Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9](=[O:19])[N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])[N:6]=[C:5]1[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].C(N(C(C)C)CC)(C)C.[CH3:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C=O)C.O>[CH2:15]([N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[C:9]([C:7]1[N:6]=[C:5]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=2[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[N:4]([CH2:3][CH2:2][N:53]2[CH2:54][CH2:55][N:50]([CH3:49])[CH2:51][CH2:52]2)[CH:8]=1)=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN(CCCC)C(=O)c1cn(CCCl)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(CCCC)C(=O)c1cn(CCN2CCN(C)CC2)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Temperature: 90 °C
Yield: 45 %

Procedure:
To a solution of 3-benzyl 1-methyl 4-(1-(2-chloroethyl)-4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (120 mg, 0.21 mmol) in dry DMF (2 mL) was added diisopropylethyl amine (26.5 mg, 0.21 mmol) and 1-methylpiperazine (21 mg, 0.21 mmol at room temperature. The reaction mixture was heated at 90° C. for 16 h, diluted with water and extracted with MTBE (3×). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude material was purified by flash chromatography (gradient from 0 to 5% MeOH/CH2Cl2) to provide the title compound (60 mg, 45%). MS(ESI+) m/z 619.2 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][C:9]([CH3:15])([CH3:14])[CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][C:9]([CH3:15])([CH3:14])[CH2:10][NH:11]2)=[CH:6][CH:5]=1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CNc2cc(N)ccc2C1
Yield: 91 %

Procedure:
A solution of 7-nitro-1,2,3,4-tetrahydro-3,3-dimethylquinoline (39 mg, 0.187 mmol) in ethyl acetate (2 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (4 mg) at rt for 2 h. Filtration over Celite™ afforded 30 mg (91%) of 7-amino-1,2,3,4-tetrahydro-3,3-dimethylquinoline (structure 72A of Scheme LII, where R1-2 =R5 =H, R3-4 =methyl) that was used without further purification in the next step. Compound 437 was prepared by General Method 13 (EXAMPLE 147) from 7-amino-1,2,3,4-tetrahydro-3,3-dimethylquinoline (30 mg, 0.17 mmol), ZnCl2 (34 mg, 025 mmol) and ethyl 4,4,4-trifluoroacetoacetate (25 mL, 0.17 mol) to afford 13 mg (26%) of Compound 437 as a yellow solid. Data for Compound 437: 1H NMR (400 MHz, DMSO-d6) 11.71 (bs, 1H), 7.11 (s, 1H), 7.01 (s, 1H), 6.40 (s, 1H), 6.37 (s, 1H), 2.89 (s, 2H), 2.51 (s, 2H), 0.93 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13]C(C2SC=CC=2NC2C=CN=C3NC=CC=23)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCCC(N)C1)(OC(C)(C)C)=O.[NH:45]1[C:49]2=[N:50][CH:51]=[CH:52][C:53]([NH:54][C:55]3[S:56][CH:57]=[CH:58][C:59]=3[C:60]([OH:62])=O)=[C:48]2[CH:47]=[CH:46]1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:60]([C:59]2[CH:58]=[CH:57][S:56][C:55]=2[NH:54][C:53]2[CH:52]=[CH:51][N:50]=[C:49]3[NH:45][CH:46]=[CH:47][C:48]=23)=[O:62])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: O=C(O)c1ccsc1Nc1ccnc2[nH]ccc12
Agent: CC(C)(C)OC(=O)N1CCCC(N)C1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccsc2Nc2ccnc3[nH]ccc23)C1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 1-BOC-3-aminopiperidine instead of 1-BOC-3-aminopyrrolidine and 2-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-3-carboxylic acid instead of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid. LCMS (ESI) 428 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.85 (1H, br. s.) 11.67 (1H, br. s.) 8.28 (1H, d, J=6.83 Hz) 8.15 (1H, d, J=5.42 Hz) 7.57 (1H, d, J=5.81 Hz) 7.38 (1H, dd, J=3.27, 2.68 Hz) 6.99 (1H, d, J=5.47 Hz) 6.93 (1H, d, J=6.05 Hz) 6.47 (1H, dd, J=3.49, 1.88 Hz) 4.40-4.59 (1H, m, J=12.24, 6.09, 6.09, 5.83 Hz) 3.51-3.64 (1H, m) 3.41 (1H, t, J=7.74 Hz) 3.21 (1H, td, J=9.91, 5.52 Hz) 2.06-2.19 (1H, m) 1.90 (1H, td, J=11.17, 6.61 Hz) 1.41 (9H, br. s.)
Reaction SMILES: O=C1[N:6]([CH2:7][CH2:8]NS(C)(=O)=O)[C@:5]2([CH2:22][C@@H:21]3[N:16]([CH2:17][CH2:18][C:19]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[O:23][C:20]=43)[CH2:15][CH2:14]2)CN1.NCC[NH:33][S:34]([CH3:37])(=[O:36])=[O:35].C[Si]([C:42]#[N:43])(C)C.[ClH:44]>O>[ClH:44].[ClH:44].[C:42]([CH:14]1[C@@H:15]2[N:16]([CH2:17][CH2:18][C:19]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][C:20]=32)[CH2:21][CH2:22][C@H:5]1[NH:6][CH2:7][CH2:8][CH2:37][S:34]([NH2:33])(=[O:36])=[O:35])#[N:43]
Reactant: C[Si](C)(C)C#N
Reactant: CS(=O)(=O)NCCN1C(=O)NC[C@]12CCN1CCc3c(oc4ccccc34)[C@@H]1C2
Reactant: CS(=O)(=O)NCCN
Agent: Cl
Solvent: O
Product: N#CC1[C@H]2c3oc4ccccc4c3CCN2CC[C@H]1NCCCS(N)(=O)=O

