Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:7][C:6]1[CH:8]=[CH:2][C:3]([CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=3)[CH2:13][CH2:12]2)=[CH:4][C:5]=1[F:9]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1cc(Cl)c(CC2CCNCC2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Yield: 99.6 %

Procedure:
5-Chloro-2-fluoro-4-(piperidin-4-ylmethyl)aniline (1.730 mmol, 420 mg), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.730 mmol, 583 mg) and potassium carbonate (3.46 mmol, 478 mg) were combined and stirred at room temperature in acetonitrile (20 mL) for 2 hours. The reaction mixture was filtered and the filtrate concentrated under vacuum. The residue was purified by SCX chromatography to afford the title compound (800 mg). MS (ESI) m/z 499.5 [M+H]+
Reaction SMILES: [ClH:1].[C:2]([CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:6]=1)#[N:3].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[ClH:1].[CH2:15]([S:22][C:2]([CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:6]=1)=[NH:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: SCc1ccccc1
Reactant: CCOC(=O)c1ccc(CC#N)o1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)c1ccc(CC(=N)SCc2ccccc2)o1

Procedure:
Gaseous hydrogen chloride is passed for 30 minutes at 10° C. through a solution of 94.5 g (0.53 M) of ethyl 5-cyanomethylfuran-2-carboxylate and 61.9 ml (0.53 M) of benzyl mercaptan in 2000 ml of diethyl ether.
Reaction SMILES: Cl[C:2]1[C:9]([Cl:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=O.[SH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[OH-].[K+]>CN(C=O)C.O>[CH3:19][O:18][C:16]([C:15]1[S:14][C:2]2[C:9]([Cl:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=2[CH:4]=1)=[O:17]
Reactant: O=Cc1cc([N+](=O)[O-])cc(Cl)c1Cl
Reactant: COC(=O)CS
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc([N+](=O)[O-])cc(Cl)c2s1
Reaction time: 2 h

Procedure:
To a solution of 2,3-dichloro-5-nitrobenzaldehyde (10 g, 0.045 mol) and methyl mercaptoacetate (6.6 mL, 0.06 mol) in DMF (200 mL) was added KOH (6 g) in 50 mL water. After stirring for 2 h, the reaction mixture was poured in ice cold water and the mixture was extracted in ethyl acetate. The organic layer was washed with water and dried. The evaporation of the solvent gave crude product which was purified by repetitive washing with hexane to yield 7-chloro-5-nitro-benzo[b]thiophene-2-carboxylic acid methyl ester, 12.3 g.
Reaction SMILES: CO[N:3]=[C:4]1[C:12]2[C:7](=[C:8]([Cl:13])[N:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1.B>C1COCC1>[Cl:13][C:8]1[N:9]=[CH:10][CH:11]=[C:12]2[CH:4]([NH2:3])[CH2:5][O:6][C:7]=12
Reactant: CON=C1COc2c1ccnc2Cl
Agent: B
Solvent: C1CCOC1
Product: NC1COc2c1ccnc2Cl
Temperature: 60 °C

Procedure:
To a solution of 7-chlorofuro[2,3-c]pyridin-3(2H)-one O-methyl oxime (0.045 mmol) in 1 mL THF were added 10 mL of a borane solution (1M solution in THF). The mixture was heated to 60° C. overnight in a closed vessel. At RT, the reaction mixture was quenched with sat. aq. NaHCO3 solution and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as yellow oil;
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:7]=2[CH2:6][CH2:5]1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:30]1([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:2][CH2:3][CH:4]3[CH2:10][CH2:9][C:8]4[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:7]=4[CH2:6][CH2:5]3)=[CH:29][CH:28]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCI)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1ccc(-c3ccccc3)cc1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.8 %

