Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](C(OCC)=O)=[C:5]([CH3:14])[C:6]=1[CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].[OH-].[Na+].Cl>>[C:9]([CH2:8][CH2:7][C:6]1[C:5]([CH3:14])=[CH:4][NH:3][C:2]=1[CH3:1])([OH:11])=[O:10]
Reactant: CCOC(=O)CCc1c(C)[nH]c(C(=O)OCC)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c[nH]c(C)c1CCC(=O)O
Temperature: 50 °C
Yield: 101.2 %

Procedure:
2,4-Dimethyl-5-ethoxycarbonyl-3-(2-ethoxycarbonylethyl)pyrrole (1.07 kg) and 3.2 L 5 N sodium hydroxide were mechanically stirred in a 12 L three-neck round bottom flask equipped with a reflux condenser and an addition funnel and heated in an oil bath. The mixture was refluxed for 3 hours after which time the internal temperature was 96° C., all solids were dissolved and thin layer chromatography showed hydrolysis to be complete. The heating bath was removed and the mixture cooled to 50° C. in a water bath. 12 N Hydrochloric acid (˜1.3 L) was slowly added. After about 50% of the acid was added gas evolution began and the temperature reached 60° C. As more acid was added, gas evolution increased and a yellow precipitate formed. The final pH was adjusted to 3.5 with hydrochloric acid. The mixture was cooled in an ice bath to 8° C. The solids were collected by vacuum filtration, washed twice with 0.5 L of distilled water and dried for 48 hours in a vacuum oven at 55-60° C. to give 677 g (101% yield) of 3-(2-carboxyethyl)-2,4-dimethylpyrrole.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:19][C:20]([F:50])([F:49])[C:21]([N:23]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)[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][CH3:39])=[O:22]>ClCCl>[F:19][C:20]([F:49])([F:50])[C:21]([N:23]([C:40]1[CH:48]=[CH:47][C:43]([C:44]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[O:45])=[CH:42][CH:41]=1)[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][CH3:39])=[O:22]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Nc2ccc(C(=O)OCC)cc2)cc1

Procedure:
To a stirred solution of 1.65 g. of ethyl p-amino-benzoate and 1.6 ml. of pyridine in 5 ml. of dichloromethane at 0° C. is added a solution of 4.75 g. of p-(2,2,2-trifluoro-N-hexadecylacetamido)benzoyl chloride in 10 ml. of dichloromethane. After 20 hours at ambient temperature the solution is diluted with dichloromethane and washed with water and sodium bicarbonate solution. The residue obtained on evaporation of solvent is recrystallized from hexane-ether to give a white, crystalline solid, m.p. 91°-93° C.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1([Li])C=CC=CC=1.C1CCCCC1.C(OCC)C>C(OCC)C>[C:8]1([CH2:14][N:15]2[CH2:16][CH2:17][NH:18][CH:19]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:20]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Fc1cccnc1
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: c1ccc(CN2CCNC(c3cccnc3)C2)cc1
Reaction time: 2.5 h

