Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3.[NH2:16][NH2:17]>CN(C=O)C.C(O)C>[N:16](=[C:1]1[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3)[NH2:17]
Reactant: O=C1Nc2ccc3ncccc3c2C1=O
Reactant: NN
Solvent: CN(C)C=O
Solvent: CCO
Product: NN=C1C(=O)Nc2ccc3ncccc3c21
Temperature: 25 °C
Yield: 70.7 %

Procedure:
A solution of 2.3 g (12 mmol) of 3-H-pyrrolo[3,2-f]quinoline-1,2-dione and 2.0 ml (0.06 mol) of hydrazine in 50 ml of DMF and 50 ml of ethanol was stirred at reflux for 2 h. The resulting suspension was allowed to cool to ambient temperature and was then chilled in an ice bath and filtered. The solid was washed with a small volume of ethanol and allowed to air dry to give 1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinolin-2-one as an orange solid (1.8 g, 73%): 1H NMR (DMSO-d6): δ 7.37 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.4, 4.2 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 8.71 (dd, J=4.2, 1.6 Hz, 1H), 8.80 (d, J=8.4 Hz, 1H), 9.90 (br d, J=14.7 Hz, 1H), 10.89 (br d, J=14.7 Hz, 1H), 10.95 (br s, 1H); ESI-MS m/z 213 (M+H)+. A solution 1.8 g (8.5 mmol) of 1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinolin-2-one in 50 ml of freshly prepared 0.5 M sodium ethoxide solution was stirred at reflux for 3 h. The solution was diluted with 50 ml of water, neutralized with acetic acid, and concentrated on a rotary evaporator until cloudy. The solution was stored in a refrigerator overnight. The solid was filtered off, and the filtrate was extracted with three 80-ml portions of EtOAc. A solution of the solid in MeOH/EtOAc was combined with the extracts and passed through a short pad of silica gel, eluting with EtOAc. The solution was then concentrated to a small volume on a rotary evaporator, and the resulting suspension was diluted with an equal volume of ethanol, sonicated, and filtered to give 3-H-pyrrolo[3,2-f]quinoline-2-one as a light green solid (0.52 g, 33%); 1H NMR (DMSO-d6): δ 3.80 (s, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.4, 4.2 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.70 (dd, J=4.2, 1.6 Hz, 1H), 10.57 (br s, 1H); APCI-MS m/z 183 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11](Cl)[CH:10]=[CH:9]2)=[O:5])[CH3:2].[NH2:17][C@H:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:17][C@H:18]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19]1)[CH:10]=[CH:9]2)=[O:5])[CH3:2]
Reactant: N[C@@H]1CCc2ccccc21
Reactant: CCOC(=O)c1ccc2nc(Cl)ccc2c1
Product: CCOC(=O)c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 120 °C
Yield: 95.4 %

Procedure:
A stirred mixture of 2-chloro-quinoline-6-carboxylic acid ethyl ester [CAS-No. 29969-56-0] (500 mg, 2.12 mmol) and commercially available (R)-1-aminoindane (848 mg, 6.36 mmol) was heated in a sealed tube for 16 h at 120° C. Purification by flash chromatography on silica gel (ethyl acetate/heptane) yielded 2-((R)-indan-1-ylamino)-quinoline-6-carboxylic acid ethyl ester as a light brown solid (672 mg, 95%), MS (ISP) 333.2 [(M+H)+]; m.p. 137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([NH:15][O:16][CH3:17])=[O:14].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([NH:15][O:16][CH3:17])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1cc(I)c(Cl)cn1
