Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45]C)=[C:41]([C:47]([O:49]C)=[O:48])[CH:40]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([C:26]([O:28]C)=[O:27])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:51]>>[BrH:51].[BrH:51].[CH2:1]([N:8]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([C:47]([OH:49])=[O:48])[CH:40]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:26]([OH:28])=[O:27])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(CCN(CCCCCCN(CCc2ccc(OC)c(C(=O)OC)c2)Cc2ccccc2)Cc2ccccc2)ccc1OC
Agent: Br
Product: O=C(O)c1cc(CCN(CCCCCCN(CCc2ccc(O)c(C(=O)O)c2)Cc2ccccc2)Cc2ccccc2)ccc1O

Procedure:
A mixture of 1.56 g. (0.0023 m.) of N,N'-dibenzyl-N,N'-bis[2-(3-carbomethoxy-4-methoxyphenyl)-ethyl]-hexamethylenediamine and 40 ml. of 48% aqueous hydrobromic acid is refluxed for four hours. The cooled reaction mixture is filtered to give N,N'-dibenzyl-N,N'-bis[2-(3-carboxy-4-hydroxyphenyl)-ethyl]-hexamethylenediamine dihydrobromide. The latter is hydrogenated with palladium-on-carbon as described in Example 1 to yield N,N'-bis[2-(3-carboxy-4-hydroxyphenyl)-ethyl]-hexamethylenediamine dihydrobromide. The free base obtained from this dihydrobromide (0.8 g., 0.0018 m.) is added to an ice cold solution of 40 ml. of 1M borane in tetrahydrofuran (0.04 m.) while stirring under nitrogen. The temperature is maintained at 0°C. for 20 hours, the solution is then refluxed for one hour and concentrated in vacuo. Several portions of methanol are added, the solution is concentrated and the residue is dissolved in ethanol and filtered. Sulfuric acid is added to pH 2.0 to give N,N'-bis[2-(4-hydroxy-3-hydroxymethylphenyl)-ethyl]-hexamethylenediamine sulfate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O>ClCCl>[Br:11][C:7]1[C:5]([NH2:6])=[CH:4][C:3]([O:9][CH3:10])=[C:2]([F:1])[CH:8]=1
Reactant: COc1cc(N)ccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1cc(N)c(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 4-fluoro-3-methoxyaniline (9.87 g, 70 mmol) and N-bromosuccinimide (12.46 g, 70 mmol) in dichloromethane (150 ml) was stirred at room temperature for 1 h (exothermic). The reaction mixture was evaporated in vacuo to give a dark slurry which was chromatographed on silica gel (˜350 g) using a gradient elution 20-50% ethyl acetate in hexane to give the title compound as a brown solid (12.70 g, 82%).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=[O:25])[NH:18][CH:19]([C:23]#[N:24])[CH:20]1[CH2:22][CH2:21]1)C1C=CC=CC=1.[CH3:27][C:28]([OH:30])=[O:29].C1CCCCC1>CCOC(C)=O.[Pd]>[C:28]([OH:30])(=[O:29])[CH3:27].[C:23]([CH:19]([NH:18][C:17]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[NH2:10])=[O:25])[CH:20]1[CH2:21][CH2:22]1)#[N:24]
Reactant: N#CC(NC(=O)C1CCCCC1NC(=O)OCc1ccccc1)C1CC1
Agent: [Pd]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#CC(NC(=O)C1CCCCC1N)C1CC1
Reaction time: 0.75 h

