Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].C[C:23]([N:25](C)C)=O>O>[C:23]([C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8])#[N:25]
Reactant: CC(=O)N(C)C
Reactant: Nc1c(I)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Solvent: O
Product: N#Cc1cc(-c2ccccc2C(F)(F)F)cc([N+](=O)[O-])c1N
Temperature: 140 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
The title compound was prepared by an adaptation of the method described by Youngblood, W. J. (J. Org. Chem. 2006, 71, 3345-3356). 3-Iodo-5-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (230 mg, 0.564 mmol, as prepared in the previous step) and Cu(I)CN (1.5 eq., 7.57 mg, 0.845 mmol) were placed in an 8 mL vial equipped with a magnetic stir bar. Dry DMA (2.5 mL) was added via syringe, and the vial was tightly capped and placed in a heating block. The reaction was stirred at 140° C. for 14 h, cooled to RT, and poured into water. The precipitate was isolated by filtration and washed with water (10 mL). The precipitate was dissolved in EtOAc (25 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by preparative TLC on a 2000 μm SiO2 plate developed with EtOAc/hexanes, 1:9 v/v, yielding 86 mg (50%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.37 (d, J=1.8 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.62 (t, J=7.3 Hz, 1H), 7.55 (t, J=7.7 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 6.84 (br. s., 2H).
Reaction SMILES: C([S:5][C:6]1[C:11]([CH2:12][NH:13][C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][C:9]([CH2:23][CH3:24])=[C:8]([CH3:25])[N:7]=1)(C)(C)C.Cl.N1C=CC=CC=1>O>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[NH:13][CH2:12][C:11]1[C:6](=[S:5])[NH:7][C:8]([CH3:25])=[C:9]([CH2:23][CH3:24])[CH:10]=1
Reactant: CCc1cc(CNc2nc3ccccc3o2)c(SC(C)(C)C)nc1C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCc1cc(CNc2nc3ccccc3o2)c(=S)[nH]c1C
Temperature: 150 °C

Procedure:
A mixture of 2-t-butylthio-3-{[(benzoxazol-2-yl)amino]methyl}-5-ethyl-6-methylpyridine (78 mg, 0.22 mmol) and pyridine hydrochloride (325 mg, 2.81 mmol) was warmed in a pre-heated oil bath at 150° C. for 25 minutes. The mixture was cooled, diluted with water and the yellow precipitated product was collected by filtration. This residue was dissolved in methylene chloride, filtered through a pad of charcoal and then hexane was added and the methylene chloride boiled off as the product crystallized out to yield 42 mg (64%), m.p. 238°-240° C. Anal Calcd. for C16H17N3OS: C, 64.18; H, 5.72; N, 14.04. Found: C, 63.86; H, 5.69; N, 13.81.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][CH3:16])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Br[CH:28]([CH2:33][CH2:34][CH2:35][Cl:36])[C:29]([O:31][CH3:32])=[O:30].O>CN(C=O)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([N:2]([CH3:1])[CH:28]([CH2:33][CH2:34][CH2:35][Cl:36])[C:29]([O:31][CH3:32])=[O:30])(=[O:5])=[O:4])=[CH:7][CH:8]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC)cc1
Reactant: COC(=O)C(Br)CCCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCCl)C(=O)OC)cc1
Reaction time: 0.25 h