Reactant: CONC(=O)c1ccccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Temperature: 110 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A mixture of 2,5-dichloro-4-iodo-pyridine (40 g, 146.5 mmole, 1 eq), 2-amino-N-methoxy-benzamide (24.32 g, 146.5 mmole, 1 eq) and K3PO4 (77.72 g 366.2 mmole, 2.5 eq) in 1,4-dioxane (600 mL) was degassed with N2 for 1 h. To this were added Pd(OAc)2 (0.657 g, 2.93 mmole, 0.02 eq), DPEPhos (6.31 g, 11.7 mmole, 0.08 eq) and again degassed for 15 min with N2. The resulting mixture was stirred at 110° C. for overnight. After completion of reaction, solid material was collected by filtration, dissolved in water (500 mL) and extracted with ethyl acetate (5×200 mL). Combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Solid compound so obtained was purified by washing with hexane to give the title compound as yellowish solid (40 g, 53%). 1H-NMR (400 MHz, DMSO-d6): δ 3.63 (s, 3H), 7.06 (s, 1H), 7.15-7.22 (m, 1H), 7.48-7.57 (m, 2H), 7.66-7.67 (d, 1H, J=7.48 Hz), 8.25 (s, 1H), 10.66-11.45 (brs, 1H). LC-MS [M+H]+=312.3.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:10][C:6]1[C:3]([C:4]2[NH:13][N:12]=[N:11][N:5]=2)=[C:2]([CH:9]=[CH:8][CH:7]=1)[NH2:1]
Reactant: N#Cc1c(N)cccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1cccc(Cl)c1-c1nnn[nH]1
Temperature: 100 °C
Yield: 21.2 %

Procedure:
To a mixture of 2-amino-6-chlorobenzonitrile (500 mg, 3.3 mmol), sodium azide (4.3 mmol, 1.3 eq.), and triethylamine hydrochloride (4.3 mmol, 1.3 eq.) in a sealed tube, 8 mL of toluene was added. The tube was tightly capped and the reaction was stirred and heated to 100° C. overnight. The mixture was cooled to room temperature, diluted with another 10 mL of toluene, transferred to a separatory funnel and washed with water (3×20 mL). The aqueous extractions were combined and acidified to a pH of 4 with concentrated HCl. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 137 mg of 3-chloro-2-(1H-tetrazol-5-yl)aniline. MS (EI) for C7H6ClN5: 196 (M+H). Step 2: N-[3-Chloro-2-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide: To a solution of the tetrazole intermediate 3-chloro-2-(1H-tetrazol-5-yl)aniline (137 mg, 0.7 mmol) in 3 mL of DCM, DIPEA (1.4 mmol, 2.0 eq.) was added followed by thiophene-2-carbonyl chloride (1.0 mmol, 1.5 eq.). The reaction was stirred at room temperature overnight. The organic solution of the crude reaction mixture was extracted twice with aqueous HCl (0.1 M), twice with aqueous sodium hydroxide (0.1 M), and once with a saturated aqueous solution of sodium chloride. The basic aqueous extractions and final brine extraction were combined and acidified to a pH of 4 with concentrated HCl. The resulting solid was collected by filtration. This was then washed with acetonitrile, and dried under vacuum to afford 80 mg of desired N-[3-chloro-2-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide. 1H-NMR (400 MHz, d6-DMSO): 10.25 (s, 1H), 7.83 (dd, 1H), 7.73 (dd, 1H), 7.68-7.64 (m, 2H), 7.62-7.59 (m, 1H), 7.17 (t, 1H). MS (EI) for C12H8ClN5OS: 306 (M+H).