Procedure:
The mixture of 7-(2-iodoethyl)-1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene(1.64 g),4-hydroxybiphenyl (797 mg), potassium carbonate (1.08 g), and DMF (16 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (toluene) to yield the entitled compound (1.73 g) as crystals.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([O:9][C:10]([C:12]1[NH:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH3:8].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.O.O.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>[CH2:7]([O:9][C:10]([C:12]1[NH:13][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1ccc(Br)[nH]1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccccc2)[nH]1
Yield: 67.7 %

Procedure:
Na2CO3 (97.5 mg, 0.92 mmol) was added to a stirred solution of 5-bromo-1H-pyrrole-2-carboxylic acid ethyl ester (100 mg, 0.46 mmol) in toluene: H2O (5:1, 11 mL). Pd (PPh3)4 (53 mg, 0.046 mmol) and phenylboronic acid (84.3 mg, 0.7 mmol) were then added and the reaction mixture was heated to reflux for 2 hrs. The reaction mixture was then diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated to get the residue. The residue obtained was purified by column chromatography (using silica gel of 60-120 mesh and 5% EtOAc in Hexane as eluent) afford 67 mg (67.95% yield) of 5-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester. 1H NMR (CDCl3): δ 9.4 (s, 1H), 7.64 (d, 2H), 7.48 (t, 2H), 7.36 (d, 11H), 7.0 (s, 1H), 6.58 (s, 1H), 4.4 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [OH-].[K+].O.C([O:6][C:7](=[O:19])[C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([CH3:10])[CH3:9])C.Cl>C(O)C>[F:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C:8]([CH3:10])([CH3:9])[C:7]([OH:19])=[O:6]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(Oc1cccc(F)c1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a solution of KOH (2.38 g, 42.4 mmol) in mixed solvents of water (50 mL) and ethanol (70 mL) was added ethyl-2-(3-fluorophenoxy)-2-methylpropanoate (3.20 g, 14.1 mmol) in one portion and the mixture was stirred at 40° C. for 2 h. The mixture was cooled to 0° C., acidified to pH 3 with concentrated hydrochloric acid and extracted with DCM (20 mL×2). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a white solid (1.70 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:14]2[N:13]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: Nc1ccccc1-c1ncccn1
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: FC(F)(F)c1cnc(Cl)cc1Nc1ccccc1-c1ncccn1
Temperature: 130 °C

Procedure:
The mixture of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (142 mg, 0.46 mmol), 2-(pyrimidin-2-yl)aniline (78 mg, 0.46 mmol), Pd2(dba)3 (23 mg, 0.025 mmol), xantphos (23 mg, 0.040 mmol) and cesium carbonate (325 mg, 1.0 mmol) in dioxane (4.5 ml) was microwave heated in a Biotage Initiator microwave synthesizer at 130° C. for 30′. The solvent was removed and the residue was purified by preparative HPLC (0.1% TFA in water/acetonitrile gradient) to yield the title compound.
Reaction SMILES: [C:1]([C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[C:7]([O:36][CH2:37][CH3:38])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:41][S:42]([CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:44])=[O:43]>>[ClH:25].[C:1]([C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14]2[N:15]([C:33]([N:50]3[CH2:49][CH2:48][N:47]([CH2:46][CH2:45][S:42]([CH3:41])(=[O:43])=[O:44])[CH2:52][CH2:51]3)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:18]=2)=[C:7]([O:36][CH2:37][CH3:38])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)c(OCC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)c(OCC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12f) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 729.4 [(M+H)+]
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=1[CH2:22][C:23](O)=[O:24])[CH3:9].[S:26](=[O:45])(=[O:44])([O:28][C:29]1[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][C:32]([N+:38]([O-:40])=[O:39])=[CH:31][C:30]=1[CH:41]([CH3:43])[CH3:42])[NH2:27].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O.ClCCl>[CH:35]([C:34]1[CH:33]=[C:32]([N+:38]([O-:40])=[O:39])[CH:31]=[C:30]([CH:41]([CH3:43])[CH3:42])[C:29]=1[O:28][S:26](=[O:45])(=[O:44])[NH:27][C:23](=[O:24])[CH2:22][C:11]1[C:10]([CH:8]([CH3:7])[CH3:9])=[CH:15][C:14]([CH:16]([CH3:18])[CH3:17])=[CH:13][C:12]=1[CH:19]([CH3:21])[CH3:20])([CH3:37])[CH3:36]
Reactant: CC(C)c1cc([N+](=O)[O-])cc(C(C)C)c1OS(N)(=O)=O
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)O)c(C(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc([N+](=O)[O-])cc2C(C)C)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
Oxalyl chloride (0.52 mL, 5.9 mmol) was added dropwise to a solution of 2,4,6-tris(1-methylethyl)-phenyl acetic acid in 150 mL toluene with four drops N,N-dimethylformamide added as a catalyst. The resulting solution was stirred for 4 hours at room temperature and concentrated in vacuo. The residue was redissolved in 200 mL dichloromethane with 2,6-bis(1-methylethyl)-4-nitrophenyl sulfamate (1.50 g, 4.9 mmol) and excess (3 mL) triethylamine and stirred for 16 hours. The reaction was washed with 1 M HCl, dried over MgSO4, filtered, and concentrated to give an oily solid. Recrystallization from hexanes gave 2.37 g (87%) of the title compound as a white solid; mp 85-89° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:13])([P:9]([OH:12])(=[O:11])[OH:10])[P:5]([OH:8])(=[O:7])[OH:6].[OH-].[Na+:15]>O>[NH2:1][CH2:2][CH2:3][C:4]([OH:13])([P:5]([OH:8])(=[O:6])[OH:7])[P:9]([O-:12])(=[O:10])[O-:11].[Na+:15].[Na+:15]
Reactant: NCCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCCC(O)(P(=O)([O-])[O-])P(=O)(O)O
Temperature: 25 °C

