Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Cl:6].[CH2:11]([C:18]1([N:25]([CH3:27])[CH3:26])[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:11]([C:18]1([N:25]([CH3:26])[CH3:27])[CH2:23][CH2:22][C:21]([CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[F:2])([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[ClH:6].[CH2:11]([C:18]1([N:25]([CH3:26])[CH3:27])[CH2:23][CH2:22][C:21]([CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[F:2])([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reactant: Fc1ccccc1CCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C1(Cc2ccccc2)CCC(O)(Cc2ccccc2F)CC1
Product: Cl
Reaction time: 1 h

Procedure:
757 mg magnesium were stirred into 15 ml analytical grade diethyl ether under a nitrogen atmosphere and approximately one third of the solution of 4.05 g 2-fluorobenzyl chloride in 15 ml analytical grade diethyl ether was added. The remainder of the solution was rapidly added dropwise after the Grignard formation had started, and when the addition had ended the mixture was subsequently stirred for one hour, 3.60 g 4-benzyl-4-dimethylaminocyclohexanone, dissolved in 40 ml analytical grade diethyl ether, were then added dropwise and the reaction mixture was stirred overnight. For working up, 31 ml ammonium chloride solution (20 per cent by weight) were added, while cooling with ice, the phases were separated, the aqueous phase was extracted twice with 40 ml diethyl ether each time, the combined organic phases were washed with 30 ml water and extracted three times with 40 ml dilute hydrochloric acid (5 per cent by weight) each time, the combined aqueous extracts were washed with 30 ml diethyl ether, adjusted to pH 9 with ammonia solution (25 per cent by weight) and extracted three times with 40 ml methylene chloride each time, the combined methylene chloride extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. The crude product obtained (5.02 g) was chromatographed over silica gel with diethyl ether/hexane (v/v=1:1). 2.44 g of the nonpolar diastereoisomer of 4-benzyl-4-dimethylamino-1-(2-fluorobenzyl)cyclohexanol were obtained, from which 2.53 g of the corresponding hydrochloride were prepared as described for example 4.
Reaction SMILES: BrCCCOC1C=CC2SC=[N:11]C=2C=1.[Na+].[I-].[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41]CC(=O)[NH:44]3)=[CH:39][CH:38]=2)[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CC#N>[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:46]=[C:45]3[C:40]([CH:41]=[N:11][NH:44]3)=[CH:39][CH:38]=2)[CH2:27][CH2:26]1
Reactant: BrCCCOc1ccc2scnc2c1
Reactant: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Clc1cccc(N2CCCN(CCCCOc3ccc4cn[nH]c4c3)CC2)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
A mixture of intermediate 51 (54.2 mg, 0.20 mmol) and NaI (60.3 mg, 0.40 mmol) in CH3CN (3 mL) was heated to reflux for 30 min and then cooled to rt. To this mixture was added intermediate 2 (62.4 mg, 0.22 mmol), followed then by DIEA (0.077 mL, 0.44 mmol). The resulting mixture was heated to reflux and stirred for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by ISCO to give 6-(4-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)butoxy)-1H-indazole (compound 47) (50.8 mg, 59%). HPLC: 99%, RT 4.526 min. MS (ESI) m/z 433.20 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5](I)=[CH:4][N:3]=1.[CH2:9]([N:13]1[CH:17]=[CH:16][N:15]=[N:14]1)[CH2:10][C:11]#[CH:12].C(N(CC)CC)C.ClCCl>CN(C=O)C.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[CH:4][N:3]=1
Reactant: Brc1cnc(I)cn1
Reactant: C#CCCn1ccnn1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Brc1cnc(C#CCCn2ccnn2)cn1
Reaction time: 5 h

Procedure:
