Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)[CH2:2][CH3:3].[CH3:13][O:14][C:15]1[CH:26]=[C:25]2[C:18]([NH:19][CH:20]=[C:21]2[CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1.[BH4-].[Na+]>CCO>[CH3:13][O:14][C:15]1[CH:26]=[C:25]2[C:18](=[CH:17][CH:16]=1)[NH:19][CH:20]=[C:21]2[CH2:22][CH2:23][NH:24][CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: CCCOc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCOc1cccc(CNCCc2c[nH]c3ccc(OC)cc23)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Combine 3-propoxybenzaldehyde (14.05 g, 0.0856 mole) and 5-methoxytryptamine (13.64 g, 0.0717 mole) in 390 mL absolute EtOH. Add molecular sieves (19.2 g) and heat the suspension to reflux. After 4 hours, cool to room temperature and add NaBH4 (37.32 g, 0.2146 mole) in 3 portions. Stir the mixture for 1 hour at room temperature, filter, evaporate the filtrate to a mass of about 100 g, add water and dichloromethane. After separation, wash the aqueous phase with dichloromethane, combine the organic layers, dry over MgSO4, filter, evaporate the solvent in vacuo to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[BH4-].[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([C:9]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ccccc2)c(CO)c1
Reaction time: 6 h

Procedure:
450 g of 3-nitro-6-(phenylthio)-benzaldehyde are suspended in 4 litres of ethanol and treated portionwise with 111 g of sodium borohydride. The mixture is stirred for a further 6 hours. The mixture is then diluted with 4 litres of water and extracted with ether. The organic solution is washed successively with water and aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated under reduced pressure. The crude product is recrystallised from benzene/petroleum ether. There is obtained 3-nitro-6-(phenylthio)-benzyl alcohol of melting point 104°-107° C.
Reaction SMILES: C(N(CC)CC)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[C:23]([NH:42][C:43]1[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=1[C:45]([OH:47])=O)(=[O:41])[CH2:24][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][CH3:40].[CH3:52][N:53]([CH3:58])[CH2:54][CH2:55][CH2:56][NH2:57]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:52][N:53]([CH3:58])[CH2:54][CH2:55][CH2:56][NH:57][C:45]([C:44]1[CH:48]=[CH:49][CH:50]=[CH:51][C:43]=1[NH:42][C:23](=[O:41])[CH2:24][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][CH3:40])=[O:47]
Reactant: CN(C)CCCN
Reactant: CCCCCCCCCCCCCCCCCC(=O)Nc1ccccc1C(=O)O
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1ccccc1C(=O)NCCCN(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.44 ml) and diphenylphosphinic chloride (0.48 ml) were added to a suspension of 2-(octadecanoylamino)benzoic acid (0.85 g) in methylene chloride (10 ml). After being stirred for 3 hours at 0° C., the mixture, with N,N-dimethyl-1,3-propanediamine (0.33 ml) added thereto, was stirred for 44 hours at room temperature. The reaction mixture was then diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 20 g, chloroform-methanol), thereby yielding 0.53 g of N-{2-{N-{3-(dimethylamino)propyl}carbamoyl}phenyl}octadecaneamide and 0.37 g of the aimed compound as colorless crystals.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([C@H:27]1[C@@H:32]([NH:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:31]2[CH2:39][C@@H:28]1[CH2:29][CH2:30]2)=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([C@H:27]1[C@@H:32]([N:33]([C:17](=[O:19])[CH2:16][C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=3[S:13](=[O:14])(=[O:15])[N:12]=2)[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:31]2[CH2:39][C@@H:28]1[CH2:29][CH2:30]2)=[O:26])[CH3:23]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.216 g, 0.649 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). (1S,2R,3S,4R)-3-(3-Methyl-butylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.164 g, 0.649 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g, 0.681 mmol). Then N-methylmorpholine (0.138 g, 1.36 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 4 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-[[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a light yellow oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C25H36N4O7S2 568.2, found 569.5 [M+H+].
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][C@H:28]1[CH2:33][C:32]2[C:34]([N:39]3[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]3)=[CH:35][CH:36]=[C:37]([CH3:38])[C:31]=2[O:30][CH2:29]1>CN(C)C=O>[NH3:2].[CH3:38][C:37]1[C:31]2[O:30][CH2:29][C@@H:28]([NH:27][C:9](=[O:11])[C:8]3[CH:7]=[CH:6][C:5]([C:3]([N:2]([CH3:1])[CH3:14])=[O:4])=[CH:13][CH:12]=3)[CH2:33][C:32]=2[C:34]([N:39]2[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]2)=[CH:35][CH:36]=1
Reactant: CN(C)C(=O)c1ccc(C(=O)O)cc1
Reactant: Cc1ccc(N2CCN(C)CC2)c2c1OC[C@@H](N)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(C)CC2)c2c1OC[C@@H](NC(=O)c1ccc(C(=O)N(C)C)cc1)C2