Procedure:
To a solution of 2-[(1-cyano-1-cyclopropyl-methyl)-carbamoyl]-cyclohexyl-carbamic acid benzyl ester (0.15 g, 0.42 mmol) in 50 ml EtOAc with 1% HOAc (v/v) is added Pd/C (10%) (0.05 g) carefully under nitrogen. The mixture is degassed completely before the reaction flask is filled with H2 through a balloon. The reaction mixture is stirred for 45 minutes. TLC showed that the starting material has disappeared. The reaction mixture is filtered through Celite. The filtrate is concentrated to give a yellow oil. Yield: 0.17 g, 100%. The isolated cis- and trans-forms of the product are obtained by starting from the corresponding cis- or trans-form of the cyclohexane derivative.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O.CCOC(C)=O>[N:15]([CH2:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)=[O:4])=[N+:16]=[N-:17]
Reactant: O=C(CCl)c1cccc2cccnc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC(=O)c1cccc2cccnc12
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-1-quinolin-8-yl-ethanone (5.85 g, 28.5 mmol) in DMSO (60 mL), as prepared in the last step, was added NaN3 (2.2 g, 33.9 mmol). After 2 hours, the reaction was diluted with EtOAc (250 mL) and washed with H2O (3×100 mL). The organic phase was washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. Purification via SiO2 chromatography (20% EtOAc/hexanes) affored the product as a pale yellow solid (4.95 g). 1H NMR (300 Hz, CDCl3) δ 9.0-8.97 (m, 1H), 8.26-8.22 (m, 2H), 8.04-8.02 (m, 1H), 7.68-7.63 (m, 1H), 7.52-7.48 (m, 1H), 5.12 (s, 2H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:28]=[C:29]([OH:31])[CH:30]=1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[C:32](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: O=C([O-])[O-]
Reactant: O=C(OCc1ccccc1)c1cc(O)cc(OCCCCCCCCC2OCCO2)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cc(OCCCCCCCCC2OCCO2)cc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.8 %

Procedure:
To an ice-cooled solution of benzyl 3-((8-(1,3-dioxolan-2-yl)octyl)oxy)-5-hydroxybenzoate (1.94 g, 4.53 mmol) in dimethyl formamide (25 mL), was added potassium carbonate (0.93 g, 6.75 mmol) followed by iodomethane (0.42 mL, 6.75 mmol). The reaction mixture was allowed to warm to room temperature over 16 hours and stood at room temperature for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound (1.76 g, 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=[C:16]([C:17]#[N:18])[C:9]=23)[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[I:37]I>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[C:15]([I:37])=[C:16]([C:17]#[N:18])[C:9]=23)[CH:7]=1
Reactant: II
Reactant: COc1ccc(F)cc1-c1ccnc2c1c(C#N)cn2COCC[Si](C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1ccnc2c1c(C#N)c(I)n2COCC[Si](C)(C)C
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 248B (0.7 g, 1.76 mmol) in tetrahydrofuran (50 mL) was cooled to −75° C. and treated dropwise with 2N lithium diisopropylamide in tetrahydrofuran (1.7 mL, 3.40 mmol). The mixture was stirred at −75° C. for 30 minutes and iodine (0.85 g, 3.52 mmol) in 2.5 mL tetrahydrofuran was added. The mixture was slowly brought to room temperature and quenched with aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (twice). The organic layers were concentrated and purified by column chromatography (Combi Flash Rf) (silica gel, 30% ethyl acetate in hexane) to afford the title compound. MS (ESI+) m/z 524 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[S:11][C:12]3[N:13]=[C:14]([NH2:23])[N:15]=[C:16](S(C)(=O)=O)[C:17]=3[N:18]=2)[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:47]=[CH:46][C:35]([O:36][CH2:37][C:38]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:39])=[CH:34][CH:33]=1>O1CCOCC1>[NH2:23][C:14]1[N:15]=[C:16]([N:43]2[CH2:44][CH2:45][N:40]([C:38](=[O:39])[CH2:37][O:36][C:35]3[CH:46]=[CH:47][C:32]([Cl:31])=[CH:33][CH:34]=3)[CH2:41][CH2:42]2)[C:17]2[N:18]=[C:10]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:9])[S:11][C:12]=2[N:13]=1
Reactant: CC(c1ccc(F)cc1)c1nc2c(S(C)(=O)=O)nc(N)nc2s1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(c1ccc(F)cc1)c1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Temperature: 70 °C
Yield: 67.8 %