2-Bromo-5-iodo-pyrazine (13.69 g, 48.0 mmol), 1-but-3-ynyl-1H-[1,2,3]triazole (7.01 g, 57.9 mmol) and triethyl amine (NEt3) (94 ml) are dissolved in DMF (188 ml) and copper iodide (CuI) (0.984 g, 5.17 mmol) is added under stirring. After passing a stream of argon through the mixture for 10 min tetrakis(triphenylphosphine)palladium(0) (2.844 g, 2.46 mmol) is added and stirring is continued for 5 h at r.t. Dichloromethane (300 ml) is added; the mixture is washed with 0.5N hydrochloric acid (HCl) and brine, dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/hexanes 7:3) yielding 2-bromo-5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrazine as a colorless solid. Yield 9.99 g (75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([CH3:11])[S:8][C:7]=2[CH:12]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:18](=[O:19])[C:17]3[CH:16]=[C:15]([O:14][CH3:13])[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=3)=[C:9]([CH3:11])[S:8][C:7]=2[CH:12]=1
Reactant: COc1ccc2cc(C)sc2c1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: ClCCCl
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(C)sc2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
To a mixture of 6-methoxy-2-methylbenzo[b]thiophene (0.024 g; 0.132 mmol) and 3,4,5-trimethoxybenzoyl chloride (0.052 g; 0.225 mmol) in 1,2-dichloroethane (1 ml) SnCl4 (0.023 ml) was added. The resulting mixture was stirred for 1 h at 40° C., quenched with H2O (1 ml), diluted to 15 ml with diethyl ether, washed with 5% NaHCO3 (5 ml), brine (10 ml), dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2; hexane/ethyl acetate 9:1) to give pure title compound (0.020 g; 41%) as a colourless crystals. 1H-NMR (CDCl3) 2.47 (s, 3H); 3.8 (s, 6H); 3.84 (s, 3H); 3.93 (s, 3H); 6.90 (dd, 1H, J=2.4, 8.89 Hz); 7.1 (s, 2H); 7.24 (d, 1H, J=2.4 Hz); 7.42 (d, 1H, J=8.89 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][C:10]([OH:14])([C:12]#[CH:13])[CH3:11].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:13]#[C:12][C:10]([CH3:11])([OH:14])[CH3:9])=[CH:6][CH:7]=1
Reactant: C#CC(C)(C)O
Reactant: Nc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(N)nc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
A mixture of commercially available 2-amino-5-bromopyridine (25 g, 144 mmol), 2-methyl-3-butyn-2-ol (21.2 mL, 217 mmol), Et3N (30.2 mL, 217 mmol), PdCl2(PPh3)2 (507 mg, 0.5 mol %) and PPh3 (95 mg, 0.25 mol %) in DMF (140 mL) was purged for 10 min with argon. Then CuI (83 mg, 0.3 mol %) was added and the reaction mixture was heated up to 90° C., stirring was continued at 90° C. for 16 h. Cooled to 23° C., the reaction mixture was concentrated in vacuum to remove all volatiles left a dark brown residue which was purified by flash chromatography with n-heptane and ethyl acetate to give the title compound as a brown solid (24 g, 94%, contains residual DMF). MS (ISP) 177.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](I)=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C(OCC)C.CCCCCC>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([B:17]([OH:20])[OH:18])=[C:6]([F:8])[CH:7]=1
Reactant: COc1cc(I)c(F)cc1Cl
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cc(B(O)O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2.0 g (7.0 mmol) of 2-chloro-4-fluoro-5-iodo-anisole (made from the compound of Example 11, Step A by methylation) stirring in 30 ml of diethyl ether at -78° C., 4.8 ml (7.7 mmol) of 1.6M n-butyl lithium was added dropwise (keeping the temperature below -69° C.). After stirring 0.5 h, 0.91 ml (8.0 mmol) of trimethyl borate in 15 ml of diethyl ether was added dropwise and the reaction mixture stirred 3 h before allowing to warm to room temperature. Slowly, 1N aqueous hydrogen chloride was added and the resulting biphase system stirred 1 h. The separated aqueous phase was separated and washed with an additional 30 ml of diethyl ether. Combined organic layers were washed with brine and dried over magnesium sulfate. Evaporating in vacuo gave a white solid which was suspended in hexane, filtered, and dried to afford 0.86 g of a technical sample of 4-chloro-2-fluoro-5-methoxyphenylboronic acid (m.p. 280-290° C.).
