (17.5 g, 77.5 mmol) in concentrated HCl (36 mL). The reaction is then stirred for 1 hour in an ice/water bath followed by an hour at room temperature. The reaction is then filtered and the solid is treated with aqueous 50% NaOH solution (30 mL) and ether (50 mL). The aqueous phase is extracted once more with ether and the combined organics are dried over MgSO4 and filtered. The resulting solution is treated with 5 mL of 4 M HCl in dioxane while stirring and the resulting solid is collected and dried under high vacuum to afford 2.44 g of (4-Bromo-2-fluoro-3-trifluoromethyl-phenyl)-hydrazine hydrochloride; LC/MS calculated for [M+H]+ C7H5BrF4N2: 273.0, found: 272.9.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]Cl)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C1(C)C=CC=CC=1>O>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: ClCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(C(=C2CCN(CCN3CCNCC3)CC2)c2ccccc2)cc1
Yield: 86 %

Procedure:
A mixture of 2.2 g (7 mmole) of 4-(diphenylmethylene)-1-(2-chloroethyl)piperidine [prepared as described in step (b) above], 4.8 g (55.7 mmole) of anhydrous piperazine and 60 ml of toluene was heated under reflux overnight. At the end of this time, water was added to the reaction mixture, the toluene layer was separated, and a 10% w/v aqueous solution of acetic acid was added to the toluene layer to extract the desired compound. The aqueous layer was separated and made alkaline by the addition of a 10% w/v aqueous solution of sodium hydroxide, after which it was extracted with diethyl ether. The diethyl ether was removed by distillation under reduced pressure, to obtain the title compound as crystals, melting at 73°-75° C., in a yield of 86%.
Reaction SMILES: [Cl-].[Cl-].[CH:3]1([Zr+2:8][CH:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH:7]=[CH:6][CH:5]=[CH:4]1.C[Li]>CCCCCC>[CH:9]1([Zr:8][CH:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)[CH:10]=[CH:11][CH:12]=[CH:13]1
Reactant: C1=CC([Zr+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Agent: [Li]C
Solvent: CCCCCC
Product: C1=CC([Zr]C2C=CC=C2)C=C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 300 ml round bottom flask, 7.5 g of commercially available biscyclopentadienylzirconium dichloride was introduced, and the interior of the flask was thoroughly flushed with nitrogen. Then, 120 ml of ethyl ether was added thereto at -20° C. to obtain a slurry. To this slurry, 32 ml of a hexane solution of methyllithium (1.6M) was gradually added at -20° C, and the mixture was stirred at 0° C for 30 minutes. Then, the solvent was evaporated, and the remained solid was sublimed and purified under reduced pressure of 2×10-4 mmHg at a temperature of from 60 to 80° C to obtain biscyclopentadienylzirconium dimetyl. Separately, an aqueous solution containing 3.40 g of silver nitrate and 6.84 g of sodium tetraphenyl borate were mixed to obtain silver tetraphenyl borate.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]#[N:9].C([O-])([O-])=O.[K+].[K+].[CH2:16]([O:18][C:19](=[O:22])[CH2:20][SH:21])[CH3:17]>CCO.C1COCC1>[CH2:16]([O:18][C:19]([C:20]1[S:21][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8]=1[NH2:9])=[O:22])[CH3:17]
Reactant: N#CC1=C(Cl)CCCC1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1sc2c(c1N)CCCC2
Temperature: 90 °C
Yield: 101.4 %

Procedure:
A 250 mL flask was charged with 2-chloro-cyclohex-1-enecarbonitrile (3.0 g, 21 mmol) in a 6:1 mixture of EtOH/THF (42 mL), K2CO3 (2.9 g, 21 mmol), and mercapto-acetic acid ethyl ester (3.5 mL, 32 mmol), after which it was fitted with a reflux condenser under N2 atmosphere and heated to 90° C. for 24 h. The mixture was filtered through a pad of diatomaceous earth, such as Celite®, rinsing thoroughly with MeOH (400 mL). After concentration, the title compound was purified by FCC (60% ethyl acetate (EtOAc)/hexanes) to give an amber-colored oil (4.8 g). MS: 226.1. 1H NMR (400 MHz, CDCl3) δ ppm 5.35 (s, 2H), 2.71-2.64 (m, 2H), 2.36-2.26 (m, 2H), 1.87-1.77 (m, 4H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([OH:3])=[O:2]>CCO>[CH3:13][O:12][C:10]1[CH:11]=[C:4]2[C:5]([CH:6]=[C:4]([C:1]([OH:3])=[O:2])[O:3][C:1]2=[O:2])=[CH:8][CH:9]=1
Reactant: COc1ccc(C=O)c(C(=O)O)c1
Solvent: CCO
Product: COc1ccc2cc(C(=O)O)oc(=O)c2c1

Procedure:
7-Methoxyisocoumarin-3-carboxylic acid, mp. (EtOH) 280°-3°, (Found: C, 60.11; H, 3.93. C11H8O5 requires C, 60.00; H, 3.66) was prepared from 2-carboxy-4-methoxybenzaldehyde by an analogous procedure to that described in Example 1.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][CH2:7][CH2:8][CH2:9]C.[CH3:11][CH2:12][O:13][CH2:14][CH3:15]>>[CH2:6]([C:11]1[CH:15]=[CH:14][O:13][CH:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC
Reactant: CCOCC
Agent: [Li]C(C)(C)C
Product: CCCCc1ccoc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
The iodo-product obtained from Step B above (2.2 g, 8.8 mmol) was dissolved in 60 mL of ether, and stirred in a −78° C. bath. A 1.7 M solution of t-butyllithium in pentane (10.4 mL, 17.7 mmol) was added dropwise. After 20 min, cooling bath was removed. Reaction was continued for 2.5 h, and quenched with H2O (20 mL). The aqueous mixture was stirred overnight and separated. The aqueous layer was extracted with ether (30 mL). The combined organic layers were washed with brine, dried by Na2SO4, and filtered through a Celite pad. Removal of solvent gave 1.10 g (100%) of 3-butylfuran as a reddish-yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[C:21]2[C:8]([S:9](=[O:24])(=[O:23])[NH:10][C:11]3[C:20]2=[CH:19][CH:18]=[C:17]2[C:12]=3[N:13]=[CH:14][CH:15]=[CH:16]2)=[CH:7][CH:6]=1)=O.[NH3:25]>CO>[O:23]=[S:9]1(=[O:24])[C:8]2[C:21](=[CH:22][C:5]([C:3]([NH2:25])=[O:2])=[CH:6][CH:7]=2)[C:20]2[C:11](=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[N:13]3)[NH:10]1
Reactant: N
Reactant: COC(=O)c1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Solvent: CO
Product: NC(=O)c1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Yield: 17 %

Procedure:
A solution of 6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid methyl ester 307 (50 mg, 0.15 mmol) in 7M NH3 in MeOH (5 ml) was heated at 90 C in sealed tube for 36 h. After cooling, the mixture was concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (95:5) as the eluent to give the title compound (8 mg, 17%).