Procedure:
To a solution of 2-(1-(4-fluorophenyl)ethyl)-7-(methylsulfonyl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.14 mmol) and triethylamine (30 μl, 0.21 mmol) in dioxane (1 ml) was added 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (51 mg, 0.21 mmol). The reaction mixture was heated at 70° C. for 3 hours. After cooling down to room temperature, the volatiles were removed under reduced pressure. The crude residue was purified by chromatography on silica gel (CH2Cl2/MeOH 70:1) furnishing the title compound as a white solid (50 mg, 67%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[I-].[Mg+2].[I-].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:23][CH3:24])=[C:14]([CH:16]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]2=[O:22])[CH:15]=1>ClCCl.CO>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:23][CH3:24])=[C:14]([CH:16]2[C:20](=[O:21])[CH:19]3[CH:18]([CH:5]4[O:1][CH:2]3[CH:3]=[CH:4]4)[C:17]2=[O:22])[CH:15]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C=CC1=O
Reactant: c1ccoc1
Agent: [I-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc(Br)cc1C1C(=O)C2C3C=CC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Furan (4.0 ml, 55.0 mmol) and magnesium iodide (1.00 g, 3.6 mmol) are added to a solution of 2-(5-bromo-2-ethylphenyl)cyclopent-4-ene-1,3-dione (5.0 g, 17.9 mmol) in dichloromethane (20 ml) and the mixture is stirred at room temperature for 3 days. A further quantity of furan (1.3 ml, 17.8 mmol) is added and stirring continued for 18 hours, and then a further quantity of furan (1.3 ml, 17.8 mmol) is added and the mixture is stirred for 48 hours, and then allowed to stand at room temperature for 5 days. The reaction mixture is dissolved in methanol and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(5-bromo-2-ethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-8-en-3,5-dione.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]4[CH2:20][C@H:19]4[CH:21]=O)[CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:23]=1.[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.[BH4-]>C(Cl)Cl>[N:30]1([CH2:29][CH2:28][CH2:27][NH:26][CH2:21][C@@H:19]2[CH2:20][C@H:18]2[CH2:17][N:14]2[CH2:15][CH2:16][N:11]([C:10]3[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:25])([F:24])[F:1])=[CH:23][C:7]=4[S:8][CH:9]=3)[CH2:12][CH2:13]2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: NCCCn1ccnc1
Reactant: O=C[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Agent: [BH4-]
Solvent: ClCCl
Product: FC(F)(F)c1ccc2c(N3CCN(C[C@@H]4C[C@H]4CNCCCn4ccnc4)CC3)csc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (1R,2R)-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarbaldehyde (36.8 mg, 0.1 mmol) and 1-(3-aminopropyl)imidazole (0.0235 ml, 2.1 mmol) in anhydrous methylene chloride (3 ml) is added to a solution of polymer supported borohydride (0.863 g, 3 mmol) soaked in anhydrous methylene chloride (4 ml). This mixture was shook on an orbital shaker at room temperature overnight. The reaction was then quenched with water (2 ml) and products extracted with ethyl acetate (10 ml), then washed with brine, dried with sodium sulfate, and concentrated in vacuo. Silica gel chromatography eluted with methylene chloride/methanol (95:5) yielded the pure title compound, (3-Imidazol-1-yl-propyl)-{(1R,2R)-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropylmethyl}-amine as verified by NMR and LC/MS, yielding 36.2 mg, 76%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[N:14]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[CH2:27]([N:29]([CH2:30][CH3:31])[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[N:14]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1)[CH3:28]
Reactant: CCNCC
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(I)cc4)no3)cc2C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(-c2noc(-c3cc(C)n(Cc4ccc(C)cc4)n3)n2)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 19 %

Procedure:
A mixture of 3-(4-iodophenyl)-5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazole (Example 13, 250 mg, 0.55 mmol), diethylamine (113 μl, 1.1 mmol), sodium tert-butylat (74 mg, 0.77 mmol), palladium(II) acetate (25 mg, 0.11 mmol), 2-(dicyclohexylphosphino)-1,1′-biphenyl (19 mg, 0.06 mmol) and toluene (3 ml) was stirred at 80° C. for 15 h. The reaction mixture was cooled and water (100 mL) and ethyl acetate (100 mL) was added. The layers were separated and the organic layer was washed with water and brine and then dried with magnesium sulfate. The solvent was evaporated and the residue was purified, first using preparative HPLC, then via flash chromatography (silica, cyclohexane/ethyl acetate, 10:1→1:1) to afford the title compound as a white solid (42 mg, 19%): 1H NMR (400 MHz, CDCl3) 8.03 (d, 2H), 7.12 (d, 2H), 7.07 (d, 2H), 6.78 (s, 1H), 6.71 (d, 2H), 5.40 (s, 2H), 3.41 (quart, 4H), 2.32 (s, 3H), 2.25 (s, 3H), 1.20 (t, 6H); ES-MS m/z 402 (MH)+, HPLC RT (Method E) 2.68 min.
Reaction SMILES: O=CCCCC([O-])=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:32][C:31]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.[OH-].[Na+]>FC(F)(F)C(O)=O.O1CCCC1.O.C(OCC)(=O)C>[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:32][C:31]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)CCCCc1ccc(-c2ccc(C)cc2)s1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: O=CCCCC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2ccc(CCCCC(=O)O)s2)cc1
Reaction time: 96 h