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:30][CH:29]=1.C(N(CC)CC)C>C(Cl)Cl>[F:27][C:28]1[CH:29]=[CH:30][C:31]([S:34][CH:35]2[CH2:40][CH2:39][N:38]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:15]([NH:14][C:8]4[C:7]5[C:12](=[CH:13][C:4]([C:3]([F:25])([F:24])[F:2])=[CH:5][CH:6]=5)[N:11]=[CH:10][CH:9]=4)=[CH:16][CH:17]=3)[CH2:37][CH2:36]2)=[CH:32][CH:33]=1
Reactant: Fc1ccc(SC2CCNCC2)cc1
Reactant: O=C(Cl)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCC(Sc2ccc(F)cc2)CC1
Yield: 35.4 %

Procedure:
4-[[7-(Trifluoromethyl)-4-quinolyl]amino]benzoyl chloride hydrochloride (0.94 g) was added slowly to a stirred mixture of 4-[(4-fluorophenyl)thio]piperidine hydrochloride (0.60 g) and triethylamine (1.69 ml) in dry methylene chloride (12.5 ml) at room temperature. The resultant mixture was stirred at the same temperature for 3.5 hours. The precipitated powder was collected by filtration and washed with methylene chloride and diethyl ether to give 4-[(4-fluorophenyl)thio]-1-[4-[[7-(trifluoromethyl)-4-quinolyl]amino]benzoyl]piperidine (0.45 g) as colourless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=O.[CH3:17][NH2:18].[BH4-].[Na+].O>CO>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([CH:9]([NH:18][CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:4]=1
Reactant: CN
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNC(c1ccccn1)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (2-Amino-5-bromo-phenyl)-pyridin-2-yl-methanone (500 mg, 1.8 mmol) in MeOH (20 mL) is added Ti(i-OPr)4 (1.0 g, 3.6 mmol) and methylamine (2M in THF, 4.5 mL). Then the mixture is stirred at room temperature for 6 h. Sodium borohydride (137 mg, 3.6 mmol) is added in one portion. The mixture is stirred at room temperature for 2 h. Water (10 mL) is added and the mixture is filtered and washed with EtOAc. The filtrate is washed with brine, the organic layer is concentrated in vacuum to give the desired product as a crude mixture. This is used in next step with no further purification.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:20])[N:8]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:9]3=[N:10]2)=[CH:5][CH:4]=1.[CH3:23]I>>[CH3:23][N:13]1[C:9]2=[N:10][C:11]3[C:6]([C:7](=[O:20])[N:8]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]1=2)=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:12]=3
Reactant: O=c1c2ccc(C(F)(F)F)cc2nc2[nH]c3ccccc3n12
Reactant: CI
Product: Cn1c2ccccc2n2c(=O)c3ccc(C(F)(F)F)cc3nc12

Procedure:
6-Methyl-3-trifluoromethylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3-trifluoromethylbenzimidazo[2,1-b]-quinazolin-12(6H)one and methyl iodide.