Procedure:
32.7 g of 3-amino-1-hydroxypropane-1,1-diphosphonic acid are suspended in 106 ml of demineralised water. The suspension is heated to 35° and, while stirring vigorously, 28 ml of 30% aqueous sodium hydroxide solution are added dropwise at such a rate that the temperature of the reaction mixture rises to 54°. A clear solution is obtained initially from which crystallisation begins immediately. The whole is allowed to cool slowly to room temperature while stirring is continued, and then stirred for 8 hours at room temperature, filtered with suction, washed with a mixture of 2 parts by volume of methanol and 1 part by volume of water and dried at 30° under approximately 20 mbar until the weight is constant. Disodium 3-amino-1-hydroxypropane-1,1-diphosphonate is obtained in the novel crystal form containing water of crystallisation (modification E), the IR spectrum of which is identical to that of the product obtained according to Example 1.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[CH:8][C:7]=1[OH:14])=[O:5].[OH-].[Na+].Cl>O>[Cl:12][C:10]1[CH:11]=[C:6]2[C:7](=[CH:8][C:9]=1[OH:13])[O:14][CH2:2][CH2:3][C:4]2=[O:5]
Reactant: O=C(CCCl)c1cc(Cl)c(O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CCOc2cc(O)c(Cl)cc21
Temperature: 10 °C
Yield: 62.7 %