Procedure:
The process of the invention for the manufacture of N-(2-((2R,12bS)-2′-oxo-1,3,4,6,7,12b-hexahydrospiro[benzofuro[2,3-a]quinolizine-2,4′-imidazolidine]-3′-yl)ethyl)-methanesulfon-amide having the formula I comprises the steps, where in the first step (S)-1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one of formula II and N-(2-aminoethyl)methanesulfonamide of formula III are contacted with trimethylsilyl cyanide in the presence of an agent capable of capturing water molecules, in an organic solvent, followed by adding hydrogen chloride to obtain (2R,12bS)-[2-[(cyano-1,3,4,6,7,12b-hexahydrobenzofuro-[2,3-a]quinolizine-2-yl)-amino]ethyl]methanesulfon-amide dihydrochloride, in the second step (2R,12bS)-[2-[(cyano-1,3,4,6,7,12b-hexahydrobenzofuro-[2,3-a]quinolizine-2-yl)-amino]-ethyl]methanesulfonamide dihydrochloride is contacted with 1,1′-carbonyldiimidazole in the presence of a hydrogen chloride acceptor in an organic solvent to obtain (2R,12bS)-1,3,4,6,7,12b-hexahydro-[2,3-methylsulfonyl)-2-oxo-1-imidazolidinyl]-2H-benzo-furo[2,3-a]quinolizine-2-carbonitrile, and in the third step (2R,12bS)-1,3,4,6,7,12b-hexahydro-[2,3-methylsulfonyl)-2-oxo-1-imidazolidinyl]-2H-benzofuro[2,3-a]quinolizine-2-carbonitrile is contacted with hydrogen in the presence of Raney nickel catalyst and sodium methoxide or potassium tert-butoxide in methanol solvent to yield N-(2-((2R,12bS)-2′-oxo-1,3,4,6,7,12b-hexa-hydrospiro-[benzofuro[2,3-a]quinolizine-2,4′-imidazolidine]-3′-yl)ethyl)-methanesulfonamide.
Reaction SMILES: [C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:45]=[CH:44][C:20]([O:21][C:22]2[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:43])[N:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH2:34][CH2:33]3)[CH3:31])[CH:23]=2)=[CH:19][CH:18]=1.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])=[CH:49][CH:48]=1>C(O)C>[CH3:42][N:40]([CH3:41])[CH2:39][CH2:38][N:35]1[CH2:36][CH2:37][CH:32]([N:30]([CH3:31])[C:29]([NH:28][C:24]2[CH:23]=[C:22]([O:21][C:20]3[CH:44]=[CH:45][C:17]([NH:16][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:50]4[CH:51]=[CH:52][C:47]([F:46])=[CH:48][CH:49]=4)=[S:58])=[CH:18][CH:19]=3)[N:27]=[CH:26][N:25]=2)=[O:43])[CH2:33][CH2:34]1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ncn2)CC1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
After adding (1S)-(+)-10-camphorsulfonic acid (127 mg) to a solution of crude 3-[6-(4-aminophenoxy)pyrimidin-4-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (119 mg) in ethanol (3.0 ml), the mixture was stirred for 15 minutes at room temperature. After then adding 2-(4-fluorophenyl)acetyl isothiocyanate (4.08 ml, 0.25 M solution in toluene) thereto, the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate (10 ml) and ethyl acetate (30 ml). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1). Fractions containing the target compound were concentrated, and the residue was purified by LC-MS (water-acetonitrile-trifluoroacetic acid system). Fractions containing the target compound were concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was then dried over anhydrous sodium sulfate. The dried organic layer was concentrated. Diethyl ether was added to the obtained solid to produce a suspension. The resulting precipitate was filtered and then dried to provide the title compound (12.4 mg) as white powder.
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[F:12].[C:13]1(=O)[CH2:16][CH2:15][CH2:14]1>C(O)(=O)C>[F:12][C:6]1[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=1[NH:4][C:13]1([C:1]#[N:2])[CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCC1
Reactant: [C-]#N
Reactant: Nc1ccc(O)cc1F
Agent: [Na+]
Solvent: CC(=O)O
Product: N#CC1(Nc2ccc(O)cc2F)CCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.5 %