Procedure:
To a solution of ethyl 5-5—(4-methylphenyl) thiophen-2-yl]-5-oxovalerate (4.50 g) in trifluoroacetic acid (7.66 ml) was added triethylsilane(5.7 ml) at room temperature, and the mixture was stirred for 4 days. To the reaction mixture was added ethyl acetate, and the mixture was made alkaline with saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:9) to give crude ethyl 5-[5—(4-methylphenyl)thiophen-2-yl]valerate. To a solution of the crude ethyl 5-[5—(4-methylphenyl)thiophen-2-yl]valerate in tetrahydrofuran (50 ml) was added 1N sodium hydroxide (20 ml) at room temperature, and the mixture was stirred for 24 hours. To the reaction mixture was added water, and the mixture was washed with diethylether. The aqueous layer was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to precipitate crystals, which were collected by filtration and washed with hexane to give 5-[5—(4-methylphenyl)-thiophen-2-yl]valeric acid (2.88 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=2[NH:12][C:11](=[S:31])[CH2:10][N:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(F)c(F)cc2N1
Product: Fc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=S)N2

Procedure:
5-(2-chlorophenyl)-1,3-dihydro-7,8-difluoro-2H-1,4-benzodiazepin-2-thione (IImm) was prepared by reacting 0.003 moles of 5-(2-chlorophenyl)-1,3-dihydro-7,8-difluoro-2H-1,4-benzodiazepin-2-one (Imm) with Lawesson's reagent in a manner analogous to Example 38.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@H:45]([O:48][CH2:49][CH3:50])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:49]([O:48][C@H:45]1[CH2:44][CH2:43][C@H:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:21]3[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([CH2:9][P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:11][C:12]=4[O:28][CH3:29])[N:22]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH2:47][CH2:46]1)[CH3:50]
Reactant: CCO[C@H]1CC[C@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OCC)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (40.0 mg, 0.0944 mmol) and 7-amino-4-(trans-4-ethoxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 166B). 1H NMR (CDCl3, 400 MHz): δ=1.19-1.32 (m, 9H), 1.34-1.46 (m, 2H), 1.58-1.69 (m, 2H), 1.92 (d, J=12.88 Hz, 2H), 2.23 (d, J=10.11 Hz, 2H), 2.51 (t, J=12.00 Hz, 1H), 3.14-3.21 (m, 2H), 3.22 (s, 3H), 3.31-3.43 (m, 1H), 3.59 (q, J=6.99 Hz, 2H), 3.93 (s, 3H), 3.99-4.12 (m, 4H), 4.40 (s, 2H), 6.89 (d, J=8.08 Hz, 1H), 6.94 (s, 1H), 7.34 (d, J=8.59 Hz, 1H), 7.70 (br. s., 1H), 8.28 (d, J=7.58 Hz, 1H), 8.39 (br. s., 1H), 8.62 (d, J=8.59 Hz, 1H), 10.54 (br. s., 1H). MS (ES+): m/z 706.26 [MH+] (TOF, polar).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[CH:11]=[CH:10]2.[C:19](=[O:21])=[O:20]>CCCCCC.C1COCC1>[CH3:18][O:17][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:19]([OH:21])=[O:20])[CH:8]=2)[N:13]=1
Reactant: COc1ccc2cc(Br)ccc2n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2cc(C(=O)O)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (63 cm3 of a 1.6M solution in hexane) was added dropwise to a stirred solution of 6-bromo-2-methoxyquinoline (20 g) in THF (250 cm3) at -70° under nitrogen. After 0.5 hours, solid carbon dioxide (50 g) was added, the solution was allowed to warm to room temperature, and volatile material was removed in vacuo. The residue was partitioned between dichloromethane (100 cm3) and water (100 cm3), the aqueous phase was separated and acidified to pH 3.5 with 5M hydrochloric acid. The precipitated solid was filtered and dried (14.2 g). Recrystallisation of a small portion from isopropanol afforded 2-methoxyquinoline-6-carboxylic acid, m.p. 220°-222°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])=[CH:6][C:5]=1[CH3:16])([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:29].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:29].[ClH:29].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])=[CH:6][C:5]=1[CH3:16]
Reactant: Cc1cc(NCCC(C)O)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1cc(NCCC(C)O)ccc1N