Procedure:
To a solution of 5.0 g (0.0515 mol) of 3-fluoropyridine and 43.5 ml of 1-(phenylmethyl)piperazine in 300 ml of anhydrous diethylether was added dropwise, at boiling temperature, within 2.5 hours, 56 ml (0.112 mol) of a 2 molar solution of phenyllithium in a cyclohexane-diethylether mixture (7/3 v/v) and the resulting mixture was then kept at reflux temperature for a further 4 hours. The crude reaction product obtained as an oil after working up in the usual way was purified by column chromatography over silica gel (30-60 μm) using FM1/cyclohexane (7/3 v/v)as eluant. 12.0 g (92% of theory) of a colourless oil were obtained, Rf0.52 (FM4; Macherey-Nagel, POLYGRAM® SIL G/UV254 Pre-coated plastic sheets for TLC)
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([C:15](=[N:16][O:17][CH3:18])[CH2:14][N:13]([C:19]3[C:28]([F:29])=[C:27]4[C:22]([C:23](=[O:36])[C:24]([C:33]([OH:35])=[O:34])=[CH:25][N:26]4[CH:30]4[CH2:32][CH2:31]4)=[CH:21][C:20]=3[F:37])[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(OCC)C>ClCCl>[CH:30]1([N:26]2[C:27]3[C:22](=[CH:21][C:20]([F:37])=[C:19]([N:13]4[CH2:14][C:15](=[N:16][O:17][CH3:18])[C:10]5([CH2:11][NH:8][CH2:9]5)[CH2:12]4)[C:28]=3[F:29])[C:23](=[O:36])[C:24]([C:33]([OH:35])=[O:34])=[CH:25]2)[CH2:31][CH2:32]1
Reactant: CON=C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC12CN(C(=O)OC(C)(C)C)C2
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON=C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC12CNC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
150 mg of 7-[2-(t-butoxycarbonyl)-8-(methoxyimino)-2.6-diazaspiro[3,4]oct-6-yl]-1-cyclopropyl-6,8-difluoro-4-oxo-1.4-dihydro-3-quinolinecarboxylic acid was dissolved in 5 ml of dichloromethane and thereto 1 ml of trifluoroacetic acid was added dropwise. The mixture was stirred for 5 hours at room temperature and thereto 10 ml of ethylether was added. It was additionally stirred for 1 hour, and thus precipitated solid was filtered and dried. Thus obtained solid was dissolved in 5 ml of diluted sodium hydroxide and neutralized with diluted hydrochloric acid. The resulting precipitate was filtered and dried to give 115 mg of the titled compound(yield: 87.4%).
Reaction SMILES: [Cl-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][N+:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[CH:3]1>CO.[Pt]>[C:21]1([CH:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][CH2:12][CH2:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[NH:2][CH:3]=3)[CH2:20][CH2:19]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(-c2cc[n+](CCCCc3c[nH]c4ccccc34)cc2)cc1
Agent: [Pt]
Agent: [Cl-]
Solvent: CO
Product: c1ccc(C2CCN(CCCCc3c[nH]c4ccccc34)CC2)cc1

Procedure:
1 g of 1-[4-(3-indolyl)-butyl]-4-phenylpyridinium chloride is dissolved in 25 ml of methanol and hydrogenated on 0.1 g of platinum at 25° and normal pressure until the reaction has ceased; the reaction mixture is filtered; the filtrate is evaporated; and, after customary working up, 3-[4-(4-phenyl-1-piperidyl)-butyl]-indole is obtained; hydrochloride, m.p. 213°-215°.
Reaction SMILES: [F:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3]1.CC([O-])(C)C.[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1>[F:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:3]1
Reactant: OCCCN1CCC(F)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCCN2CCC(F)C2)cc1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 82 %