Procedure:
Sodium cyanide (0.194 g, 4 mmol) was added to a mixture of 4-amino-3-fluorophenol (0.29 g, 2.28 mmol) and cyclobutanone (0.175 g, 2.5 mmol) in 90% acetic acid (3 ml). The reaction mixture was stirred at room temperature for 15 hours. The medium was washed with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated and chromatographed (dichloromethane:acetone, 90:10) to yield 1-(2-fluoro-4-hydroxyphenylamino)-cyclobutanecarbonitrile (53b) (0.271 g, 1.31 mmol, 58%) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 2.13-2.20 (m, 2H), 2.36-2.41 (m, 2H), 2.70 2.75 (m, 2H), 4.00 (bs, 1H), 6.46 (bs, 1H), 6.52 (ddd, J1=2.2 Hz, J2=0.65 Hz, J3=0.22 Hz, 1H), 6.57 (d, J=2.3 Hz), 6.62 (dd, Jf=3.0 Hz, J2=0.67 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 15.7, 34.1, 50.9, 104.0 (d, J=21.9 Hz), 111.0 (d, J=3.4 Hz), 115.8 (d, J=3.7 Hz), 121.8, 125.3 (d, J=12.3 Hz), 150.1 (d, J=10.4 Hz), 152.8 (d, J=239.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[N:14]=2)=[N:6][C:7]=1Br.C(N)C1C=CC=CC=1.O.C[C:33]([N:35](C)[CH3:36])=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[N:14]=2)=[N:6][C:7]=1[N:35]([CH3:36])[CH3:33]
Reactant: CC(=O)N(C)C
Reactant: Cn1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Solvent: O
Solvent: NCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CN(C)c1nc(-c2ccc(=O)n(C)n2)c(-c2ccccc2)nc1N
Temperature: 122.5 °C

