Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][C:17]([O:19]CC)=O)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[N:3]([CH2:15][CH2:16][C:17]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:19])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1
Reactant: CCOC(=O)CCn1c(C)nc2cnc3ccccc3c21
Reactant: C1COCCN1
Product: Cc1nc2cnc3ccccc3c2n1CCC(=O)N1CCOCC1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A solution of ethyl 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (4.0 g, 15 mmol) and morpholine (10 mL, 100 mmol) was heated for three days in a high-pressure vessel at 100° C., allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in dichloromethane, and the resulting solution was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 4.8 g of 2-methyl-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])C(=O)[NH:8]2)=[CH:4][CH:3]=1.[OH:13]O>[OH-].[Na+]>[NH2:8][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[C:6]([OH:12])=[O:13]
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Br)ccc1C(=O)O
Temperature: 25 °C

Procedure:
To a solution of the 6-bromoindoline-2,3-dione (e.g., 6-bromo-7-fluoroindoline-2,3-dione, 1 equiv) in 1 N NaOH (0.14 M) was added H2O2 (1.8 M) dropwise and the resulting mixture was stirred at room temperature until the reaction was complete (approximately 2 hours). The mixture was filtered and the filtrate was acidified to pH 2 with hydrochloric acid. The precipitate that formed was filtered, washed with water, and concentrated to provide the 2-amino-4-bromobenzoic acid (e.g., 2-amino-4-bromo-3-fluorobenzoic acid).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([O:33][CH2:34][CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:34]([O:33][CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:24])=[O:25])=[CH:18][CH:17]=2)=[CH:11][CH:12]=1)[C:4]([OH:36])=[O:3])[CH3:35]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(=O)(=O)Cc3ccccc3)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2ccc(OS(=O)(=O)Cc3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Yield: 92.6 %

Procedure:
2-Ethoxy-3-{4-[2-(4-phenylmethanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 30) (0.21 g; 0.41 mmol) was dissolved in tetrahydrofuran (4 ml) and lithium hydroxide (0.021 g; 0.48 mmol) dissolved in water (1 ml) was added dropwise. The resulting solution was stirred at room temperature over night and then acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying with magnesium sulfate and evaporation gave 0.184 g (92%) of 2-ethoxy-3-{4-[2-(4-phenylmethanesulfonyloxy-phenyl)ethoxy]phenyl}propanoic acid as an oil.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH3:5][C:6]([CH3:10])=[CH:7][CH2:8]Br>O1CCCC1>[CH3:5][C:6]([CH3:10])=[CH:7][CH2:8][O:4][CH2:1][C:2]#[CH:3]
Reactant: C#CCO
Reactant: CC(C)=CCBr
Solvent: C1CCOC1
Product: C#CCOCC=C(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 29.6 ml (0.5 mol) of 2-propyn-1-ol in 500 ml of tetrahydrofuran was treated at -78° under argon with 67.3 g (0.6 mol) of potassium tert.-butylate. The mixture was stirred at -78° for 4 hours. 69.4 ml (0.6 mol) of 3,3-dimethylallyl bromide were then added and the mixture was stirred at -78° for a further 3 hours and at at room temperature for 20 hours. The reaction mixture was poured on to ice/water and extracted twice with ether. The combined organic phases were dried over magnesium sulphate and concentrated. There was obtained 1-[(3-methyl-2-butenyl)oxy]-2-propyne as a yellow oil which was processed without purification.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>C(O)C>[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([N:20]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: CC(C)c1ccc(N2CCC(C(=O)O)C2=O)cc1
Yield: 5 %

Procedure:
A mixture of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g; 2.94 mmol) and 4-isopropylaniline (1.21 mL; 8.82 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. The mixture was concentrated under reduced pressure and the residue was dissolved in a solution of sodium hydroxide 6N, washed with dichloromethane, acidified with a solution of hydrochloric acid 6N to pH=2, extracted with ethyl acetate dried and concentrated under reduced pressure to yield 0.036 g (5%) of a pale green solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7]OCC1N=CNC=1)=[S:4].N[C:16]1[S:17][C:18]([CH2:21]O)=NN=1>>[CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:16][S:17][CH2:18][C:21]1[N:5]=[CH:3][NH:2][CH:1]=1)=[S:4]
Reactant: CNC(=S)NCCOCc1c[nH]cn1
Reactant: Nc1nnc(CO)s1
Product: CNC(=S)NCCCSCc1c[nH]cn1

