Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].N12CCCN=C1CCCCC2.[C:21](O)(=O)C=C.[N+:26](C)([O-:28])=[O:27]>>[N+:26]([CH:2]([CH2:3][CH3:21])[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])([O-:28])=[O:27]
Reactant: C[N+](=O)[O-]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: C=CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(C(=O)OC(C)(C)C)[N+](=O)[O-]

Procedure:
537 ml (3.7 mol) of tert-butyl acrylate were added dropwise, at a bath temperature of 70° C., to an initially introduced solution of 2.0 l of nitromethane and 7 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), with the pH, which could possibly have declined due to traces of acrylic acid, being maintained constant by the addition of appropriate quantities of DBU. After the exothermic reaction had subsided (rise of temperature to 90° C.), the mixture was allowed to cool for 60 min and then washed several times with dilute aqueous hydrochloric acid and water, dried and concentrated under reduced pressure, with 660 g of a reddish-brown oil remaining which was further purified by distillation (bp5 : 90° C.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([CH3:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[S:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:42][CH2:41][C:39]1[N:40]=[C:36]([C:32]2[CH:31]=[C:30]([C:29]3[CH2:28][C:27](=[O:50])[NH:20][C:9]4[CH:10]=[C:11]([CH3:19])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[S:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-methyl-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.21 g) (Example J24) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (Example K27) (0.31 g) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.09 g).
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]2[N:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:9]([C:12]3[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[CH3:26][C:27]1[NH:28][CH:29]=[CH:30][N:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(=O)OCC>CS(C)=O>[NH:1]1[C:5]([CH2:6][C:7]2[N:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:9]([C:12]3[CH:17]=[CH:16][C:15]([N:28]4[CH:29]=[CH:30][N:31]=[C:27]4[CH3:26])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1
Reactant: Cc1ncc[nH]1
Reactant: Oc1ccc(-n2c(Cc3nnn[nH]3)ccc2-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nccn1-c1ccc(-c2ccc(Cc3nnn[nH]3)n2-c2ccc(O)cc2)cc1
Yield: 14.3 %

Procedure:
To a mixture of 4-(2-((1H-tetrazol-5-yl)methyl)-5-(4-bromophenyl)-1H-pyrrol-1-yl)phenol (1.0 g, 2.52 mmol) and 2-methyl-1H-imidazole (2.07 g, 25.2 mmol) in DMSO (10.0 mL) was added 8-HQ (54 mg, 0.38 mmol), Cu2O (0.29 g, 2.52 mmol), Cs2CO3 (0.986 g, 3.03 mmol) and PEG-2000 (0.29 g). The resultant mixture was heated at 150° C. for 3 h under microwave irradiation. The mixture was treated with EA (60 mL), the resultant precipitate was filtered and purified by Biotage-flash (Solid phase: C18; Mobile phase: A: CH3CN, B: H2O (0.05% CF3COOH); gradient: 12%→24% B in A; flow rate: 40 mL/min) to afford an off white solid (143 mg, yield 14%)
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.Cl[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>CC(O)C>[N:31]1[CH:32]=[CH:33][C:28]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]3)[CH2:10][CH2:9]2)=[CH:29][CH:30]=1
Reactant: Clc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccncc3)CC2)C1
Temperature: 90 °C