Procedure:
A mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-methyl-3(2H)-pyridazinone (150 mg) and benzylamine (0.138 ml) in DMA (0.3 ml) was heated at 120-125° C. for 50 hours. After addition of water (4 ml), an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel. By elution with a mixture of n-hexane and EtOAc (60:40 v/v) was obtained 6-[5-amino-6-(dimethylamino)-3-phenyl-2-pyrazinyl]-2-methyl-3(2H)-pyridazinone as a solid (83 mg) and by elution with a mixture of n-hexane and EtOAc (20:80 v/v) was obtained 6-[5-amino-6-(benzylamino)-3-phenyl-2-pyrazinyl]-2-methyl-3(2H)-pyridazinone as a solid (48 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:13]=[C:12]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][C:29]([F:32])([F:31])[F:30])[N:11]=2)[CH2:4][CH2:3]1.Br[CH2:34][CH2:35][CH2:36][CH2:37]Br.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[N:1]1([C@H:2]2[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]3[C:15]([C:16]([F:17])([F:18])[F:19])=[CH:14][N:13]=[C:12]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][C:29]([F:31])([F:32])[F:30])[N:11]=3)[CH2:6][CH2:7]2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2C(F)(F)F)CC1
Reactant: BrCCCCBr
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccccc1CNc1ncc(C(F)(F)F)c(NC[C@H]2CC[C@H](N3CCCC3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N4-[(trans-4-aminocyclohexyl)methyl]-N2-[2-(trifluoromethoxy)benzyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (100 mg, 0.22 mmol) in DMF (2 mL) were added 1,4-dibromobutane (140 mg, 0.65 mmol) and DIPEA (113 μL, 0.65 mmol). The reaction mixture was stirred at room temperature for 16 h and then heated at 65° C. for another 2 h. The reaction mixture was then diluted with EtOAc and washed with water (×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 10:1 CH2Cl2:MeOH as an eluent to afford 49 mg of the title compound as a while solid, m/z 518.6 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17]Br>CN(C=O)C>[O:8]1[CH2:17][CH2:16][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: Nc1ccccc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)NCCO2
Temperature: 125 °C
Yield: 65.1 %

Procedure:
To a suspension of 2-aminophenol (1.0 g, 9.2 mmol) and potassium carbonate (6.36 g, 46 mmol) in dry DMF (10 mL) was added 1,2-dibromoethane (2.59 g, 13.8 mmol). The mixture was then heated at 125° C. for 15 hours. After cooling, the mixture was treated with crushed ice and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether 1:10 (v:v) as eluent to give 3,4-dihydro-2H-benzo[b][1,4]oxazine as reddish oil (0.81 g, 65%). LC-MS (ES-API); rt 7.51 min; m/z calculated for C8H9NO [M+H]+ 136.1, found 136.1.
Reaction SMILES: [Cu:1].[CH2:2]([CH:4]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][O:6][P:7](=[O:18])([OH:17])[O:8][CH2:9][CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])[CH3:3]>>[P:7]([O-:18])([O:6][CH2:5][CH:4]([CH2:2][CH3:3])[CH2:19][CH2:20][CH2:21][CH3:22])([O:8][CH2:9][CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:17].[Cu+2:1].[CH2:2]([CH:4]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][O:6][P:7]([O-:18])([O:8][CH2:9][CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:17])[CH3:3]
Reactant: CCCCC(CC)COP(=O)(O)OCC(CC)CCCC
Reactant: [Cu]
Product: CCCCC(CC)COP(=O)([O-])OCC(CC)CCCC
Product: [Cu+2]