Procedure:
By the method of Example 58 (i) and (ii) 4(5)-hydroxymethylimidazole was converted first to the intermediate 4(5)-[(3-aminopropyl)thiomethyl]-imidazole dihydrobromide and thence to the title compound (m.p. 118°-120° C, after recrystallisation from water).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C([O:13][CH:14](O)[C:15]([F:18])([F:17])[F:16])C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1>[OH:13][CH:14]([NH:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:15]([F:18])([F:17])[F:16]
Reactant: CCOC(O)C(F)(F)F
Reactant: NC(=O)c1ccc(Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NC(O)C(F)(F)F)c1ccc(Cl)cc1

Procedure:
A solution of 4-chlorobenzamide (22.0 g, 0.141 mol) and trifluoroacetaldehyde ethyl hemiacetal (25.0 g as is, 22.5 g real, 0.156 mol) in dioxane (200 mL) is treated with anhydrous sodium sulfate (10 g, to dry the 10% water in the hemiacetal) and refluxed for 60 hours. The solids are filtered and the filtrate is evaporated to a solid. The solids are dissolved in about 200 mL of 15% ethyl acetate in heptane. Unreacted starting material (5.6 g) crystallizes out and is filtered. The title product is obtained from the mother liquors as a white crystalline solid (22.1 g, 82.9% based on recovery of starting material): mp 139.5-140.5° C.; characterized by 1H and 19F NMR and Mass spectra. 1H NMR (DMSO-d6) δ9.45 (d, J=8.7 Hz, NH), 7.93, 7.54 (AB with fine splitting, J=8.4 Hz, ArH), 7.54 (broad s, OH), 5.90 (m, J=8.7, 2.9, 5.8 Hz, CH); 19F NMR δ−80.3 (d, J=5 Hz).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[N:3]1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>CCOC(C)=O.CCCCCCC>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[CH:6][N:2]([O:1][C:17](=[O:18])[N:16]([CH3:15])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:3]=2)=[CH:8][CH:9]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: COc1ccc(-c2ccn(O)n2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc(-c2ccn(OC(=O)N(C)c3ccccc3)n2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-3-(4-methoxyphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (93%, oil). HPLC-MS m/z=346.1 (M+Na), Rt: 4.21 min. δH(300 MHz; CDCl3): 3.45 (bs, 3H), 3.84 (s, 3H), 6.50 (d, 1H), 6.91 (d, 2H), 7.30-7.48 (m, 6H), 7.70 (d, 2H).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Cl:5][C:6]1([C:9](=[O:16])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH2:8][CH2:7]1.II>O1CCCC1.[Zn]>[Cl:5][C:6]1([C:9]([OH:16])([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH2:3][CH:2]=[CH2:1])[CH2:8][CH2:7]1
Reactant: O=C(Cn1cncn1)C1(Cl)CC1
Reactant: C=CCBr
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CCC(O)(Cn1cncn1)C1(Cl)CC1
Reaction time: 24 h