Procedure:
tert-Butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (10.403 mmol, 1 eq) and N-ethyl-diisopropylamine (41.608 mmol, 4 eq) were dissolved in 2-propanol (20 ml). 4-Chloropyridine (31.206 mmol, 3 eq) was added and the mixture was heated at 90° C. for 16 h. Saturated sodium bicarbonate solution (50 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (4×50 ml) and the combined org. phases were washed with saturated sodium chloride solution (50 ml), dried over magnesium sulfate and concentrated. After purification by column chromatography (silica gel, ethyl acetate/methylene chloride/methanol/ammonia (25% aq) (100:100:25:1), the desired product was obtained as a yellow oil. Yield: 1.8 g (55%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10](=[O:13])[CH2:11]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([SH:24])[C:19]1[O:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>O1CCCC1.[OH-].[Na+]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10](=[O:13])[CH2:11][S:24][CH2:18][C:19]1[O:23][CH:22]=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)CCl
Reactant: SCc1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)CSCc1ccco1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
6.54 g of (S)-3-tert-butoxycarbonylamino-l-chloro-2-heptanone and 3.11 g of furfuryl mercaptan were dissolved in 200 ml of tetrahydrofuran, to which 13 ml solution of 2N sodium hydroxide was added. The reaction solution was stirred at a room temperature for 17 hours and a sodium hydrogencarbonate solution was then added thereto. The solution was extracted with ethyl acetate. The extracted solution was washed with a saturated sodium chloride solution and dried over magnesium sulfate, which was then filtered, concentrated and purified by the silica gel column chromatography (eluent: 10% ethyl acetate containing hexane). The object of 7.82 g was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[C:11]1([NH:17][N:18]=[C:19]([C:21]2[O:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[CH3:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=C(C=[N+](C)C)[CH:31]=N1>O>[N+:26]([C:23]1[O:22][C:21]([C:19]2[C:20]([CH:8]=[O:9])=[CH:31][N:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:18]=2)=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: C[N+](C)=Cc1cn[nH]c1
Reactant: CC(=NNc1ccccc1)c1ccc([N+](=O)[O-])o1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
At 10° to 20° C add 77 g of phosphorus oxychloride dropwise to 183 g of dimethylformamide. Stir for 30 minutes at room temperature and, at a temperature not exceeding 40° C, add thereto 55.7 g of 5-nitro-2-acetylfuran-phenylhydrazone. Stir under nitrogen for 1 hour at this temperature and then for 2.5 hours at 50° C. Pour the resulting solution (containing 4-pyrazolylmethylenedimethylammonium salt) onto 2.5 kg of ice and water. Heat for 2 hours at 40° C before vacuum filtering at 20° to 30° C. Wash the residue well with water to obtain a 98% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde [m.p. 208° to 209° C (from dimethylformamide/water)].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)([O-:18])=[O:17].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(O)CCC>[C:11]([C:7]1[CH:8]=[C:9]([CH:23]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:22]2[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C1CCNCC1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Solvent: CCCCO
Product: CC(C)(C)c1cc(C(c2ccc([N+](=O)[O-])cc2)N2CCCCC2)cc(C(C)(C)C)c1O
Yield: 23.6 %

Procedure:
A mixture of 2.1 g (0.01 mol) of 2,6-di-tert-butylphenol, 1.51 g (0.01 mol) of 4-nitrobenzaldehyde and 0.9 g (0.0105 mol) of piperidine is refluxed under nitrogen in 15 ml n-butanol for 24 hours. The solution is then evaporated in vacuo. The residue is then chromatographed on silica gel with hexane:ethyl acetate (4:1 ). The pure fractions are recrystallized from acetonitrile to give 1.0 g of the title compound as pale yellow crystals, melting at 147° -148° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]([CH:12]=[CH2:13])[CH2:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[NH:22])[NH2:21])[CH:15]=3)[C:8]2=[O:23])[CH2:3][CH2:2]1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>O1CCCC1>[C:24]1([S:30]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]([CH:12]=[CH2:13])[CH2:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[NH:21])[NH2:22])[CH:15]=4)[C:8]3=[O:23])[CH2:3][CH2:2]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C=CC1CN(c2cccc(C(=N)N)c2)C(=O)N1C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC1CN(c2cccc(C(=N)N)c2)C(=O)N1C1CCN(S(=O)(=O)c2ccccc2)CC1