Product: N
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
4-(Dimethylaminocarbonyl)benzoic acid (described in: Jurewicz, A.T ; U.S. Pat. No. 3,607,918, 1971) (38 mg, 0.20 mmol) and 1,1′-carbonyldiimidazole (34 mg, 0.21 mmol) were dissolved in dry N,N-dimethylformamide (4 mL) and stirred at 75° C. for 1.5 h. The reaction mixture was cooled to room temperature and a solution of (S)-3-amino-8-methyl-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (49 mg, 0.19 mmol) in dry N,N-dimethylformamide (5 mL) was added. The reaction mixture was stirred at 50° C. for 14 h and the solvent was evaporated in vacuo giving 120 mg of a crude product. Purification by preparative TLC using chloroform/ methanol/conc. NH3 (95:5:0.5) as the eluent afforded 40 mg (48% yield) of the title compound as a white foam: EIMS (70 eV) m/z (relative intensity) 436 (26, M+); [α]21D−9° (c 0.20, chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][C@H:17]([CH3:23])[C:18]([CH3:22])([CH3:21])[C:19]#[N:20].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][C@@H:17]([C:18]([C:19]#[N:20])([CH3:22])[CH3:21])[CH3:23])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: C[C@@H](N)C(C)(C)C#N
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C(C)(C)C#N
Temperature: 100 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (250 mg, 0.911 mmol) and (R)-3-amino-2,2-dimethylbutanenitrile hydrochloride (165 mg, 0.408 mmol) in DMF (10 mL) taken in a pressure tube (25 mL) was added DIPEA (0.477 mL, 2.73 mmol) at rt. The resulting reaction mixture was heated 100° C. and stirred for overnight. Reaction was monitored by LCMS. Reaction mass was quenched with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layer was dried and concentrated under reduced pressure to get crude as brown colored oil. The crude was purified by combiflash using 24 g silicycle column eluted with 50% EA in hexane. The fractions were concentrated under reduced pressure to get (R)-6-bromo-4-((3-cyano-3-methylbutan-2-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (165 mg, 0.408 mmol, 44.7% yield) as pale brown solid. 1HNMR (400 MHz, DMSO-d6) δ ppm: 11.16-11.13 (d, J=9.6 Hz, 1H), 8.32 (s, 1H), 7.96-7.93 (d, J=13.2 Hz, 2H), 7.92 (bs, 2H), 7.22-7.21 (d, J=1.6 Hz, 2H), 4.43-4.39 (q, J=6.4, 3.6 and 6.4 Hz, 1H), 1.43-1.35 (m, 9H). HPLC purity: Column: Sunfire C18 (4.6×150 mm, 3.5μ, Buffer: 0.05% TFA in H2O pH 2.5, Solvent A: Buffer: CH3CN (95:5). Solvent B: Buffer: CH3CN (5:95). Time: 0-10, 12-100, 15-100 min, Flow: 1.0 mL/min Retention Time: 9.68: Purity: 91.94%. LCMS Purity: Column: Purospher@star RP-18 (4×55) mm, 3 μm. Buffer: 20 mM NH4OAc in water Mobile Phase A: Buffer: CH3CN (90:10). Solvent B: Buffer: CH3CN (10:90).Flow: 2.5 mL/min, Time: 0-0, 2-100, 2.5-100, 3.0-0 min. Retention Time: 1.688 min. Purity: 91.5% (m/z=348.2 M-2).
Reaction SMILES: [C:1]([CH:6]1[CH:10]2[O:11][C:12](=[O:22])[CH:13]3[CH:14]([C:15]([O:17]C(C)(C)C)=[O:16])[CH:7]1[CH2:8][CH:9]23)(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(C)C=CC=CC=1.C(OC(C)(C)C)=O>C(O)=O>[C:1]([CH:6]1[CH:10]2[O:11][C:12](=[O:22])[CH:13]3[CH:14]([C:15]([OH:17])=[O:16])[CH:7]1[CH2:8][CH:9]23)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)C1C2CC3C1OC(=O)C3C2C(=O)OC(C)(C)C
Agent: CC(C)(C)OC=O
Solvent: Cc1ccccc1
Solvent: O=CO
Product: C=C(C)C(=O)C1C2CC3C1OC(=O)C3C2C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
In 80 g of formic acid was dissolved 20.0 g of the methacrylate obtained in Example 1-1-1. The solution was stirred at room temperature overnight. Toluene was added to the reaction solution, from which formic acid and tert-butyl formate were azeotroped off. Recrystallization from hexane yielded 14.7 g of the target compound (yield 89%).
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([CH3:33])[CH:26]=[CH:25][C:24]([S:27]([N:30]=[C:31]=[O:32])(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[C:21]1([CH3:33])[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:31]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:32])(=[O:28])=[O:29])=[CH:25][CH:26]=1
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCCCC/C=C(\c2ccccc2)c2cccnc2)cc1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (2.0 g, 7.4 mmoles) was dissolved in methylene chloride (20 ml), and p-toluenesulfonyl isocyanate (1.5 g, 7.6 mmoles) was added to the solution. The mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using isopropyl ether-ethyl acetate (1:1) as the developing solvent. Recrystallization of the product from ethyl acetate gave 1-(p-toluenesulfonyl)aminocarbonyloxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (2.1 g, 60%) (Compound Id-29).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:26][OH:27])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NCC(=O)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(NCC(=NO)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.1 %