Procedure:
A solution of 12. 1 g (0.1 mol) of allyl bromide and 16.65 g (0.09 mol) of 1-(1-chlorocyclopropyl)-2-(1,2,4-triazol-1-yl)-ethan-1-one in 50 ml of tetrahydrofuran are added dropwise at 20° C. under nitrogen atmosphere in the course of 0.5 hours to a stirred mixture of 7.2 g (0.11 mol) of zinc dust, 0.1 g of iodine and 50 ml of absolute tetrahydrofuran. When the addition has ended, stirring is continued for 24 hours at room temperature, the mixture is then concentrated by stripping off the solvent and treated with aqueous ammonium chloride solution. The resulting mixture is extracted several times using dichloromethane. The combined organic phases are dried over sodium sulphate and then concentrated by stripping off the solvent under reduced pressure. In this manner, 10.2 g (50% of theory) of (4-(1-chloro-cyclopropyl)-4-hydroxy-5-(1,2,4-triazol1-yl)-pent-1-ene are obtained in the form of a solid substance of melting point 75° to 76° C. ##STR40##
Reaction SMILES: [C:1]([O:5][C:6](=[O:65])[C@@H:7]([NH:13][C:14](=[O:64])[CH2:15][CH2:16][C@@H:17]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[NH:18][C:19](=[O:56])[CH2:20][CH2:21][C@@H:22]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:23][C:24](=[O:48])[CH2:25][CH2:26][CH2:27][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][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:79]1[C:84](=[O:85])[CH2:83][CH2:82][C:80]1=[O:81])=[N+](C)C)C>>[O:81]=[C:80]1[CH2:82][CH2:83][C:84](=[O:85])[N:79]1[O:11][C:10](=[O:12])[CH2:9][CH2:8][C@H:7]([NH:13][C:14](=[O:64])[CH2:15][CH2:16][C@@H:17]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[NH:18][C:19](=[O:56])[CH2:20][CH2:21][C@@H:22]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[NH:23][C:24](=[O:48])[CH2:25][CH2:26][CH2:27][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][C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:65]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
(S)-2-{(S)-4-tert-Butoxycarbonyl-4-[(S)-4-tert-butoxycarbonyl-4-(17-tert-butoxycarbonylheptadecanoylamino)butyrylamino]butyrylamino}pentanedioic acid 1-tert-butyl ester (2.8 g, 3.02 mmol) was activated with TSTU (1.0 g, 3.325 mmol) using the same method as described above, giving crude (S)-2-{(S)-4-tert-butoxycarbonyl-4-[(S)-4-tert-butoxycarbonyl-4-(17-tert-butoxycarbonylheptadecanoylamino)butyrylamino]butyrylamino}-pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl)ester. LCMS (electrospray): m/z=1024 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:23]=[CH:22][C:11]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)[O:6][CH:7]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:24][C:7]1[O:6][C:5]([C:8]2[CH:23]=[CH:22][C:11]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[N:4][C:3]=1[CH2:2][Cl:1]
Reactant: ClCc1coc(-c2ccc(Cn3cnc4ccccc43)cc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: ClCc1nc(-c2ccc(Cn3cnc4ccccc43)cc2)oc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A solution of 1-{4-[4-(chloromethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole (0.40 g, 1.24 mmol) in dry chloroform was treated with N-bromosuccinimide (NBS) (0.24 g, 1.36 mmol), stirred at room temperature for 1 h and concentrated in vacuo. The resultant residue was partitioned between CH2Cl2 and water. The organic phase was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. This residue was purified by column chromatography (silica, CH2Cl2:MeOH 98:2) to afford the title compound in 56% yield, identified by NMR and mass spectral analyses. 1H NMR (300 MHz, DMSO-d6): 8.43 (s, 1H), 7.93 (m, 2H), 7.59-7.76 (m, 1H), 7.47-7.53 (m, 1H), 7.45 (m, 2H), 7.10-7.31 (m, 2H), 5.60 (s, 2H), 4.65 (s, 2H). LCMS (ESI+) 402, 404 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH2:5][C@H:6]([CH2:11][C:12](=[O:22])[NH:13][C@H](C1C=CC=CC=1)C)[CH2:7][CH:8]([CH3:10])[CH3:9].O1CCCC1.N.[Na]>O>[CH3:1][O:2][C:3](=[O:23])[NH:4][CH2:5][C@H:6]([CH2:11][C:12](=[O:22])[NH2:13])[CH2:7][CH:8]([CH3:9])[CH3:10]
Reactant: COC(=O)NC[C@H](CC(=O)N[C@@H](C)c1ccccc1)CC(C)C
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)NC[C@H](CC(N)=O)CC(C)C
Yield: 60.5 %