Procedure:
The crude 3-(3-Fluoro-pyrrolidin-1-yl)-propan-1-ol (assumed 3.06 mmol) was dissolved in THF (8 mL) and was cooled to 0° C. The 0° C. solution was treated consecutively with KOtBu (1.5 g, 13.5 mmol) then 4-fluoronitrobenzene (423.3 mg, 3 mmol). The resulting reaction mixture was allowed to warm to room temperature and stir for an additional 4.5 h. The reaction mixture was quenched with the addition of ice water (50 mL) followed by extraction with EtOAc (75 mL). The organics were subsequently washed with room temperature H2O (75 mL), then saturated NaHCO3 (aq) (75 mL), and finally with brine (75 mL). The organics then were dried over anhydrous sodium sulfate, decanted and concentrated in vacuo to yield crude 3-Fluoro-1-[3-(4-nitro-phenoxy)-propyl]-pyrrolidine (660 mg) as a yellow oil. This material was carried on without further purification.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[C:34]([NH:37][C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)(=[O:36])[CH3:35]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:40]5[CH2:41][CH2:42][CH:38]([NH:37][C:34](=[O:36])[CH3:35])[CH2:39]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: CC(=O)N[C@@H]1CCNC1
Agent: OC1CCNC1
Product: CC(=O)NC1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)C1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with (3R)-(+)-3-acetamidopyrrolidine. A yellow solid 123 was obtained (0.0397 g, 78%). 1H-NMR (CDCl3, 400 MHz) δ 2.03 (s, 3H), 2.25–2.31 (m, 1H), 2.34–2.42 (m, 1H), 3.80–3.90 (m, 3H), 4.02–4.11 (m, 1H), 4.28–4.34 (m, 4H), 4.63–4.68 (m, 1H), 6.78 (s, 1H), 6.93–6.97 (m, 2H), 7.05 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.09–7.13 (m, 2H), 7.18 (brs, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.83 (s, 1H), 8.07 (d, J=6.6 Hz, 1H); MS (APCI) m/z 516 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccc(OCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc(OCc2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 11.0 g. of 3-[p-(benzyloxy)phenyl]propanol and 10.4 ml. of triethylamine in 175 ml. of dichloromethane chilled to -10° C. is added dropwise, over 10 minutes, a solution of 3.89 ml. of methanesulfonyl chloride in 10 ml. of dichloromethane. The solution is stirred at -10° C. for 30 minutes, washed with 150 ml. of cold water, 75 ml. of cold 10% HCl, 75 ml. of cold saturated sodium bicarbonate, 75 ml. of cold saturated sodium chloride solution and dried over magnesium sulfate. The solvent is removed in vacuo to give off-white crystals, m.p. 65°-69° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][CH:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:25][CH2:24][CH2:23][CH:22]([CH3:26])[CH3:21])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CC(C)CCN
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CC(C)CCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 3-methylbutylamine (43 mg, 0.49 mmol). The title compound was obtained as a solid (40 mg, 23% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.76 (1H, m), 8.42 (1H, s), 3.21 (2H, t), 1.58 (1H, m), 1.37 (2H, m), 0.93 (6H, m). MS m/z: 418.06, 420.08 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[C:6]=1[C:16](=O)[CH2:17][C:18]([O:20]CC)=O>C(O)C>[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[C:6]=1[C:16]1[CH:17]=[C:18]([OH:20])[N:2]([CH3:1])[N:3]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCO
Product: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
A solution of 1.0 g of methylhydrazine in 15 ml of ethanol was added dropwise to 6.0 g of ethyl 3-(2,6-dichloro-4-trifluoromethylphenyl)-3-oxopropionate (5) in 50 ml of ethanol at room temperature, and the mixture was thereafter stirred at room temperature for 1 hour and further refluxed overnight. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was washed with hexane to give 2.8 g of the desired compound in the form of white crystals (crude yield 50.0%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.[Cl:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[C:22](Cl)[C:21]([CH3:28])=[C:20]([CH3:29])[N:19]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:10]([N:7]1[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][NH:1][C:22]2[C:21]([CH3:28])=[C:20]([CH3:29])[N:19]=[C:18]([Cl:17])[C:23]=2[N+:24]([O-:26])=[O:25])[CH2:9][CH2:8]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCCC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCC2CCN(Cc3ccccc3)CC2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.4 %

Procedure:
A solution of 4-(2-aminoethyl)-1-benzylpiperidine (9.88 g, 45.2 mmol) in N,N-dimethylformamide was added dropwise to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (10.00 g, 45.2 mmol) and triethylamine (12.6 mL, 90.5 mmol) in N,N-dimethylformamide (320 mL). The reaction mixture was allowed to stir at ambient temperature for about 20 hours and then it was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with brine, dried over sodium sulfate and then concentrated under reduced pressure to provide an orange oil. The oil was purified by flash chromatography (400 mL silica gel eluting initially with 10% ethyl acetate in hexane, then with 15% ethyl acetate in hexane and finally with 40% ethyl acetate in hexane) to provide 11.00 g of N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-chloro-5,6-dimethyl-3-nitropyridin-4-amine.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[CH:5]=[CH:4][C:3]1=2.O[CH:19]([C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:23][CH:22]=1)[CH3:20]>>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([O:16][CH:19]([C:21]3[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:23][CH:22]=3)[CH3:20])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Reactant: C=CCOC(=O)c1ccc(C(C)O)cc1
Product: C=CCOC(=O)c1ccc(C(C)OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 4(c), by reaction of 3 g (12.9 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoic acid with 2.65 g (12.9 mmol) of allyl 4-(1-hydroxyethyl)benzoate, 2.8 g (52%) of the expected allyl ester are obtained in the form of a slightly yellow oil.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[N:11]1[N:12]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[N:13]=[N:14][CH:15]=1.S(=O)(=O)(O)O.FC(F)(F)[C:30](O)=[O:31]>>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([N:12]2[N:13]=[N:14][CH:15]=[N:11]2)=[CH:21][C:20]=1[CH:30]=[O:31]
Reactant: Oc1ccc(-n2ncnn2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Product: O=Cc1cc(-n2ncnn2)ccc1O