Procedure:
In this case the title compound was prepared by sulfonylation of 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone with phenylsulfonyl chloride in tetrahydrofuran with triethylamine followed by amidine formation as described above; HRMS (M+H)+ calc. 454.191287, found 454.191418.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)=[N+]=[N-])[CH:2]=[CH2:3]>CCCCCCC.C(OCC)(=O)C>[Br:15][C:11]1[CH:10]=[C:9]([C:6]23[CH2:3][CH:2]2[CH2:1][O:4][C:5]3=[O:16])[CH:14]=[CH:13][CH:12]=1
Reactant: C=CCOC(=O)C(=[N+]=[N-])c1cccc(Br)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C1OCC2CC12c1cccc(Br)c1

Procedure:
The compound was prepared in an analogous manner as described for intermediate B5A from (3-bromo-phenyl)-diazo-acetic acid allyl ester (intermediate B4B) (8.71 g, 31 mmol). The compound was obtained after silica gel column chromatography with n-heptane/ethyl acetate as light green oil (6.585 g, 84%). MS (ISP): m/z=270.1 [(M+NH4)+] and 272.1 [(M+2+NH4)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH2:11]=O.O.ClCCl.[CH3:17][NH:18][CH3:19]>>[OH:10][C:4]1[C:3]([CH2:17][N:18]([CH3:11])[CH3:19])=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=1
Reactant: CNC
Reactant: Oc1cc(F)c(F)c(F)c1
Reactant: C=O
Solvent: O
Solvent: ClCCl
Product: CN(C)Cc1c(O)cc(F)c(F)c1F
Temperature: 0 °C
Reaction time: 20 h

Procedure:
400 g of 3,4,5-trifluorophenol are initially charged in 359 ml of 40% aqueous dimethylamine solution and cooled to 0° C. At 0-5° C., 243 ml of 37% aqueous formaldehyde solution are added dropwise within 90 min. Subsequently, the mixture is stirred at room temperature for 20 hours. The mixture is admixed with 600 ml of water and 500 ml of dichloromethane. The organic phase is removed, the aqueous phase is extracted once with dichloromethane, the combined organic phases are dried and the solvent is distilled off under reduced pressure. The crude product is taken up in 500 ml of water and adjusted to pH 1-2 with cooling in an ice bath using dilute hydrochloric acid. The acidic solution is extracted once with dichloromethane and subsequently adjusted to pH 8-9 with cooling in an ice bath using dilute sodium hydroxide solution. The alkaline reaction solution is extracted three times with dichloromethane, the combined organic phases are washed once with water and dried, and the solvent is removed under reduced pressure. The crude product is subsequently fractionally distilled under reduced pressure. 305 g (55% of theory) of a light yellow liquid having a boiling point of 96° C. at 10 mbar are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].C(Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: BrCc1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.9 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (451 mg, 1.34 mmol, Intermediate 1) in DCM (12 ml) was treated with TEA (0.42 ml, 3 mmol) and benzyl bromide (0.54 ml, 4.5 mmol), and stirred at RT for 5 h. The mixture was washed with water, the pH value was adjusted to 5 with a 0.5 M HCl, then dried and concentrated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 95:5) to give (E)-3-{1′-benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (440 mg) as a light yellow solid.
Reaction SMILES: [NH2:1][C@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][CH2:3]1.N[C@@H](C(O)=O)CS.[C:21]([O:25][C:26]([NH:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](O)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([NH:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31]([NH:1][C@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][CH2:3]1)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: N[C@@H]1CSc2ccccc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Agent: N[C@H](CS)C(=O)O
Product: CC(C)(CC(=O)N[C@@H]1CSc2ccccc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3(S)-amino-3,4-dihydro-1,5-benzothiazepin-4(5H)-one (prepared from D-cysteine (S-cysteine) by the method of Slade, et al, J. Med. Chem., 28, 1517-1521 (1985)) and 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.38 (s,6H), 1.45 (s,9H), 2.32 (d,10 Hz, 1H), 2.50 (d,14 Hz, 1H), 2.70 (d,14 Hz, 1H), 2.92 (T,11 Hz, 1H), 3.93 (dd;7,11 Hz; 1H), 4.76 (m,1H), 7.02 (d,8 Hz, 1H), 7.1-7.3 (m,2H), 7.40 (t,8 Hz, 1H), 7.66 (d,7 Hz, 1H), 8.23 (br s,1H). FAB-MS: calculated for C19H27N3O4S 393; found 394 (M+H,36%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5](OCC)=[O:6].[CH2:12]([O:14][CH:15]([O:20][CH2:21][CH3:22])[CH2:16][CH2:17][C:18]#[N:19])[CH3:13]>O1CCCC1>[CH2:21]([O:20][CH:15]([O:14][CH2:12][CH3:13])[CH2:16][CH:17]([C:5](=[O:6])[C:4]([F:11])([F:10])[F:3])[C:18]#[N:19])[CH3:22]
Reactant: CCOC(CCC#N)OCC
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(CC(C#N)C(=O)C(F)(F)F)OCC