Procedure:
The 4-(4-nitro-3-methylphenylamino)butan-2-ol (31) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH:22]=2)[C:18](OC)=[O:19])(=[O:12])=[O:11])[CH2:6][CH2:5]1>CO>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH:22]=2)[C:18]([NH:1][NH2:2])=[O:19])(=[O:12])=[O:11])[CH2:6][CH2:5]1
Reactant: NN
Reactant: COC(=O)c1cncc(S(=O)(=O)N2CCN(C)CC2)c1
Solvent: CO
Product: CN1CCN(S(=O)(=O)c2cncc(C(=O)NN)c2)CC1
Yield: 79.9 %

Procedure:
Hydrazine (11.78 mg, 0.367 mmol) was added to the methyl 5-((4-methylpiperazin-1-yl)sulfonyl)nicotinate (55 mg, 0.184 mmol) in methanol (10 mL) and refluxed for overnight. The reaction was monitored by TLC, after completion of the reaction, Solvent was removed by vacuum and then compound was purified by column chromatography (3% methanol/DCM) afforded the title compound 5-((4-methylpiperazin-1-yl)sulfonyl)nicotinohydrazide (45 mg, 0.147 mmol, 80% yield) as a solid. 1HNMR (400 MHz, CDCl3): δ 9.07 (s, 1H), 9.02 (s, 1H), 8.33 (s, 1H), 7.46 (bs, 1H), 4.09 (bs, 2H), 3.05 (m, 4H), 2.43 (m, 4H), 2.21 (s, 3H). ESI-MS: 300.1 [M+H]+
Reaction SMILES: NC(CCCCCCCCC(N)CCC)CCC.C(C1CC=CCCC=CCC(CCC)N=N1)CC.[CH2:37]([CH:41]1[CH2:52][CH:51]=[CH:50][CH2:49][CH2:48][CH:47]=[CH:46][CH2:45][CH:44]([CH2:53][CH2:54][CH2:55][CH3:56])[N:43]=[N:42]1)[CH2:38][CH2:39][CH3:40]>>[NH2:42][CH:41]([CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH:44]([NH2:43])[CH2:53][CH2:54][CH2:55][CH3:56])[CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCC1CC=CCCC=CCC(CCCC)N=N1
Agent: CCCC(N)CCCCCCCCC(N)CCC
Agent: CCCC1CC=CCCC=CCC(CCC)N=N1
Product: CCCCC(N)CCCCCCCCC(N)CCCC
Yield: 62.2 %

Procedure:
If there is used in the manner described under (a), instead of 942 g (3.79 mols), of 3,12-dipropyl-1,2-diaza-1,5,9-cyclododecatriene, 208 g (0.75 mol) of 3,12-dibutyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, the procedure otherwise being the same, there is obtained as the main fraction 132.8 g (62.3% of theory) of 5,14-diaminooctadecane as colourless oil (b.p. 149° C./0.001 Torr; nD20 =1.4593; IR (liquid) inter alia bands at 3333, 3267 and 1613 cm-1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:33]([F:36])([F:35])[F:34])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)=[O:16])[C:10](=[O:32])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:33]([F:36])([F:34])[F:35])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)=[O:16])[C:10](=[O:32])[CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CC2)n2ccc(-c3cc(Cl)ccc3C(F)(F)F)cc2=O)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(NC(=O)C(CC2CC2)n2ccc(-c3cc(Cl)ccc3C(F)(F)F)cc2=O)cc1

Procedure:
200 mg (purity 48%, 0.19 mmol) of methyl 4-[(2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoyl)amino]benzoate (racemate) (Example 6.1G) were hydrolysed with lithium hydroxide according to General Method 3. Yield: 46 mg (49% of theory)