Procedure:
To a solution of 3.38 g of N-[2-(3,5-dichloropyridin-2-yl)-2-oxoethyl]-2-(trifluoromethyl)benzamide and 0.934 g of hydroxylamine hydrochloride in 20 ml of ethanol, 1.10 g of sodium acetate was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 40 ml of water and extracted with ethyl acetate (20 ml×2), the resulting organic layers were combined, washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 2:8 to 4:6) as the eluent to obtain 1.90 g of the desired product as white crystals.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17]>C(O)C>[CH3:15][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:9])=[O:10])[N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1
Reactant: NNc1ccccn1
Reactant: CC(=O)Cc1nc2ccccc2c(=O)o1
Solvent: CCO
Product: Cc1cc(Nc2ccccc2C(=O)O)n(-c2ccccn2)n1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
A solution of 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (68.2 g, 0.34 mol) and 2-hydrazinopyridine (37.1 g, 0.34 mol) in ethanol (500 mL) was heated under reflux for 1 hour. After the solution was cooled to room temperature, the resulting crude crystals were filtered. The crystals were washed with ethanol and air-dried to give the title compound (50.2 g, 51% yield).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[O:8][C@H:7]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=O.[NH2:23][CH2:24][CH2:25][CH2:26][NH2:27]>>[NH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH:7]1[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[O:8]1
Reactant: NCCCN
Reactant: CCCCC[C@H]1O[C@H]1C/C=C\CCCCCCCC(=O)OC
Product: CCCCCC1OC1CC=CCCCCCCCC(=O)NCCCN