Procedure:
Hexamethylenetetramine (5.6 g) was added to 4-tetrazol-2-yl-phenol (1.6 g) in trifluoroacetic acid (40 ml) and the mixture heated at 60° for 24 h. On cooling, the solution was poured into sulphuric acid (2N, 100 ml), extracted with ether (3×100 ml), dried (Na2SO4) and evaporated. The residue was purified by FCC (dichloromethane) to give the title compound as a yellow solid (930 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([NH:15][C:16](=[O:22])OC(C)(C)C)[CH:9]=[CH:8]2)[CH3:3].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31](C(O)=O)=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1.CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C>FC(F)(F)C(O)=O.CN(C)C=O.C(OCC)(=O)C>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:31]=[CH:32][C:33]([C:16]([NH:15][C:10]3[CH:9]=[CH:8][C:7]4[C:12](=[CH:13][CH:14]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH:6]=4)[CH:11]=3)=[O:22])=[CH:34][CH:35]=2)=[CH:28][CH:29]=1
Reactant: CN(C)Cc1ccc2cc(NC(=O)OC(C)(C)C)ccc2c1
Reactant: O=C(O)c1ccccc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1ccc2cc(NC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
The tert-butyl 6-[(N,N-dimethylamino)methyl]-2-naphthylcarbamate (237 mg, 0.789 mmol) obtained in Reference Example 1 was dissolved in trifluoroacetic acid (4 ml), the solution was stirred at room temperature for 1 hour, and the solvent was concentrated under reduced pressure. To the residue were added ethyl acetate and an aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue, 4′-chlorobiphenylcarboxylic acid (184 mg, 0.789 mmol) and dimethylaminopyridine (96.4 mg, 0.789 mmol) were dissolved in N,N-dimethylformamide (4 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg, 0.789 mmol) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 16 hours. To the reaction solution were added ethyl acetate and an aqueous potassium carbonate solution, the mixture was extracted, the organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by alumina column chromatography (developing solvent: ethyl acetate), and the insolubles were crystallized from a mixed solution of ethyl acetate and diisopropyl ether (1:5) to obtain the titled compound (207 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:4][CH:3]=1.B.O1CCCC1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CC(OC)(C)C.O>[CH3:1][C:2]1[S:6][C:5]([NH:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[N:4][CH:3]=1
Reactant: Cc1ccc(CC(=O)Nc2ncc(C)s2)cc1
Agent: B
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CCNc2ncc(C)s2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
To a suspension of N-(5-methyl-thiazol-2-yl)-2-p-tolyl-acetamide (1.31 g, 5.33 mmol) in THF (11 mL) was added dropwise under a nitrogen atmosphere borane-tetrahydrofuran complex (1 M in THF, 11 mL, 11 mmol). The reaction mixture was stirred for 18 h at 80° C. To the solution was added very carefully a aqueous hydrochloric acid (1 M, 10 mL) and stirred for 30 min at 80° C. After cooling it was diluted with TBME (25 mL), water (20 mL) and basified by addition of Na2CO3. The aqueous layer was extracted with TBME (25 mL) and the organic layers were washed with brine (15 mL). The combined organic layers were dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate:methanol=90:10:0 to 40:50:10) afforded the title compound (630 mg, 51%) as a white solid. MS m/e: 233.0 [M+H]+.
Reaction SMILES: [CH:1]1[N:10]2[C:4]([S:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[C:8](=O)[CH2:9]2)=[CH:3][CH:2]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:8]2[C:7]3[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=3[S:5][C:4]3=[CH:3][CH:2]=[CH:1][N:10]3[CH:9]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: O=C1Cn2cccc2Sc2ccccc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Product: CN1CCN(C2=Cn3cccc3Sc3ccccc32)CC1
Reaction time: 3 h
Yield: 34.5 %