Procedure:
In the drawing, a leach liquor containing for example 75 g/liter copper and 25 g/liter Zn in the form of sulfates is first adjusted, if necessary, to a pH of between 0.5 and 6 and then led in stream 1 where it is contacted with copper di-(2-ethylhexyl) phosphate (Cu(DEP)2) to extract zinc into the organic phase as Zn(DEP)2 leaving copper sulfate in the aqueous phase. The zinc-containing organic phase, Zn(DEP)2 in stream 2 is stripped with dilute sulfuric acid to recover the zinc as a zinc sulfate solution and to generate di-(2-ethylhexyl) phosphoric acid (DEHPA) in stream 7. The zinc sulfate solution can then be subjected to electrowinning to recover zinc metal in a zinc recovery stage. The aqueous phase containing copper sulfate in stream 3 is led to a copper electrowinning circuit where a copper drop down to about 30 g/liter is taken to produce cathode copper in stream 5. The exit solution from electrowinning in stream 6 is then contacted in a copper stripping stage with the generated di-(2-ethylhexyl) phosphoric acid (DEHPA) in stream 7, to produce Cu(DEP)2 in stream 4 which is recycled to the incoming leach liquor in stream 1. The spent dilute copper solution after reaction with DEPH is then either recycled to the leach (not shown) or discarded.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH:3]=[N:2]1.Cl[CH2:18][C:19]1[C:20]([CH3:25])=[N:21][O:22][C:23]=1[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:25][C:20]1[C:19]([CH2:18][N:1]2[CH:5]=[C:4]([N:6]3[C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])[CH:3]=[N:2]2)=[C:23]([CH3:24])[O:22][N:21]=1
Reactant: Cc1noc(C)c1CCl
Reactant: O=C1c2ccccc2C(=O)N1c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)c3ccccc3C2=O)cn1
Yield: 39.9 %

Procedure:
2-(1H-pyrazol-4-yl)isoindoline-1,3-dione (example 9-1a) (1.5 g, 7 mmol), 4-(chloromethyl)-3,5-dimethylisoxazole (1.5 g, 10 mmol), and cesium carbonate (3.3 g, 10 mmol) were stirred in DMF (20 mL) at 80° C. for 3 hours. The reaction was cooled, diluted with H2O (150 mL), and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated on the rotovap. The solid product was triturated with ethyl acetate/hexanes (1/9) and re-crystallized from refluxing absolute ethanol (30 mL) to afford 2-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)isoindoline-1,3-dione (900 mg, 38%) as a bright, light yellow solid. 1H NMR (DMSO-d6, 400 MHz) 1.36 (d, 3H,δ J2.16 (s, 3H), 2.41 (s, 3H),=7.2 Hz), 5.22 (s, 2H), 7.81 (s, 1H), 7.91-7.83 (m, 4H), 8.21(s, 1H). MS M+H calculated 323.11; found 323.1. Melting point: 170-171° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.18 μM.
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[CH2:5][C:6]#[N:7])[CH2:2][CH3:3].[OH2:11]>>[CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[CH2:5][C:6]([NH2:7])=[O:11])[CH2:2][CH3:3]
Reactant: CCCC(CC#N)CCC
Reactant: O
Product: CCCC(CCC)CC(N)=O
Temperature: 80 °C

Procedure:
While stirring, 139.2 g (1 mol) of 3-n-propyl-hexanenitrile were added. The mixture was heated to 80° C. and maintained at this temperature for 2 hours. After cooling to room-temperature, the medium was hydrolysed while stirring with 1500 g of distilled water for 1 hour. The crude product so obtained was suction-filtered and taken up, while stirring for 1 hour at room-temperature, with 1500 g of distilled water. The medium was again suction-filtered, washed and dried to constant weight in a drying-oven under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]([CH3:15])[CH2:7][C:6]2=[O:16].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:8]([CH3:15])[CH2:7][C:6]2=[O:16]
Reactant: CCOC(=O)Cl
Reactant: COc1cc2c(cc1OC)C(=O)CC(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Reaction time: 72 h

Procedure:
A mixture of 15 g. of the quinoline product of Example 4, 95 g. of potassium carbonate, and 225 ml. of methylene chloride was stirred for 1 hr., then 14.7 g. of ethyl chloroformate in 20 ml. of methylene chloride was added dropwise and the suspension was allowed to stir for 72 hrs. at room temperature. Additional 7.3 g. portions of ethyl chloroformate were added after 24 and 48 hrs. and 47 g. of potassium carbonate was added after 48 hrs. The reaction mixture was quenched with water and extracted several times with methylene chloride. The combined organic extracts were washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give an oil which solidified upon standing; trituration with 5% ethyl acetate in hexane gave 17 g. of a solid, m.p. 112°-116°. This solid was chromatographed on silica gel, eluting with 1:1 ethyl acetate/hexane, and recrystallized from 1:1 ethyl acetate/hexane to give 13.9 g. of white crystals, m.p. 116.5°-18°.
Reaction SMILES: [C:1]([O:5]CC)(=[O:4])[CH:2]=[CH2:3].[C:8]([O:13][CH3:14])(=[O:12])[C:9]([CH3:11])=[CH2:10].N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C>[C:8]([O:13][CH3:14])(=[O:12])[C:9]([CH3:11])=[CH2:10].[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCC
Agent: C=C(C)C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: C=CC(=O)O