Procedure:
A 20-liter 4-neck round-bottom flask was charged with water (10 L) and 3-chloro-1-(5-chloro-2,4-dihydroxyphenyl)propan-1-one (1.62 kg, 6.89 mol), and the resulting mixture was stirred and cooled to 10° C. A solution of sodium hydroxide (606.5 g, 15.16 mol) in water (2.96 L) was added dropwise over 40-60 minutes, maintaining the temperature at 10-15° C. The resulting mixture was stirred at ambient temperature for a further 30 minutes, then cooled to 5° C. Concentrated hydrochloric acid (1.31 L, 15.98 mol) was added dropwise over 30 minutes, maintaining the temperature at or below 10° C. The resulting mixture was stirred at ambient temperature for a further 30 minutes, and the resulting precipitate was collected by filtration, washed with water (3×5.5 L), and dried at 40° C. until the moisture content fell below 1%. This crude product (1.2 kg) was transferred to a 10-liter 4-neck round-bottom flask and stirred with acetonitrile (6.0 L) at ambient temperature for 2 hours, then cooled to 0-5° C. and stirred for an additional 2 hours. The resulting precipitate was collected by filtration, washed with 4:1 water:acetonitrile (1.5 L) and water (1.2 L), and dried in a fan dryer at 40° C. until the moisture content fell below 0.5%, to afford 6-chloro-7-hydroxychroman-4-one as an off-white solid (858 g, 62.7% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9]C(C)(C)C)=[O:8])[NH:4][C:3]1=[O:14]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH:5]([C:7]([OH:9])=[O:8])[NH:4][C:3]1=[O:14]
Reactant: CN1CC(C(=O)OC(C)(C)C)NC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC(C(=O)O)NC1=O
Yield: 100 %

Procedure:
A solution of 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate (3.8 g, 11.36 mmol) (prepared as described in step (ii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in methanol (50 ml) containing Pd/C (10% paste, 400 mg) was hydrogenated at room temperature and pressure for 18 hours. The mixture was filtered through a filter pad and the pad washed with methanol. The filtrates were combined, evaporated and dried to give 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (1.001 g, 5 mmol) (2.17 g, 95%); LC/MS [M+H]+=201. (ii) A solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (1.001 g, 5 mmol) in TFA/DCM (1:2, 7.5 ml) was stirred at room temperature for 6 hours. The solution was evaporated and the residue was dried to give crude 1-methyl-2-oxo-4-imidazolidinecarboxylic acid (assume 5 mmol), which was used in the next step. LC/MS [M+H]+=145.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([NH2:23])=[C:9]([Cl:24])[C:8]=1[Cl:25].B(O)(O)O.S(=O)(=O)(O)O>>[C:1]([CH2:2][CH2:3][NH:23][C:10]1[C:11]2[C:12](=[O:22])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19](=[O:21])[C:20]=2[C:7]([NH:6][CH2:3][CH2:2][C:1]([OH:5])=[O:4])=[C:8]([Cl:25])[C:9]=1[Cl:24])([OH:5])=[O:4]
Reactant: Nc1c(Cl)c(Cl)c(N)c2c1C(=O)c1ccccc1C2=O
Reactant: C=CC(=O)O
Agent: O=S(=O)(O)O
Agent: OB(O)O
Product: O=C(O)CCNc1c(Cl)c(Cl)c(NCCC(=O)O)c2c1C(=O)c1ccccc1C2=O
Reaction time: 60 h
Yield: 93 %

Procedure:
20 Parts of acrylic acid are gradually added to a mixture of 15.8 parts of 1,4-diamino-2,3-dichloroanthraquinone, 3.1 parts of boric acid and 100 parts of 100% sulphuric acid at 25°-30° C, and the mixture is then stirred for 60 hours at 25°-30°. The reaction mixture is then processed as described in Example 1 to give 21 parts (93%) of 1,4-bis(β-carboxyethylamino)-2,3-dichloroanthraquinone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:22][O:23][CH2:24][CH2:25][C:26](Cl)=O.C(N(CC)CC)C>>[CH3:22][O:23][CH2:24][CH2:25][C:26]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: COCCC(=O)Cl
Reactant: CCOC(=O)CCCCNc1c(N)cnc2ccccc12
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCn1c(CCOC)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Ethyl 5-(3-aminoquinolin-4-ylamino)pentanoate (23.0 g, 88.6 mmol, prepared in Parts A and B of Example 34) was treated according to the method described in Part A of Example 12. The addition of methoxypropionyl chloride (12.97 g, 106.3 mmol) was carried out at 0° C., and the reaction was stirred at ambient temperature for two hours. The reaction with triethylamine (49.4 g, 354 mmol) was heated at reflux for four hours. After the work-up procedure, 28.6 g of ethyl 5-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]pentanoate were obtained as a brown oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:2][C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)=[O:3]
Reactant: O=C(O)CCCCc1cn(-c2cccnc2)c2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCc1cn(-c2cccnc2)c2ccccc12