Procedure:
A solution of 7.17 g (30 mmol) N-methyl-[4-(2-butynyloxy)-phenyl]sulfonamide] in 25 ml of DMF was cooled to 0° C. and 30 ml of 1M sodium hexamethyldisilazide (30 mmol) was slowly added and this mixture was stirred for 15 min and then added to a solution of 6.89 g (30 mmol) of methyl 2-bromo-5-chloropentanoate in 25 ml of DMF and was stirred at room temperature for 18 hours. The mixture was combined with water and the precipitate was collected and purified by chromatography on silica gel using hexane-ethyl acetate, 4:1 to give methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)-amino]-5-chloropentanoate Electrospray Mass Spec 410.2 (M+Na)+.
Reaction SMILES: CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:25]1([S:28]([C:31]2[CH:36]=[CH:35][C:34](/[C:37](=[CH:41]\[CH:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)/[C:38](O)=[O:39])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:27][CH2:26]1.[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=1>C(Cl)Cl>[CH:25]1([S:28]([C:31]2[CH:32]=[CH:33][C:34](/[C:37](=[CH:41]\[CH:42]3[CH2:43][CH2:44][O:45][CH2:46][CH2:47]3)/[C:38]([NH:48][C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=3)=[O:39])=[CH:35][CH:36]=2)(=[O:29])=[O:30])[CH2:27][CH2:26]1
Reactant: Nc1ccc(F)cn1
Reactant: O=C(O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cn1)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 0.5 h

Procedure:
TFFH (283 mg, 1.07 mmol) and DIPEA (373 μmol, 2.14 mmol) were added to a stirred solution of (E)-2-(4-cyclopropanesulfonylphenyl)-3-(tetrahydropyran-4-yl)acrylic acid (Preparation 23, 300 mg, 0.89 mmol) in anhydrous CH2Cl2 (18 mL). After 30 min, the solution was treated portionwise with 2-amino-5-fluoropyridine (200 mg, 1.78 mmol) over 30 min, before being stirred further for 16 h. Solvent evaporation and purification by RP-HPLC furnished the title compound: RTA=3.34 min; m/z (ES+)=431.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([F:22])([F:21])[C:6]([F:20])([F:19])[C:7]([F:18])([F:17])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH3:2].[CH3:23][CH:24]([CH2:38][CH3:39])[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=1>>[CH3:23][CH:24]([CH2:38][CH3:39])[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([O:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:7]([F:17])([F:18])[C:6]([F:19])([F:20])[C:5]([F:21])([F:22])[CH2:4][O:3][CH2:1][CH3:2])=[CH:11][CH:12]=2)=[O:34])=[CH:31][N:30]=1
Reactant: CCC(C)CCCOc1ccc(C(=O)O)cn1
Reactant: CCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc(O)cc1
Product: CCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc(OC(=O)c2ccc(OCCCC(C)CC)nc2)cc1

Procedure:
4-(5-Ethoxy-2,2,3,3,4,4-hexafluoropentoxy)phenyl 6-(4-methylhexyloxy)nicotinate (Compound 6, Table 1) was prepared by esterification of 4-(5-ethoxy-2,2,3,3,4,4-hexafluoropentoxy)phenol (prepared essentially as in Example 4) with 6-(4-methylhexyloxy)nicotinic acid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([C:26]3[CH:38]=[CH:37][C:29]4[O:30]C(C)(C)[O:32][C:33](=[O:34])[C:28]=4[CH:27]=3)[C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CCO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:26]3[CH:38]=[CH:37][C:29]([OH:30])=[C:28]([CH:27]=3)[C:33]([OH:34])=[O:32])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(O)c(C(=O)O)c1