Reaction SMILES: [C:1]1([CH:11]([N:13]2[CH:17]3[C:18](=O)[N:19]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:21][CH:16]3[CH2:15][CH2:14]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1>[C:1]1([CH:11]([N:13]2[CH:17]3[CH2:18][N:19]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:21][CH:16]3[CH2:15][CH2:14]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1cccc2ccccc12)N1CCC2CCN(CCc3ccccc3)C(=O)C21
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(c1cccc2ccccc12)N1CCC2CCN(CCc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
To a solution of 4 (4.8 g, 12 mmol) in THF (100 mL) is added slowly 1 M DIBAL in toluene, (50 mL, 50 mmol) at −78° C. The mixture is stirred at room temperature for 1 hour and quenched with 20 mL of water. The solvent is evaporated, the residue is diluted with 100 mL of 1:1 saturated Rochells salt/15% NaOH, and this extracted with EtOAc (4×50 mL). The organic extracts are combined, dried and concentrated under vacuum. The residue is purified by flash chromatography (silica gel; Hexane/EtOAc 1:9) to provide 2.3 g (48%) of the title compound. M+H+=385.26.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[I:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([N+:35]([O-:37])=[O:36])[CH:29]=1>C(Cl)(Cl)(Cl)Cl>[Br:8][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([I:27])=[CH:29][C:30]=1[N+:35]([O-:37])=[O:36]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(I)cc1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(I)ccc1CBr
Temperature: 25 °C
Yield: 45 %

Procedure:
NBS (5.45 g, 30.62 mmol) and benzoyl peroxide (75% aq, 200 mg, 0.85 mmol) were added to a solution of 4-iodo-2-nitrotoluene (4.63 g, 17.60 mmol) in CCl4 (60 mL). The mixture was heated to reflux overnight, then cooled to room temperature, concentrated in vacuo, and purified by column chromatography to yield 1-bromomethyl-4-iodo-2-nitrobenzene (2.71 g, 45%). 1H NMR (400 MHz, CDCl3): δ 8.35 (d, 1 H, J=1.8 Hz, Ph-H), 7.93 (dd, 1 H, J=1.8 and 8.1 Hz, Ph-H), 7.30 (d, 1 H, J=8.1 Hz, Ph-H), 4.76 (s, 2 H, PhCH2).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl>ClCCl.CC(OC)(C)C>[CH3:22][O:23][CH2:24][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1]
Reactant: COCCl
Reactant: Oc1ccccc1OC(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Product: COCOc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
A solution of 2-(trifluoromethyloxy)phenol (12.0 g, 67.4 mmol) in dichloromethane (45 mL) was cooled to 5° C., and N,N-diisopropylethylamine (23.5 mL, 135 mmol) and methoxymethyl chloride (7.68 mL, 135 mmol) were added dropwise, keeping the internal temperature≦15° C. The reaction mixture was warmed to ambient temperature, stirred for 15 min at ambient temperature, then diluted with MTBE (250 mL) and washed with 2N HCl (2×50 mL), water (50 mL), 2N NaOH (2×30 mL), water (30 mL), and brine (30 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give the title compound (13.9 g, 62.6 mmol, 93%). which was used without further purification. MS (DCI/NH3) m/z 222 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]([CH3:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>C(Cl)Cl>[C:1]1([N:7]2[C:11]([NH:12][C:27](=[O:28])[O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:10][C:9]([C:13]([CH3:19])([CH3:18])[C:14]([F:16])([F:17])[F:15])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(c1cc(N)n(-c2ccccc2)n1)C(F)(F)F
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of 1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (590 mg, 2.2 mmol) and potassium carbonate (304 mg, 2.85 mmol) in anhydrous DCM (5.2 ml) was added dropwise phenyl chloroformate (0.30 ml, 2.4 mmol) as a solution in DCM (2.5 ml). The reaction mixture was stirred at rt overnight, then filtered and concentrated under reduced pressure. The crude was purified by silica gel chromatography (hexane/ethyl acetate 35%) to afford phenyl 1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-ylcarbamate (748 mg, 87%) as a solid. 1H NMR (300 MHz, CDCl3) δ 1.60 (s, 6H), 6.65 (brs, 1H), 7.02-7.55 (m, 11H); LC-MS (ESI) m/z 390 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH:21]2[CH2:23][CH2:22]2)=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15][N:16](C)C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O.[NH2:24]N>CC(O)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH:21]2[CH2:23][CH2:22]2)=[C:6]([C:7]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][NH:16][N:24]=2)[CH:19]=1