Procedure:
A 2 l, four-necked flask, equipped with a mechanical stirrer, thermometer pocket and a liquid ammonia inlet, was charged with {(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)-methyl]pentyl}carbamic acid methyl ester (26) (25 g, 0.078 mole), tetrahydrofuran (175 ml), and water (25 ml). The reaction mixture was cooled to −40° to −60° C. and liquid ammonia (1000 ml) was added followed by addition of small pieces of sodium metal (7.2 g). The resultant reaction mixture was stirred vigorously for 4-10 hours until the ammonia had evaporated. Water (100 ml) was added to the reaction mass under N2 atmosphere at 5°-10° C., followed by separating the phases. The organic layer was separated and dried over anhydrous sodium sulphate and the solvent was stripped off. The residue was crystallized from diisopropyl ether to get 10.2 g (60% yield) of {(S)-2-carbamoylmethyl-4-methylpentyl)carbamic acid methyl ester with purity of 73% as measured by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[N:20]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[O:12]([C:9]1[CH:10]=[CH:11][C:6]([N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:19])[NH2:20])=[CH:7][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=N[O-]
Reactant: COC(=O)CNc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CN(N)c1ccc(Oc2ccccc2)cc1
Reaction time: 2 h

Procedure:
N-(4-Phenoxyphenyl)glycine methylester (Intermediate 75, 13.5 g, 0.0525 mol) was dissolved in a mixture of acetic acid (90 ml) and water (5 ml) and the solution was cooled to ~5° C. To this was added a solution of sodium nitrite (3,8 g, 0.55 mol) in water (10 ml) over 15 minutes. Stirring was continued for 2 hours and the reaction was cooled to ~0° C. Zinc dust (13.4 g, 0.2048 mol) was added over 30 minutes and the reaction stirred at 0°-5° C. for 2 hours before being poured into water (200 ml) and extracted with ethyl acetate (2×150 ml). The organic extract was washed with 8% sodium bicarbonate solution until effervescence had ceased, dried (MgSO4) and evaporated to give a brown semi-solid. This was triturated with ether/hexane (1:1) to recover starting material (6.5 g, 48%). The liquors were evaporated and purified by flash column chromatography on silica (Merck 9385; 250 g) eluting with ether-hexane (1:1) to give the title compound (Intermediate 76) as an off white solid (1.25 g, 9%) m.p 71°-73° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:2].[CH2:10]1[O:12][CH2:11]1>[OH-].[Na+]>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(O)cc1
Reactant: C1CO1
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc(OCCO)cc1

Procedure:
p-Ethylphenol (854 parts) is ethoxylated with ethylene oxide (348 parts) using sodium hydroxide (7 parts) as catalyst at 145° C. in a method similar to that used in Example 12 to give 2-(p-ethylphenoxy)ethanol m.p. 48°-49° C. (987 parts).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([O:21][CH:22]([CH3:24])[CH3:23])[CH:13]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4]1)[CH3:2].O.NN>C(O)C.[Pd]>[CH2:1]([N:3]1[C:7]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:21][CH:22]([CH3:23])[CH3:24])[CH:13]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCCC12CCN(c1ccc([N+](=O)[O-])c(OC(C)C)c1)C2
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN1CCCC12CCN(c1ccc(N)c(OC(C)C)c1)C2
Temperature: 80 °C
Yield: 101.1 %