Procedure:
The coupler dispersion used in Sample (V) (Dispersion 1) was prepared as follows. In 50 ml of ethyl acetate was dissolved 10 g of Cyan Coupler (C-4), 2 g of ethyl acrylate, and 5 g of methyl methacrylate, and 0.2 g of azobisisobutyronitrile was added to the solution as a polymerization initiator. The mixture was allowed to react at 60° C. for 10 hours. After completion of the reaction, the reaction mixture was concentrated to a volume of 20 ml. The resulting concentrate was added to 100 ml of an aqueous solution containing 10 g of gelatin and 0.5 g of sodium dodecylbenzenesulfonate at 60° C., and the mixture was vigorously stirred in a homogenizer to prepare a dispersion.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:23]=[CH:24][C:25]=3[O:26][CH:27]([CH3:29])[CH3:28])[CH2:14][CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:30]I>C1COCC1>[C:1]12([C:11]3[CH:12]=[C:13]([CH:23]=[CH:24][C:25]=3[O:26][CH:27]([CH3:29])[CH3:28])[CH2:14][CH2:15][N:16]([CH3:30])[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CI
Reactant: CC(C)Oc1ccc(CCNC(=O)C(F)(F)F)cc1C12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(CCN(C)C(=O)C(F)(F)F)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of the product of Step D (0.25 g, 0.61 mmol) in anhydrous THF (5 ml) 60% NaH in mineral oil (0.03 g, 0.75 mmol) was added at 0° C. and the mixture was stirred for 2 h. To it MeI (0.23 ml) was added and the resulting mixture was stirred for additional 3 h. The mixture was passed trough Celite bead and washed with CH2Cl2 (10 ml). The combined filtrates were evaporated to dryness to give the title product (0.22 g; 85.3%). 1H-NMR (CDCl3) 1.36 (d, 6H, J=6 Hz); 1.75 (s, 6H); 2.04 (s, 3H); 2.09 (s, 6H); 2.8 (tr, 2H, J=7.7 Hz); 2.96 (s, 3H); 3.59 (tr, 2H, J=6.02 Hz); 4.58-4.63 (m, 1H); 6.76 (d, 1H, J=8.32 Hz); 6.91-7.01 (m, 2H).
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:30][O:31][CH3:32])[C:12]([NH:14][C@H:15]2[C@H:18]([S:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[N:17]([S:25]([O-:28])(=[O:27])=[O:26])[C:16]2=[O:29])=[O:13])[N:10]=1)=O.[Na+:33].CSC(=S)N.[Na]>>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:30][O:31][CH3:32])[C:12]([NH:14][C@H:15]2[C@H:18]([S:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[N:17]([S:25]([O-:28])(=[O:27])=[O:26])[C:16]2=[O:29])=[O:13])[N:10]=1.[Na+:33]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1SCC(=O)OC)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1SCC(=O)OC)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of 0.273 g of sodium (3R,4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-4-methoxycarbonylmethylthio-2-oxoazetidine-1-sulfonate in 6 ml of a buffer solution (pH 6.86) is added 67.8 mg of sodium monomethyldithiocarbamate under ice-cooling. After stirring for 2 hours at room temperature, the reaction mixture is purified in the same procedure as in Example 3B to give 0.120 g of sodium (3R,4S)-3-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-4-methoxycarbonylmethylthio-2-oxoazetidine-1-sulfonate.