Reaction SMILES: C(Cl)Cl.C=O.[Br:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:15])=[CH2:14])[CH:10]=[CH:9][C:8]=1[F:16].[C:17](=O)([O-])[OH:18].[Na+]>C(OCC)(=O)C>[Br:6][C:7]1[CH:12]=[C:11]([C:13](=[CH2:15])[CH2:14][CH2:17][OH:18])[CH:10]=[CH:9][C:8]=1[F:16]
Reactant: C=C(C)c1ccc(F)c(Br)c1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C(CCO)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
A molecular sieve 4A (3.14 g) and a boron trifluoride-diethyl ether complex (2.16 mL, 17.5 mmol) were added to methylene chloride (31 mL), and the mixture was stirred at room temperature for 1 hour. Subsequently, paraformaldehyde (0.46 g, 14.6 mmol) and the compound (3.14 g, 14.6 mmol) obtained in Example 91a were added at −5° C., and the mixture was stirred at the same temperature for 18 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→3:1, v/v) to give the title compound (1.24 g; yield, 35%) as a colorless oily substance.
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1.[CH3:16]O>>[NH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]1
Reactant: O=C(O)CCC1CCNCC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCC1CCNCC1
Reaction time: 8 h

Procedure:
46.7 g (0.39 mol) of thionyl chloride are slowly added to 500 ml of methanol at -20° C., while stirring. When the addition has ended, the mixture is stirred for a further 20 minutes and 56.1 g (0.357 mol) of 3-(4-piperidinyl)-propionic acid are then slowly added, also at -20° C. The mixture is stirred at -20° C for a further hour and the temperature is then allowed to rise to room temperature overnight, with further stirring. The clear solution thus obtained is concentrated to dryness in vacuo and the residue is crystallized from acetone.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13].[CH3:14][O-:15].[Na+].O>CN(C)C(=O)C>[CH3:14][O:15][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:13][CH3:12])[CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNc1cc(OC)ccc1[N+](=O)[O-]
Temperature: 77.5 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a solution of 2,4-dichloronitrobenzene (3.0 g) in N,N-dimethylacetamide (30 ml) was added a 40% aqueous solution of methylamine (4.9 g) at room temperature, and the resulting mixture was stirred at 75-80° C. for 2 hours. Subsequently, to the reaction mixture was added a 28% methanolic solution of sodium methoxide (7.6 g), and the resulting mixture was stirred at the same temperature for 1.5 hours. Furthermore, to the reaction mixture was added a 28% methanolic solution of sodium methoxide (1.6 g), and the resulting mixture was stirred at the same temperature for 1 hour. After stirring, water (60 ml) was added to the reaction mixture, and the resulting mixture was cooled gradually to room temperature. The crystalline solid precipitated was collected by filtration and dried in vacuo to afford the title compound (2.2 g, yield: 77%) as a yellow crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH:7]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:8][C:9]1([C:14](=[O:25])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40].CO>ClCCl>[C:1]([O:5][C:6](=[O:31])[CH:7]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:39](=[O:41])[CH3:40])[CH2:8][C:9]1([C:14](=[O:25])[NH:15][C@H:16]2[CH2:17][CH2:18][C@@H:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(CCCCN)CC1(C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)CCCC1)C(=O)OC(C)(C)C
Yield: 88.7 %

Procedure:
2-(4-Aminobutyl)-3-{1-[(cis-4-carboxy-cyclohexyl)carbamoyl]cyclopentyl}propanoic acid t-butyl ester (280 mg, 0.64 mmole) was dissolved in dichloromethane (30 ml) and treated with triethylamine (152 mg, 1.51 mmole) and acetic anhydride (78 mg, 0.76 mmole). After 20 minutes at room temperature the solvent was evaporated and the residue was dissolved in ethyl acetate (50 ml), washed with 1N hydrochloric acid (50 ml) and water (2×50 ml). The organic layer was separated, dried over magnesium sulphate and evaporated to give a colourless foam. Chromatography on silica gel eluting with a mixture of methanol and dichloromethane (1:19-1:4 by volume) and evaporation of the appropriate fractions gave the title product as a colourless foam (273 mg, 89%). Found: C,60.09; H,8.68; N,4.99. C26H44N2O5,0.6 CH2Cl2 requires, C,60.10; H,8.57; N,5.27%.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13]([N:15]([CH3:33])[CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C>CCCCCC.CO>[C:8]([O:12][C:13]([N:15]([CH3:33])[CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][C:30]([O:32][CH3:1])=[O:31])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CN(CCOCCOCCOCCOCCC(=O)O)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CCOCCOCCOCCOCCN(C)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