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-butylphenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)hexanamide and NaOH 5N aq in the presence of EtOH as a white foam (87%). 1R NMR (CDCl3, 300 MHz) δ 10.72 (s, 1H), 7.56 (d, J=2.5 Hz, 1H), 7.43 (m, 4H), 7.17 (m, 4H), 7.04 (dd, J=8.8, 2.5 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 4.88 (s, 2H), 2.62 (t, J=7.7 Hz, 2H), 2.10 (t, J=7.6 Hz, 2H), 1.61 (m, 4H), 1.36 (m, 2H), 1.22 (m, 4H), 0.93 (t, J=7.3 Hz, 3H), 0.84 (t, J=6.7 Hz, 3H). M− (ESI): 496.4; M+ (ESI): 498.4. HPLC, Rt: 5.84 min (Purity: 100%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=[O:9])[CH2:2][CH3:3].[BH4-].[Na+]>CCO>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:8][OH:9])[CH2:2][CH3:3]
Reactant: CCCOc1cc(C=O)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCOc1cc(CO)ccc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
Crude 3-(propyloxy)-4-methoxybenzaldehyde (2.60 g) was dissolved in EtOH (30 mL) and cooled to 0° C. NaBH4 (0.499 g, 13.2 mmol) was added portionwise. After the addition was completed, the ice-water bath was removed and the reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added and the resulting mixture was extracted with diethyl ether (3×100 mL). The combined organic layers were dried over anhydrous MgSO4. Removal of the solvent gave a pale yellow oil which was purified by silica gel column chromatography (hexanes/EtOAc, 4:1) to give 3-(propyloxy)-4-methoxybenzyl alcohol (2.29 g, 89% over two steps) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][C:25]([OH:27])=[O:26])[C:5]2[O:10][C@@H:9]([CH2:11][O:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:8][O:7][C:6]=2[CH:23]=1.[N+:28]([O-])([OH:30])=[O:29]>ClC(Cl)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([N+:28]([O-:30])=[O:29])=[C:4]([CH2:24][C:25]([OH:27])=[O:26])[C:5]2[O:10][C@@H:9]([CH2:11][O:12][S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH2:8][O:7][C:6]=2[CH:23]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(Cl)cc(CC(=O)O)c3O2)cc1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(Cl)c([N+](=O)[O-])c(CC(=O)O)c3O2)cc1
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To 3.0 g (7.3 mmole) of (R)-(7-chloro-3-(toluene-4-sulfonyloxymethyl)-2,3-dihydro-benzo(1,4)dioxin-5-yl)-acetic acid in 50 of dichloroethane in an ice/water bath was added a solution of 3.6 ml (85 mmole) of nitric acid (sp. gr. 1.49) in 50 ml of dichloroethane. The mixture was allowed to come to room temperature and stir overnight. Ice was added to quench the reaction and the mixture was diluted to 300 ml with methylene chloride, washed with water and with saturated brine and dried over sodium sulfate. Concentration in vacuum gave 2.8 g of the title compound as an off-white solid. 1H (DMSO-d6) broad singlet, 12.75 δ (1 H); doublet, 7.80 δ (2 H); doublet, 7.45 δ (2 H);.singlet, 7.15 δ (1 H); multiplet, 4.60 δ (1 H); multiplet, 4.37 δ (2 H); multiplet, 4.15 δ (2 H); singlet, 3.45 δ (2H); singlet, 2.40 δ (3 H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].O=O.[CH3:11]O>>[CH3:11][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CO
Agent: O=O
Product: COc1ccc(O)cc1
Reaction time: 4 h

Procedure:
5.0 g of hydroquinone, 40 cm3 of methanol and 1.0 g of sulphonated styrene resin (Amberlyst 15) are fed into the autoclave. The autoclave is pressurised to 5 kg/cm2 with O2 and kept at 105° for 4 hours. 1.04 g of hydroquinone monomethyl ether are obtained (18%).
Reaction SMILES: [C:1]([N:3]=[C:4]([NH2:17])[NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([I:15])[CH:14]=1)[NH:11][C:10]([CH3:16])=[CH:9]2)#[N:2]>COCCOCCOC>[I:15][C:13]1[C:12]2[NH:11][C:10]([CH3:16])=[CH:9][C:8]=2[C:7]2[C:6]([CH:14]=1)=[N:5][C:4]([NH2:17])=[N:3][C:1]=2[NH2:2]
Reactant: Cc1cc2cc(NC(N)=NC#N)cc(I)c2[nH]1
Solvent: COCCOCCOC
Product: Cc1cc2c([nH]1)c(I)cc1nc(N)nc(N)c12
Temperature: 25 °C
Yield: 13.9 %