Procedure:
A solution of 9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepin-9-one (0.24 g, 1.11 mmol), N-methylpiperazine (0.55 mL, 0.50 g, 4.99 mmol) and trimethylsilyl triflate (0.55 mL, 0.68 g, 3.05 mmol) was heated at 120° C. under stirring, after a few minutes further 0.55 mL of N-methylpiperazine were added and the reaction was kept for 3 hours at 120° C. After that time water was added and was extracted with dichloromethane. The organic layer was dried over sodium sulphate, filtered and evaporated to give the crude product that was purified by means of a flash chromatography (20% methanol in ethyl acetate) to afford 0.114 g of the pure title compound as a yellowish solid (84% yield).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=[O:8])[N:3]=[CH:2]1.[ClH:10].[CH3:11]O>O1CCOCC1>[ClH:10].[CH3:11][O:8][C:7](=[O:9])[CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1
Reactant: CO
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1c[nH]cn1
Temperature: 60 °C

Procedure:
A solution of 4-imidazoleacetic acid (4.2 g, 26 mmol) in methanol (150 mL) is treated with HCl in dioxane (5 mL). The mixture is heated at 60° C. overnight. The solution is evaporated to give a white solid, which is then recrystallized from ether/hexane to yield 4-imidazoleacetic acid methyl ester hydrochloride. The yield is 4.5 g, 98%.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11]C)=[O:9].C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:21])C>>[NH:1]1[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8](=[O:9])[O:10][C:11]1=[O:21]
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: CCOC(=O)C1=C(N)CCCC1
Product: O=c1[nH]c2c(c(=O)o1)CCCC2

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting ethyl 2-aminocyclohex-1-ene-1-carboxylate for the product of Example 3A (0.960 g, 97%). MS (ESI−) m/z 166 (M−H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH:20][CH2:21][C:22]1[CH:33]=[CH:32][C:25]([CH2:26]OS(C)(=O)=O)=[CH:24][CH:23]=1)=[O:19]>>[N:10]1[C:11]2[CH:2]([NH:1][CH2:26][C:25]3[CH:24]=[CH:23][C:22]([CH2:21][NH:20][C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=4)=[O:19])=[CH:33][CH:32]=3)[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: NC1CCCc2cccnc21
Reactant: CS(=O)(=O)OCc1ccc(CNC(=O)c2ccccn2)cc1
Product: O=C(NCc1ccc(CNC2CCCc3cccnc32)cc1)c1ccccn1

Procedure:
Using General procedure H: Reaction of 8-amino-5,6,7,8-tetrahydroquinoline (148 mg, 1.00 mmol) with methanesulfonic acid 4-{[(pyridine-2-carbonyl)-amino]-methyl}-benzyl ester (214 mg, 0.67 mmol) for 3 h at room temperature followed by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 48:1:1) gave AMD9397 (81 mg, 33%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.72-1.83 (m, 2H), 2.00-2.06 (m, 1H), 2.16-2.20 (m, 1H), 2.75-2.83 (m, 2H), 3.82-3.84 (m, 1H), 3.88 (d, 1H, J=13.2 Hz), 3.98 (d, 1H, J=12.9 Hz), 4.65 (d, 2H, J=6.0 Hz), 7.05-7.06 (m, 1 H), 7.32-7.42 (m, 6H), 7.85 (ddd, 1H, J=7.8, 7.8, 1.8 Hz), 8.23 (d, 1H, J=7.8 Hz), 8.34 (br s, 1H), 8.37 (d, 1H, J=3.3 Hz), 8.52 (d, 1H, J=3.9 Hz). 13C NMR (75.5 MHz, CDCl3) δ 20.05, 29.00, 29.24, 43.68, 51.85, 57.85, 122.19, 122.70, 126.56, 128.37 (2C), 129.01 (2C), 132.83, 137.07, 137.23, 137.73, 140.41, 147.20, 148.46, 150.23, 157.82, 164.57. ES-MS m/z 373 (M+H). Anal. Calcd. for C23H24N4O.0.3H2O: C, 73.11; H, 6.56; N, 14.83. Found: C, 72.98; H, 6.58; N, 14.63.