2 ml of a 2M solution of trimethylsilyldiazomethane in hexane are added to a solution, cooled to 0° C., of 500 mg of 3-[2-(2-{2-[2-((tert-butoxycarbonyl)(methyl)amino)ethoxy]ethoxy}ethoxy)ethoxy]propanoic acid in 4.8 ml of MeOH. After 2 h, the mixture is neutralized by addition of 120 μl of acetic acid and then concentrated under RP, and the residue is purified by flash chromatography on silica (Analogix Super Flash SiO2 SF25-40 g) using a gradient from 0 to 5% of methanol in DCM. 400 mg of methyl 3-[2-(2-{2-[2-((tert-butoxycarbonyl)(methyl)amino)ethoxy]ethoxy}ethoxy)ethoxy]propanoate are thus obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[NH2:27][C:28]1[C:36]2[O:35][C:34]([CH3:38])([CH3:37])[CH2:33][C:32]=2[CH:31]=[CH:30][CH:29]=1>>[CH3:37][C:34]1([CH3:38])[CH2:33][C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:27][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[CH:13][C:4]=4[NH:1][S:23]([C:18]4[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=4)(=[O:25])=[O:24])[N:9]=3)[C:36]=2[O:35]1
Reactant: CC1(C)Cc2cccc(N)c2O1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Product: CC1(C)Cc2cccc(Nc3ccc4c(NS(=O)(=O)c5cc(F)cc(F)c5)cccc4n3)c2O1

Procedure:
The title compound, MS: m/e=482.1 (M+H+), was prepared in accordance with the general method of example 89 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonylchloride and 7-amino-2,3-dihydro-2,2-dimethylbenzofuran (CAS 68298-46-4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][N:19]1[C:25](=[O:26])[CH:24]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[C:21]2[CH:35]=[CH:36][CH:37]=[CH:38][C:20]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][N:19]2[C:25](=[O:26])[CH:24]([CH2:27][CH:28]3[CH2:30][CH2:29]3)[C:23]3[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=3[C:21]3[CH:35]=[CH:36][CH:37]=[CH:38][C:20]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-L), the title compound was prepared. The reaction was monitored by tlc (Rf=0.30, 5% MeOH/CHCl3) and product was purified by chromatography (silica, 3% MeOH/CHCl3).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH:13]([CH3:19])[C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=[C:8]2[CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:22][CH2:23]CCC>CCOCC>[CH2:22]([C:13]([CH3:19])([CH2:12][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([CH3:20])=[CH:9][CH:10]=1)[C:14]([OH:16])=[O:15])[CH3:23]
Reactant: CCCCC
Reactant: CCOC(=O)C(C)Cc1ccc(C)n1-c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCC(C)(Cc1ccc(C)n1-c1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A mixture of (IV) (9.4 g of crude oil, ca. 33 mmol) and Claisen's reagent (18 mL) were heated at 90–95° C. for 1 h. After cooling to room temperature, the solution was diluted with 15 g of crushed ice and acidified to pH 1–2 with 6 N HCl. The brown oily precipitate was dissolved in ether, washed with brine solution, dried over MgSO4, filtered and evaporated to waxy solids. Triteration of the solids with pentane afforded 6.6 g of V as a tan powder (84.7% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]3)=[N:33][CH:34]=2)O1>>[C:44]([O:43][C:41]([N:38]1[CH2:39][CH2:40][N:35]([C:32]2[N:33]=[CH:34][C:29]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])=[CH:30][CH:31]=2)[CH2:36][CH2:37]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)ccn2c1=O

Procedure:
Methyl 8-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (159.9 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded quantitatively the title compound as a yellow solid.