Procedure:
Preparation of (trifluoromethyl)pyrrole carbonitriles and conversion thereof to dihalo (trifluoromethyl)pyrrole carbonitriles and dihalo- alkylated N-(trifluoromethyl)pyrrole carbonitriles can be achieved by the admixture of a dispersion of sodium hydride in tetrahydrofuran with a solution of ethyl trifluoroacetate and 3-cyano propionaldehyde diethyl acetal in tetrahydrofuran. The reaction that occurs yields 3-trifluoroacetyl-3-cyanopropionaldehyde diethyl acetal which is then heated with oxalic acid dihydrate in water to give the 3-trifluoroacetyl-3-cyanopropionaldehyde. The thus prepared aldehyde is then dissolved in glacial acetic acid and the resulting solution treated with ammonium acetate to provide the 2-(trifluoromethyl)pyrrole-3-carbonitrile. Halogenation of the above-said (trifluoromethyl)pyrrole carbonitrile may then be accomplished by reaction of said (trifluoromethyl)pyrrole carbonitrile with N-bromosuccinimide or N-chlorosuccinimide in the presence of tetrahydrofuran to yield the dihalo (trifluoromethyl)pyrrole carbonitrile. Alkylation or acylation of this dihalo (trifluoromethyl)pyrrole carbonitrile with an alkyl halide or acylhalide in the presence of potassium t-butoxide and tetrahydrofuran yields the N-alkylated (or N-acylated) dihalo (trifluoromethyl)pyrrole carbonitrile.
Reaction SMILES: C(O[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>C(Cl)Cl.O>[N:13]1([C:6]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)CCN2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccccc21
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of di-tert-butylcarbonate (427.1 g, 1.96 mol) in CH2Cl2 (500 mL) was added dropwise at room temperature to a solution of indoline (212 g 1.78 mol) in CH2Cl2 (1000 mL). A solution of NaOH (85.3 g, 2.13 mol) in water (500 mL) was then added dropwise and the mixture was stirred overnight. The layers were separated and the organic layer was washed with 5% NaOH, brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure and the crude product was crystallized with petroleum ether, giving 324 g (68%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11](=[O:18])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[O:19]=[C:20]1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O.[CH2:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][NH:38]1.O>CN(C)C=O.C(O)C>[O:18]=[C:11]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=2[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:20]([N:38]3[CH2:39][C:40]4[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:37]3)=[O:19])=[CH:7][CH:6]=2)=[N:9][NH:10]1
Reactant: c1ccc2c(c1)CNC2
Reactant: Nc1ccc(-c2n[nH]c(=O)c3c2CCCC3)cc1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(Nc1ccc(-c2n[nH]c(=O)c3c2CCCC3)cc1)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 200 mg 4-(4-aminophenyl)-5,6,7,8-tetrahydro-2H-phthalazin-1-one (0.829 mmol) in 5 ml N,N-dimethylformamide were added 245 mg carbonic acid bis-(2,5-dioxo-pyrrolidin-1-yl) ester (0.912 mmol) and the reaction mixture was stirred overnight. 255 mg of isoindoline were added, the precipitation formed was dissolved by adding 0.8 ml N,N-dimethylformamide, and the reaction mixture was stirred overnight. Water was added, and the formed precipitation was washed with water/methanol and subsequently dried in vacuum to obtain the crude material. The crude material was refluxed in 20 ml ethanol for 2 hours, cooled to room temperature, filtered and dried to obtain the desired product. ESI-MS [M+H+]=387.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:10]1([O:16][C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br-].[CH2:21]([Zn+])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>C1COCC1>[CH2:21]([CH:9]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([C:17]([O:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:18])[CH:3]=[C:2]1[Br:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=Cc1cncc(Br)c1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=CC1=CN(C(=O)Oc2ccccc2)C=C(Br)C1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-bromonicotinaldehyde (7-1) (930 mg, 5 mmol, 1 eq) in anhydrous THF (10 ml) was cooled to 0° C. and treated with phenylchloroformate (783 mg, 5 mmol, 1eq). The reaction mixture was then stirred at this temperature for 1 h before the addition of benzylzinc bromide (0.5M in THF, 10 ml, 5 mmol, 1eq). The resulting solution was stirred at 0° C. for another 30 min, was then allowed to warm to room temperature and poured into saturated aqueous solution of ammonium chloride. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate, the combined organic extracts were dried and concentrated to give the title dyhydropyridine 7-2, which was used in the next step without further purification. LRMS m/z: found 398.0, 400.0, calcd. (M+H) 398.0, 400.0
Reaction SMILES: [CH3:1][C:2]([C:6]1[C:7](=O)[C:8]2[C:13]([C:14](=[O:17])[C:15]=1O)=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:5])[CH:3]=[CH2:4].Cl.[CH3:20][O:21][NH2:22].CC[O:25]CC>N1C=CC=CC=1>[CH3:1][C:2]([C:6]1([OH:25])[CH2:15][C:14](=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[N:22][O:21][CH3:20])([CH3:5])[CH:3]=[CH2:4]
Reactant: CCOCC
Reactant: CON
Reactant: C=CC(C)(C)C1=C(O)C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: c1ccncc1
Product: C=CC(C)(C)C1(O)CC(=O)c2ccccc2C1=NOC