Procedure:
A solution of N″-cyano-N-(7-iodo-2-methyl-1H-indol-5-yl)guanidine XVIII (0.86 g, 2.54 mmol) in 2-methoxyethyl ether (20 mL) was heated to 175° C. for 28 h. The reaction mixture was cooled to 25° C. and the solid formed was removed by filtration and washed with methanol. The filtrate was concentrated in vacuo and the residue triturated with methanol and ether to give a brown solid which was isolated by filtration and dried to give 6-iodo-8-methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine XIX (120 mg, 14%) as a brown solid: LRMS for C11H10IN5 (M+H)+ at m/z=340.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH:15]=[CH:14][C:13]=1[OH:25])[CH:10]=[CH2:11]>>[CH2:9]([C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH:15]=[CH:14][C:13]=1[O:25][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:10]=[CH2:11]
Reactant: BrCc1ccccc1
Reactant: C=CCc1cc(-c2ccccc2C)ccc1O
Product: C=CCc1cc(-c2ccccc2C)ccc1OCc1ccccc1

Procedure:
Following the procedure of step B but using benzyl bromide, the phenol from step C was converted into the title compound
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH3:12][O:13][NH:14][CH3:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:14]([O:13][CH3:12])[CH3:15])=[O:11]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A mixture of 2-(2-chlorophenyl)acetic acid (1.0 g, 5.9 mmol), O,N-dimethyl-hydroxylamine (0.631 g, 6.3 mmol), EDCI (1.2 g, 6.3 mmol), HOBT (0.874 g, 6.3 mmol), and NMM (2.6 mL, 23.6 mmol) in anhydrous CH2Cl2 (20 mL) was stirred at room temperature for two hours under nitrogen. The reaction mixture was diluted with a mixture of CH2Cl2 and MeOH (v/v=10:1, 100 mL). The organic layer was washed with aqueous HCl (0.5 mol/L, 30 mL×2), saturated NaHCO3 (30 mL×2) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give crude 2-(2-chlorophenyl)-N-methoxy-N-methylacetamide (0.7 g, yield: 56.0%).
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=3[C:17]#[N:18])=[CH:14][C:9]=2[N:8]([CH3:24])[S:7]1(=[O:26])=[O:25].[H-].[Na+].[CH2:30](Cl)[O:31][CH3:32]>CN(C=O)C>[F:27][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:22]=[C:21]([O:23][CH2:30][O:31][CH3:32])[CH:20]=[CH:19][C:16]=3[C:17]#[N:18])=[CH:14][C:9]=2[N:8]([CH3:24])[S:7]1(=[O:26])=[O:25]
Reactant: CN1c2cc(-c3cc(O)ccc3C#N)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(C#N)c(-c2ccc3c(c2)N(C)S(=O)(=O)N3CC2CC2(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-4-hydroxybenzonitrile (12-2) (25 mg, 0.06 mmol, 1 eq) was dissolved in anhydrous DMF (0.5 mL) and sodium hydride (3.1 mg, 0.08 mmol, 1.2 eq, 60% in oil) was added. The resulting mixture was stirred at ambient temperature for 30 minutes and MOM-Cl (0.01 mL, 0.1 mmol, 2 eq) was added. The resulting mixture stirred at ambient temperature for 10 minutes. The crude mixture was purified by reverse phase chromatography (Waters Sunfire MSC18, 10-100% acetonitrile in water with 0.1% TFA modifier) to afford 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-4-(methoxymethoxy)benzonitrile (16-1) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J=8.4 Hz, 1 H); 7.19 (dd, J=1.6, 8.0 Hz, 1 H); 7.11 (s, 1 H); 7.09 (dd, J=2.4, 8.8 Hz, 1 H); 6.95 (s, 1 H); 6.91 (d, J=8.0 Hz, 1 H); 5.26 (s, 2 H); 3.91 (d, J=6.8 Hz, 2 H); 3.50 (s, 3 H); 3.34 (s, 3 H); 2.11-2.19 (m, 1 H); 1.61-1.69 (m, 1 H); 1.36-1.44 (m, 1 H). LRMS m/z (M+H) 436.3 found, 436.1 required.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[S:13]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH2:21])=[O:20])=[CH:14]1>>[C:9]1([C@H:18]2[C@H:18]([C:15]3[CH:16]=[CH:17][S:13][CH:14]=3)[C:19](=[O:20])[NH:21][C:19]2=[O:20])[C:3]2=[C:4]3[C:5](=[CH:6][CH:7]=[CH:2]2)[CH2:16][CH2:15][CH2:14][N:12]3[CH:10]=1
Reactant: NC(=O)Cc1ccsc1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccsc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(thiophen-3-yl)pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with thiophen-3-ylacetamide. Yield 50.3 mg, 15.0%. 1H NMR (DMSO-d6) 400 MHz δ: 11.50 (s, 1H), 7.52 (m, 1H), 7.49 (m, 1H), 7.35 (s, 1H), 7.21 (dd, 1H, J=4.01.2 Hz), 7.16 (d, 1H, 7.6 Hz), 6.89 (d, 1H, J=4.4 Hz), 6.85 (t, 1H, J=6.8 Hz), 4.56 (d, 1H, J=7.2 Hz), 4.41 (d, 1H, J=7.2 Hz), 4.10 (t, 2H, J=6.0 Hz), 2.90 (t, 2H, J=6.0 Hz), 2.10 (m, 2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[S:8][C:7]([SH:9])=[N:6][N:5]=1.[C:10]([O:14][C:15](N=[N+]=[N-])=[O:16])([CH3:13])([CH3:12])[CH3:11]>O.O1CCOCC1.C(N(CC)CC)C>[C:10]([O:14][C:15]([NH:2][CH2:3][C:4]1[S:8][C:7]([SH:9])=[N:6][N:5]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: NCc1nnc(S)s1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1nnc(S)s1
Reaction time: 24 h
Yield: 65.2 %