Procedure:
Derivative 17 was prepared from methyl vernolate and 1,3-diaminopropane according to the procedure described in Example 1(f) and shown in Scheme 14.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[N:7]=[C:6]([CH3:20])[C:5]=2[C:21](O)=[O:22])[CH2:3][CH2:2]1.Cl.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:36][CH2:35][CH2:34][C@H:33]2[CH2:37][OH:38])[CH2:28][CH2:27]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:10]=[CH:11][C:12]([O:15][C:16]([F:18])([F:19])[F:17])=[CH:13][CH:14]=3)[N:7]=[C:6]([CH3:20])[C:5]=2[C:21]([N:26]2[CH2:27][CH2:28][CH:29]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[CH2:37][OH:38])[CH2:30][CH2:31]2)=[O:22])[CH2:2][CH2:3]1
Reactant: Cc1nn(-c2ccc(OC(F)(F)F)cc2)c(C2CC2)c1C(=O)O
Reactant: OC[C@@H]1CCCN1C1CCNCC1
Agent: Cl
Product: Cc1nn(-c2ccc(OC(F)(F)F)cc2)c(C2CC2)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
The title compound was prepared from 5-cyclopropyl-3-methyl-1-(4-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanoldihydrochloride (Example 161A]) in direct analogy to the general procedure used in example 150. MS: 493.2 (MH+).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17]>>[CH3:13][O:12][C:11]1[C:2](/[CH:17]=[CH:16]/[C:15]([O:19][CH3:20])=[O:18])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([CH3:14])[CH:5]=[CH:4]2
Reactant: COc1ccc2nc(C)ccc2c1Br
Reactant: C=CC(=O)OC
Product: COC(=O)/C=C/c1c(OC)ccc2nc(C)ccc12
Yield: 71 %

Procedure:
The title compound was prepared from 5-bromo-6-methoxy-2-methylquinoline (6b) and methyl acrylate using methods as described in the literature for similar compounds (Frank et al., 1978) in 71% yield. 1H NMR (DMSO-d6, HMDSO), δ: 2.63 (3H, s); 3.76 (3H, s); 4.01 (3H, s); 6.71 (1H, d, J=15.5 Hz); 7.43 (1H, d, J=8.5 Hz); 7.64 (1H, d, J=8.8 Hz); 8.02 (1H, d, J=8.8 Hz); 8.16 (1H, d, J=15.5 Hz); 8.42 (1H, d, J=8.5 Hz).
Reaction SMILES: [Br:1][C:2]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]([O:24][CH3:25])=[CH:16][C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:15])=[N:9][C:10]=2[Cl:14].OS(O)(=O)=O.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[Br:1][C:2]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]([O:24][CH3:25])=[CH:16][C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH:15][C:31](=[O:33])[CH3:32])=[N:9][C:10]=2[Cl:14]
Reactant: COc1cc(Cn2cnc3c(Cl)nc(N)nc32)c(Br)c(OC)c1OC
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: COc1cc(Cn2cnc3c(Cl)nc(NC(C)=O)nc32)c(Br)c(OC)c1OC

Procedure:
A suspension of 9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine (example 51) in acetic anhydride was treated with a catalytic amount of conc. H2SO4 at r.t. for 3 h. Work-up and purification by preparative TLC (EtOAc:hexane 9:1) gave the title compound. HPLC Rt: 5.603 min. 1H-NMR (CDCl3): δ 8.20 (s, 1H), 8.10 (s, 1H), 7.00 (s, 1H), 5.47 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H), 2.51 (s, 3H).
Reaction SMILES: Br[C:2]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:5]2[NH:6][C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15]4[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38]>>[F:31][C:32]1[CH:33]=[C:34]([C:2]2[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:5]3[NH:6][C:7]([N:9]4[CH2:10][CH2:11][N:12]([C:15]5[C:20]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:18]=[CH:17][N:16]=5)[CH2:13][CH2:14]4)=[N:8][C:4]=3[CH:3]=2)[CH:35]=[CH:36][C:37]=1[F:38]
Reactant: FC(F)(F)c1cc2[nH]c(N3CCN(c4ncccc4C(F)(F)F)CC3)nc2cc1Br
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Fc1ccc(-c2cc3nc(N4CCN(c5ncccc5C(F)(F)F)CC4)[nH]c3cc2C(F)(F)F)cc1F

Procedure:
The reaction of 5-bromo-6-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (250 mg, 0.5 mmol, Example 89 g) with 3,4-difluorophenylboronic acid (95 mg, 0.60 mmol, Aldrich) under the conditions of Example 88 afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 528.0 (M+1).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:8][N:9]=1.[Cl-:16].[NH4+:17]>CO>[ClH:16].[C:10]1([CH:6]2[CH2:7][CH2:8][NH:9][C:3](=[NH:17])[CH2:4][CH2:5]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC1=NCCC(c2ccccc2)CC1
Reactant: [Cl-]
Reactant: [NH4+]
Solvent: CO
Product: Cl
Product: N=C1CCC(c2ccccc2)CCN1
Yield: 94.6 %