Reactant: NN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)ccc1OC1CC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]nc1-c1cc(Cl)ccc1OC1CC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Ethyl 2-(5-chloro-2-cyclopropoxybenzoyl)-3-(dimethyl-amino)acrylate (24 g, 71 mmol) was dissolved in 150 mL of HOAc. The reaction mixture was cooled to 0° C. then 85% hydrazine in water (25 mL) was added dropwise. The mixture was warmed to room temperature and stirred for 6 hours, then concentrated in vacuo. The residue was purified by EtOAc/Hexanes=1:2 to afford 24 g of the title compound as a syrup. 1H NMR (DMSO-d6, 400 MHz) δ: 13.41 (s, 1H), 8.26 (s, 0.5H), 7.88 (s, 0.5H), 7.49-7.24 (m, 3H), 4.07-3.99 (m, 2H), 3.82-3.74 (m, 1H), 1.17-1.10 (m, 3H), 0.73-0.46 (m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:34])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:30](=[CH:31][CH:32]=1)[O:29][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][C:18]3[N:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[S:21][CH:22]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:33].[OH-].[Na+]>>[C:23]1([C:20]2[S:21][CH:22]=[C:18]([CH2:17][N:14]3[CH2:13][CH2:12][C:11]4([CH2:10][C:9](=[O:33])[C:8]5[C:30](=[CH:31][CH:32]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:34])=[O:2])[CH:7]=5)[O:29]4)[CH2:16][CH2:15]3)[N:19]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3csc(-c4ccccc4)n3)CC1)O2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3csc(-c4ccccc4)n3)CC1)O2
Yield: 94.4 %

Procedure:
(E)-3-{1′-(2-phenyl-thiazol-4-yl-methyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (600 mg, 1.26 mmol) was treated with 1 M NaOH following the procedure described in Example 71 Step B, giving (E)-3-{1′-(2-phenyl-thiazol-4-yl-methyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (548 mg, 95%). The resulting product was treated with NH2OTHP according to the procedure described in Example 71 Step C, giving (E)-3-{1′-(2-phenyl-thiazol-4-yl-methyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide. Finally, removal of the THP protecting group following the procedure described in Example 71 Step C gave (E)-3-{1′-(2-phenyl-thiazol-4-yl-methyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide hydrochloride (202 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.Cl.[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][CH:45]=1)([O:26][CH3:27])=[O:25]>CCOCC>[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:49])=[CH:46][CH:45]=1)([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: C1CCNCC1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)N2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperidine, 2.5 ml. of triethylamine and 0.6 g. of dimethylaminopyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.3 g. of 4-(15-carbomethoxypentadecylamino)benzoyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with 100 ml. portions of water and dried over magnesium sulfate. The solvent is removed in vacuo and the solid is recrystallized in 50 ml. of diethyl ether to yield the product.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH3:15])=[C:8]([CH:12]=2)[C:9](Cl)=O)[CH2:3][CH2:2]1.BrC1C=CC(O)=C(C=1)C(O)=O.ICC.C1(B(O)O)CC1.[Cl-].[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2([CH3:70])[C:48]([C:50]3[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=3)([CH3:49])[NH:47]C(C3C=CC(C(C)(C)C)=CC=3OCC)=[N:45]2)=[CH:40][CH:39]=1>>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2([CH3:70])[C:48]([C:50]3[CH:51]=[CH:52][C:53]([Cl:56])=[CH:54][CH:55]=3)([CH3:49])[NH:47][C:9]([C:8]3[CH:12]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[CH:6][C:7]=3[O:13][CH2:14][CH3:15])=[N:45]2)=[CH:40][CH:39]=1
Reactant: CCOc1ccc(C2CC2)cc1C(=O)Cl
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Agent: O=C(O)c1cc(Br)ccc1O
Agent: OB(O)C1CC1
Agent: [Cl-]
Solvent: CCI
Product: CCOc1ccc(C2CC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
rac-(4S*,5R*)-4,5-Bis-(4-chloro-phenyl)-2-(5-cyclopropyl-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was prepared from 5-cyclopropyl-2-ethoxy-benzoyl chloride (prepared from 5-bromo-2-hydroxy-benzoic acid by alkylation with iodoethane, Suzuki coupling with cyclopropyl boronic acid, then saponification and conversion to the chloride) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) in an analogous manner as described in example 2 (method 1).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH3:13])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:18]>CO>[NH2:18][C@H:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)c1ccccc1