Procedure:
To a mixture of 5-aminomethyl-1,3,4-thiadiazole-2-thiol hydrochloride (5.5 g) in water (50 ml), dioxane (50 ml) and triethylamine (15 ml) was added t-butoxycarbonyl azide (5.6 g) and the mixture was stirred for 24 hours at 40° to 45° C. After the reaction was over, the dioxane was distilled off under reduced pressure. The residue was adjusted to pH2 with 10% hydrochloric acid and extracted twice with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate and then evaporated to dryness to give 5-t-butoxycarbonylaminomethyl-1,3,4-thiadiazole-2-thiol (4.83 g). m.p. 144° to 146° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([NH:9][NH2:10])=[O:8])[CH2:2][CH2:3][CH3:4].[N+:15]([C:18]1[O:22][C:21]([CH:23]=[CH:24][CH:25]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>ClCCl>[N+:15]([C:18]1[O:22][C:21]([CH:23]=[CH:24][CH:25]=[N:10][NH:9][C:7](=[O:8])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=CC=Cc1ccc([N+](=O)[O-])o1
Reactant: CCCCc1ccccc1C(=O)NN
Solvent: ClCCl
Product: CCCCc1ccccc1C(=O)NN=CC=Cc1ccc([N+](=O)[O-])o1
Temperature: 25 °C