Procedure:
A solution of 5.0 g of 3-(4-carboxybutyl)-N-(3-pyridyl)indole in 50 ml of methanol is refluxed under nitrogen with 0.25 g of concentrated sulfuric acid for 2 hours. The reaction mixture is cooled and evaporated and partitioned between 50 ml of ether and 50 ml of ice-cold, saturated sodium bicarbonate solution. The organic phase is separated, dried over potassium carbonate and evaporated to yield 3-(4-methoxycarbonylbutyl)-N-(3-pyridyl)indole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2.[CH:23]1([CH2:26][C:27](O)=[O:28])[CH2:25][CH2:24]1>>[CH:23]1([CH2:26][C:27]([NH:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([NH:11][CH:7]2[C:8]4[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[CH2:5][CH2:6]2)[CH:21]=[CH:20]3)=[O:28])[CH2:25][CH2:24]1
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Reactant: O=C(O)CC1CC1
Product: O=C(CC1CC1)Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and cyclopropyl acetic acid; MS: m/e=376.2 (M+H+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]CCC)=[N+:2]=[N-:3].C1C2C(=CC=CC=2)C=CC=1C(Cl)=O.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7]([C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=1)=[O:21])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: O=C(Cl)c1ccc2ccccc2c1
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCNC(=O)c1ccc2ccccc2c1
Yield: 77 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 2-naphthoyl chloride (0.237 g, 1.24 mmol) was reacted with 2-azidoethanamine (0.107 g, 1.24 mmol) and triethylamine (0.252 g, 2.49 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-2-naphthamide (0.234 g, 77%). 1H NMR (300 MHz, CDCl3) δ 8.69 (s, 1H), δ 7.84 (m, 4H), δ 7.50 (m, 2H), 6.97 (t, 1H), δ 3.68 (q, 2H), 3.56 (t, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.3, 135.1, 132.8, 131.5, 129.2, 128.8, 128.0, 127.9, 127.1, 123.8, 51.2, 39.8 ppm; HRMS (ESI) calcd for C13H12N4O (M+) 240.1011. Found 240.1007.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]([O:13][CH3:14])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])(=[O:3])[CH3:2].[Br:17]Br>O1CCOCC1>[Br:17][CH2:2][C:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]([O:13][CH3:14])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])=[O:3]
Reactant: BrBr
Reactant: COc1cc(OC)c(C(=O)O)cc1C(C)=O
Solvent: C1COCCO1
Product: COc1cc(OC)c(C(=O)CBr)cc1C(=O)O

Procedure:
5-Acetyl-2,4-dimethoxybenzoic acid (Ber. 41, 1607, 1908) (21.1 g, 0.094 mole) was stirred in dioxane (200 ml.) at room temperature and bromine (5 ml., ca 0.1 mole) was added dropwise. The bromine colour gradually disappeared over 30 minutes and the mixture was then gently warmed in a steambath for 30 minutes, cooled and the dioxane removed in vacuo. The solid product was treated with boiling ethyl acetate, filtered hot and the filtrate evaporated to give 5-bromoacetyl-2,4-dimethoxybenzoic acid, m.p. 236° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:27]2[CH2:28][CH2:29][CH:24]([C:22](=[O:23])[C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[CH2:25][CH2:26]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Product: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Yield: 98.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-methylsulfonylbenzoic acid (2.8 g) and (4-chlorophenyl)piperidin-4-ylmethanone (2.6 g), (4-bromo-2-methanesulfonylphenyl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (4.8 g) was obtained. By reaction and treatment in the same manner as in Preparation Example 12 and using (4-bromo-2-methanesulfonylphenyl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (1.5 g) and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (796 mg), the title compound (938 mg) was obtained.