Procedure:
A solution of the product of Example 1 (b) (250 mg, 1.03 mmol) and methoxyamine hydrochloride (95 mg, 1.14 mmol) in pyridine (5 ml) was stirred for 48 hours. The reaction mixture was dissolved in ether (50 ml) and washed with water (2×10 ml) , 2M hydrochloric acid (2×10 ml), water (2×10 ml), saturated sodium chloride solution (10 ml) and dried over magnesium sulphate. Filtration and evaporation of the solvent under reduced pressure and silica gel chromatography yielded the title compound (56 mg).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[NH:10])[NH2:9].[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[N:10]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(-c2ccccn2)ns1
Temperature: 25 °C
Yield: 41.8 %

Procedure:
To a solution of pyridine-2-carboximidamide hydrochloride (2.00 g, 12.7 mmol) and perchloromethyl mercaptan (1.75 ml, 16.3 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (3.26 g, 81.5 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 1.05 g (42.0%) of the desired product as an oil.
Reaction SMILES: [S:1]1[CH:13]2[CH:4]([NH:5][C:6](=O)[C:7]3[CH2:8][NH:9][CH2:10][CH2:11][C:12]=32)[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:6]1[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4]=2[N:5]=1
Reactant: O=C1NC2C=CSC2C2=C1CNCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccsc2c2c1CNCC2
Temperature: 82.5 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
A mixture of 3a,6,7,8,9,9b-hexahydrothieno[3,2-c]-2,7-naphthyridin-5(4H)-one (2.69 g, 13.04 mmol) in phosphorus oxychloride (70 ml) was heated at 80-85° C. with stirring for 24 hours and allowed to cool to room temperature. The excess solvent was removed in vacuo and the residue was carefully quenched with ice water. The aqueous mixture was treated with solid NaOH until product precipitation ceased (pH ˜5) and the off-white, amorphous solid was collected, washed with water, and dried to give the title compound (2.51 g, 86%).