Procedure:
The product of EXAMPLE 30 (17 g, 8.6 mmol) in 20 mL of MeOH was reacted with ammonium chloride (0.43 g, 8.0 mmol) by the method of EXAMPLE 27 to yield 1.7 g (91%) of the title material.
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].[NH2:6][O:7][CH2:8][C:9]1[N:10]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[N:14]=[C:13]([NH2:21])[C:12]=2[N:22]=1.C(N(CC)CC)C>ClCCl>[ClH:5].[NH2:21][C:13]1[C:12]2[N:22]=[C:9]([CH2:8][O:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[N:10]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:11]=2[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Cn1c(CON)nc2c(N)nc3c(c21)CCCC3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(CONS(C)(=O)=O)nc2c(N)nc3c(c21)CCCC3
Product: Cl
Reaction time: 1 h
Yield: 13.3 %

Procedure:
A solution of methanesulfonyl chloride (0.253 mL, 3.27 mmol) in dichloromethane (10 mL) was added dropwise to a stirred solution of 2-[(aminooxy)methyl]-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 123, 860 mg, 2.97 mmol) and triethylamine (1.24 mL, 8.92 mmol) in dichloromethane (20 mL) at 0° C. After 1 hour, additional methanesulfonyl chloride (0.125 mL in dichloromethane (5 mL)) and triethylamine (0.5 mL) were added. The reaction mixture was stirred for an additional 30 minutes, then was concentrated under reduced pressure to afford a yellow foam. The foam was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 5-15% 1 M NH3 in methanol/dichloromethane) followed by crystallization from methanol/acetonitrile. The crystals were isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to yield 160 mg of N-{[4-amino-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}methanesulfonamide hydrochloride as a white crystals, mp 211-213° C.
Reaction SMILES: C(O)(=O)C.[CH3:5][N:6]([CH3:20])[C:7]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.[NH2:21][CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1>O1CCCC1.ClCCCl>[NH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([CH2:23][CH2:22][NH:21][CH:10]2[CH2:11][CH2:12][C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)([N:6]([CH3:20])[CH3:5])[CH2:8][CH2:9]2)=[CH:25]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccn2)CCC(=O)CC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN(C)C1(c2ccccn2)CCC(NCCc2c[nH]c3ccccc23)CC1
Reaction time: 0.25 h

Procedure:
Acetic acid (0.448 ml) was added to a solution of 4-dimethylamino-4-pyridin-2-yl cyclohexanone (873 mg) and tryptamine (640 mg) in dry tetrahydrofuran (40 ml) and anhydrous 1,2-dichloroethane (10 ml) and stirred for 15 min. Following addition of sodium triacetoxyboron hydride (1.2 g) the reaction mixture was stirred for three days under argon at room temperature. To recover the product the solvent was removed in vacuo, the residue taken up in 1N sodium hydroxide solution (40 ml) and diethyl ether (40 ml), the phases separated, the aqueous phase extracted with diethyl ether (2×30 ml), the organic phases combined, dried and concentrated to low volume. The resulting raw product was separated by column chromatography on silica gel with methanol and methanol/ammonia (100:1). The non-polar diastereoisomer of N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-yl cyclohexane-1,4-diamine was obtained as a white solid (617 mg; mp 150–152° C.).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.O>C1COCC1>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCCCc1ccccc1
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: BrCCCCCCOCCCCc1ccccc1
Yield: 48 %

Procedure:
NaH (46% dispersion in oil; 6.5 g) was added portionwise to a solution of 4-phenyl-1-butanol (15.0 g) and 1,6-dibromohexane (48.8 g) in THF (200 ml) under nitrogen. The resulting suspension was refluxed for 27 h and treated with H2O (80 ml). The mixture was extracted with ER (2×200 ml) and the dried extract was evaporated to leave an orange oil. The oil was purified on a column of silica (800 ml) [A] to give a yellow oil which on distillation gave the title compound as a colourless oil (15.0 g) b.p. 90°-95°/0.1 mmHg.