Procedure:
A solution of 1.7 g of the butyl benzhydrazide mentioned under (4) above in 20 ml of dichloromethane is mixed with a solution of 3.5 g of 3-(5-nitro-2-furyl)acrylaldehyde in 20 ml of dichloromethane, and the mixture is stirred at room temperature. The yellow-brown product (precipitated after a reaction time of 3 hours) is sucked off, the filtrate is concentrated, and the resulting solid material is likewise isolated. The two precipitates are recrystallized together from 200 ml of ethanol.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:30])[N:11]3[C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:4][CH2:3][CH2:2]1.[CH:31]1([N:34]2[C:38]([NH2:39])=[C:37](I)[CH:36]=[N:35]2)[CH2:33][CH2:32]1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O>[NH2:39][C:38]1[N:34]([CH:31]2[CH2:33][CH2:32]2)[N:35]=[CH:36][C:37]=1[C:15]1[C:6]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:25]([CH:27]1[CH2:29][CH2:28]1)=[O:26])[C@@H:10]([CH3:30])[CH2:9][CH2:8]2
Reactant: Nc1c(I)cnn1C1CC1
Reactant: C[C@H]1CCc2c(ccc(B3OC(C)(C)C(C)(C)O3)c2OC2CCC2)N1C(=O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CCc2c(ccc(-c3cnn(C4CC4)c3N)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A 50-mL round-bottom flask was charged with (S)-(5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.140 g, 0.34 mmol), 1-cyclopropyl-4-iodo-1H-pyrazol-5-amine (0.071 g, 0.29 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (23.2 mg, 0.03 mmol, 0.10 equiv), sodium carbonate (0.061 g, 0.58 mmol), 1,4-dioxane (10 mL) and water (3 mL). The resulting mixture stirred for 18 h at 80° C. and was then cooled to room temperature. The reaction mixture was filtered through a short pad of Celite, and the filtrate was concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1:5, ethyl acetate/petroleum ether) to afford ((2S)-6-(5-amino-1-cyclopropyl-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.025 g (20%) as light yellow oil. MS (ESI, pos. ion) m/z 407 [M+H]+.
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:32])=[C:19]([C@:21]2([CH3:31])[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][CH2:24][C:23](=O)[NH:22]2)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:42]2)=CC=1>O1CCOCC1>[C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:32])=[C:19]([C@:21]2([CH3:31])[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][CH2:24][C:23](=[S:42])[NH:22]2)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)C[C@@](C)(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)NC(=O)CO1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC1(C)C[C@@](C)(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)NC(=S)CO1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5,7,7-trimethyl-[1,4]oxazepan-3-one (intermediate A17A) (1.15 g, 2.7 mmol) in dioxane (80 ml) at 23° C. was added 2,4-bis-(4-methoxy-phenyl)-[1,3,2,4]dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) (681 mg, 1.7 mmol) and the mixture was stirred at 80° C. for 2 h to obtain a crude solution of the (S)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A18A), which was cooled to 23° C. and 1 M HCl (3.4 ml, 3.4 mmol) was added. After 30 min of stirring, the reaction mixture was poured on sat. NaHCO3-solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to give a dark green oil, which was purified by silica gel column chromatography with dichloromethane/ethyl acetate to give the (S)-5-(5-amino-2-fluoro-phenyl)-5,7,7-trimethyl-[1,4]oxazepane-3-thione (575 mg, 76%) as a light brown foam. MS (ISP): m/z=283.1 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][CH:13]=[O:14])=[CH:5][CH:4]=1.C=O.[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[S:9][CH2:10][CH2:11][N:12]([CH:13]=[O:14])[CH2:17][C:5]=2[CH:4]=1
Reactant: COc1ccc(SCCNC=O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CN(C=O)CCS2
Temperature: 72.5 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
A mixture of compound 14 (100 mg), paraformaldehyde (100 mg), p-toluenesulfonic acid (60 mg) in benzene (5 mL) was stirred at 70-75° C. for 2 days. Filtration, washing with sat. NaHCO3 and concentration gave crude product 15 in an estimated yield of ˜70% by TLC and NMR.
Reaction SMILES: [Na].Cl.Cl.[NH2:4][CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15]>C(O)C>[CH2:18]([O:17][C:13](=[O:16])[CH2:14][CH2:15][NH:4][CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)[CH3:19]
Reactant: C=CC(=O)OCC
Reactant: NC1CN2CCC1CC2
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCNC1CN2CCC1CC2
Reaction time: 0.08 h

Procedure:
0.92 g (20 mmol) of sodium were dissolved in 100 ml of ethanol. 4.0 g (20 mmol) of 3-amino-quinuclidine dihydrochloride were added and the mixture was stirred for 5 minutes. 2 g (20 mmol) of ethyl acrylate were added, the mixture was boiled for 20 hours, and evaporated in vacuo. The residue was shaken with little water and methylene chloride. The organic layer was separated and evaporated in vacuo, giving 3.1. g of the desired product.