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)C[C@H](N)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Ru(OAc)2((R)-dm-binap) (13.4 mg, 0.0140 mmol), methyl benzoylacetate (500 mg, 2.806 mmol), ammonium acetate (216 mg, 2.806 mmol) and methanol (2.5 mL) were placed in a 100 mL stainless steel autoclave under nitrogen atmosphere, and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled down to room temperature and further stirred under a hydrogen pressure of 3 MPa at 80° C. for 15 hours. After completion of the reaction, the solvent was removed by evaporation and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate/triethylamine=50/50/5-0/95/5) to give methyl (3S)-3-amino-3-phenylpropionate (201 mg) as a colorless oil in 40.0% yield. The enantiomeric excess of the product was determined to be 96.7% ee by HPLC analysis using a SUMICHIRAL OA-4100R column (available from SUMIKA CHEMICAL ANALYSIS SERVICE LTD.) after conversion into methyl (3S)-3-(4-nitrobenzoylamino)-3-phenylpropionate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[N:20]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[CH2:21][CH2:22][CH3:23])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:35]#[N:36].C(O)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([CH2:31][C:32]2[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=2)[C:35]#[N:36])[CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:11]=2[N:20]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[CH2:21][CH2:22][CH3:23])=[N:4][CH:3]=1
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CNc1ncc(Br)cn1
Reactant: N#Cc1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
(5-Bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amine (2.33 g) is dissolved in N,N-dimethylformamide (16.8 ml) and thereto is added sodium hydride (60%) (273 mg) under ice-cooling. Twenty minutes thereafter, thereto is added 3-bromomethyl-5-trifluoromethyl-benzonitrile (2.08 g) and the mixture is stirred at room temperature for 1 hour and 15 minutes. To the reaction solution are added acetic acid to consume the excess sodium hydride, and thereto are added ethyl acetate and water, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-({(5-bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-methyl)-5-trifluoromethyl-benzonitrile (2.81 g). MS (m/z): 626/628 [M+H]+
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:17])[O:15][CH3:16])[CH:10]=[CH:11][CH:12]=1)=[O:6].[CH3:19]I>>[CH3:18][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH3:19])[C:14](=[O:17])[O:15][CH3:16])[CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: COC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Reactant: CI
Product: COC(=O)N(C)c1cccc(C(=O)C=CN(C)C)c1

Procedure:
A 9.93 g portion of [3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]carbamic acid, methyl ester was alkylated as described in Example 3, using 6.82 g of methyl iodide, giving 10.13 g of the desired compound, mp 93°-95° C.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH:14]([NH:17][CH2:18][CH:19]([OH:22])[CH2:20]Cl)([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]([CH3:13])[C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][CH:19]([OH:22])[CH2:18][NH:17][CH:14]([CH3:16])[CH3:15])=[CH:7][CH:6]=1
Reactant: CC(C)NCC(O)CCl
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)NCC(O)COc1ccc(NC(=O)N(C)C)cc1
Reaction time: 5 h

Procedure:
A mixture of 20 g of p-(N',N'-dimethylureido)-phenol, 15 g of 3-isopropylamino-2-hydroxy-1-chloropropane, and 20 g of finely ground potassium carbonate in 250 ml of acetone is stirred at 50° for 5 hours. The solid part of the mixture is filtered off and the acetone solution is evaporated in a vacuum. The residue is dissolved in 100 ml of 2N hydrochloric acid, the undissolved part is filtered off and the remaining mixture is extracted with methylene chloride. The aqueous phase is rendered alkaline by adding 2N sodium hydroxide solution and is extracted with methylene chloride. After the evaporation of the solvent, 1-[p-(N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylaminopropane is isolated which melts at 138°-139° after recrystallisation from benzene and has the formula ##STR22##
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][C:6]3[C:11]([CH:2]12)=[CH:10][CH:9]=[CH:8][CH:7]=3.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[OH:1][C@@H:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C@H:2]1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: c1ccc2c(c1)CCC1OC21
Solvent: CCO
Product: O[C@@H]1CCc2ccccc2[C@H]1N1CCCC1

Procedure:
A mixture of 1,2-epoxy-1,2,3,4-tetrahydronaphthalene (19.8 g), pyrrolidine (15 ml) and ethanol (75 ml) was stirred at reflux for 2 hours and evaporated of the volatiles under reduced pressure. The residue was dissolved in ether and the solution was extracted with 1N hydrochloric acid (200 ml). The acid extract was washed with ether and basified with 1N sodium hydroxide aqueous solution with cooling. The mixture was extracted with ether (2X) and the combined ether extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residual viscous liquid was distilled under vacuum to yield trans-1,2,3,4-tetrahydro-2-hydroxy-1-(pyrrolidin-1-yl)naphthalene (16.5 g), b.p. 128°-135°/0.25 torr.