Procedure:
A mixture of 250 mg of 1-ethyl-7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane, 450 mg of hydrazine hydrate and 40 mg of 10% palladium-on-carbon in 10 ml of ethanol is heated at 80° C. (bath) for 4 h 30 min. 450 mg of hydrazine hydrate are then added and the reflux is maintained for 1 h. The mixture is filtered and the filtrate is concentrated under vacuum, so as to obtain 230 mg of 4-(1-ethyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)aniline in the form of a brown oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[O:12])[CH2:4][CH2:3]1.[CH2:32]([N:35]=[C:36]=[O:37])[CH2:33][CH3:34]>ClCCl>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[CH2:14][NH:13][C:11](=[O:12])[C:10]1[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=[CH:28][C:9]=1[NH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][C:36]([NH:35][CH2:32][CH2:33][CH3:34])=[O:37])[CH2:3][CH2:4]1
Reactant: CCCN=C=O
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](N)CC2)cc1OC
Solvent: ClCCl
Product: CCCNC(=O)N[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (100 mg) in dichloromethane (3 mL) was added propyl isocyanate (21.8 mg), and the mixture was stirred for 2 hours at ambient temperature. After evaporation of the solvent, the residue was triturated with ethyl acetate to give N-(3,4-dimethoxybenzyl)-5-nitro-2-[trans-4-(3-propylureido)cyclohexylamino]benzamide as yellow powders (118 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11](O)=[O:12].C(OC(=O)C)(=O)C>O>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CO
Reactant: NCCCc1ccccc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=CNCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-Phenylproylamine (10 ml, 70.0 mmol) was added at 0° C. dropwise to formic acid (80 ml). Acetic acid anhydride (30 ml) was added dropwise to the reaction mixture. After the addition the reaction mixture was warmed to room temperature. It was stirred for 2.5 h. It was cooled to 0° C. Water (30 ml) was added dropwise. The reaction mixture was warmed to room temperature. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (300 ml). The organic phase was washed with saturated sodium chloride solution (2×150 ml) and with saturated sodium hydrogen carbonate solution (200 ml). It was dried over magnesium sulfate. The solvent was removed in vacuo to furnish 5.82 g of N-(3-phenylpropyl)formamide, which was used without further purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11](Br)=[CH:12][C:7]=2[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][C:4]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:25][CH3:26])[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[C:38]([O:42][CH2:43][CH3:44])(=[O:41])[CH2:39][SH:40].Cl>O.CN(C=O)C>[O:1]=[S:2]1(=[O:31])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([S:40][CH2:39][C:38]([O:42][CH2:43][CH3:44])=[O:41])=[CH:12][C:7]=2[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][C:4]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:25][CH3:26])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)O)cc2S(=O)(=O)C1
Reactant: CCOC(=O)CS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(SCC(=O)OCC)c(OCC(=O)O)cc2S(=O)(=O)C1
Yield: 100.2 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 9; 50 mg, 0.098 mmol) and Cs2CO3 (51 mg, 0.15 mmol) were added to DMF (2.0 ml) and ethyl thioglycolate (0.02 ml, 0.15 mmol) was added. The reaction mixture was subjected to microwave irradiation in a Smith Synthesiser at 150° C. for 5 min. The reaction mixture was diluted with water (100 ml), made acidic with HCl (1 M), extracted with DCM (3×10 ml) and the collected organic layers were dried (MgSO4) to give the crude title compound (54 mg). M/z 550.2.
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Na].CCOCC>[CH2:11]([O:18][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:8][CH2:9][NH2:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: N#C/C=C/C1CCCCC1
Agent: [Na]
Solvent: CCOCC
Product: NCCC(OCc1ccccc1)C1CCCCC1
Reaction time: 4 h

Procedure:
The foregoing mixture of 2-cis and 2-trans-3-cyclohexylacrylonitrile (26.50 g) was dissolved in sodium benzylate solution prepared from sodium (0.65 g) and benzyl alcohol (90 ml) and the resulting solution heated on the steam-bath with stirring for 4 hours then set aside at room temperature for 18 hours. The resulting dark solution was diluted with ether and washed with water. The ethereal extract was dried (Na2SO4), the solvent removed in vacuo, and the residue unchanged nitrile removed by distillation under high vacuum. The residual material was taken up in ether, decolorised with activated charcoal, filtered, and the solvent removed in vacuo. The residual yellow syrup (ca. 22 g) was dissolved in dry ether (40 ml) and added dropwise at +5° to a stirred suspension of lithium aluminium hydride (3.4 g) in dry ether (125 ml). After 1 hour at room temperature, the reaction mixture was treated with water and the resulting gel filtered through Celite. The yellow organic phase was separated, dried (MgSO4), the solvent removed in vacuo, and the residual orange oil distilled, giving 3-benzyloxy-3-cyclohexylpropylamine as a colourless viscous oil, b.p. 120°-5°/0.05-0.06 mm.