Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH:7]=[CH:6][C:5]2=[O:14].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[NH:15]([C:7]1[C:8](=[O:13])[C:9]2[C:4]([C:5](=[O:14])[CH:6]=1)=[CH:3][C:2]([CH3:1])=[C:11]([CH3:12])[CH:10]=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc2c(cc1C)C(=O)C=CC2=O
Reactant: Nc1ccccc1
Solvent: CCO
Product: Cc1cc2c(cc1C)C(=O)C(Nc1ccccc1)=CC2=O
Reaction time: 8 h
Yield: 34 %

Procedure:
To a warm solution of 6,7-dimethyl-1,4-naphthoquinone (1.08g; 0.058 mole) in ethanol (20ml) was added aniline (0.5ml) and the red solution refluxed for 1 hr. on a steam bath. After standing overnight the red crystalline anilino derivative was filtered off and recrystallised from acetic acid; water to give 0.54g (34%) of material of m.p. 208°-210° C. (Found C, 78.02; H, 5,47; N, 4.88; C18H15NO2 requires; C, 77.96; H, 5.45; N, 5.05%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][O:16]C(=O)C)[C:4]=2[N:5]=[CH:6][N:7]=1.N>CO>[Cl:1][C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(=O)OCCOCn1cc(Cl)c2c(Cl)ncnc21
Agent: N
Solvent: CO
Product: OCCOCn1cc(Cl)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N-Chlorosuccinimide was added to a solution of 4-chloro-7-(2-acetoxyethoxymethyl)pyrrolo[2,3-d]pyrimidine (3) (0.35 g) in dry methylene chloride (15 mL). The reaction mixture was stirred at room temperature for 8 days. At that time, TLC established a complete disappearance of starting material. Water (50 mL) was added to the mixture and the product was extracted with CHCl3 (3+30 mL). The chloroform extracts were combined and washed with water, then dried over anhydrous Na2SO4. The solvent was removed at 40° C. in vacuo and the resulting thick syrup was subjected to column chromatography. Elution of the silica gel column (15×2 cm) with benzene; chloroform (1:1), yielded a colorless oil (single spot on TLC) after evaporation of all the UV absorbing fractions at a reduced temperature and pressure, which was crystallized from ethyl alcohol to afford colorless needles of the acetylated intermediate, (7a, 0.23 g) (59.95%). 4,5-Dichloro-7-(2-acetoxyethoxymethyl)pyrrolo[2,3-d]pyrimidine (7a, 0.31 g) was then dissolved in dry methanol (15 mL) and to this solution was added methanol which had previously been saturated with ammonia at 0° C. (25 mL). The reaction mixture was stirred in a pressure bottle at room temperature for 20 hours. The solvent was evaporated at 30° C. in vacuo and the semi-solid mass was subjected to column chromatography. Elution of the product from a silica gel column (15×2 cm) with 2% meOH in CHCl3 yielded a colorless compound, after evaporation of all the appropriate UV absorbing fractions.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([CH2:12][CH3:13])([CH2:10][CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[S-:14][C:15]#[N:16].[K+]>>[CH2:10]([C:4]([CH2:12][CH3:13])([CH2:3][CH2:2][S:14][C:15]#[N:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:11]
Reactant: N#C[S-]
Reactant: CCOC(=O)C(CC)(CC)CCCl
Agent: [K+]
Product: CCOC(=O)C(CC)(CC)CCSC#N

Procedure:
Using ethyl 4-chloro-2,2-diethylbutyrate as obtained in Reference Example 8and potassium thiocyanate, the title compound was produced in the same manner as in Reference Example 11.
Reaction SMILES: Cl([O-])=O.[Na+].[F:5][C:6]1[CH:34]=[CH:33][C:9]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]3[C@H:18]4[C@H:28]([CH2:29][CH2:30][C@:13]23[CH3:14])[C@:26]2([CH3:27])[C:21]([CH:22]=[C:23]([CH:31]=[O:32])[CH2:24][CH2:25]2)=[CH:20][CH2:19]4)=[O:11])=[CH:8][CH:7]=1.P([O-])([O-])([O-])=[O:36].[Na+].[Na+].[Na+].O>CC(=CC)C.C1COCC1.C(O)(=O)C.C(O)(C)(C)C>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]3[C@H:18]4[C@H:28]([CH2:29][CH2:30][C@:13]23[CH3:14])[C@:26]2([CH3:27])[C:21]([CH:22]=[C:23]([C:31]([OH:36])=[O:32])[CH2:24][CH2:25]2)=[CH:20][CH2:19]4)=[O:11])=[CH:33][CH:34]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)c1ccc(F)cc1
Reactant: O=P([O-])([O-])[O-]
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C(=O)O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)c1ccc(F)cc1

Procedure:
Sodium chlorite is added to a mixture of 17β-(4-fluorobenzoyl)-androsta-3,5-diene-3-carboxaldehyde, sodium phosphate, monobasic monohydrate in 2-methyl-2-butene in THF, H2O, and t-butanol at RT. After 6 h acetic acid was added, then the aqueous layer is extracted with EtOAc, the combined organic extracts are dried (MgSO4), filtered, concentrated, and flash chromatographed to yield the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[OH:12][C@@H:13]([C@H:15]1[C:21](=[O:22])[N:20]2[C@@H:16]1[CH2:17][C:18]([CH2:36][S:37][CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=1)=[O:42])=[C:19]2[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])[CH3:14]>C(Cl)Cl.CS(C)=O>[OH:12][C@@H:13]([C@H:15]1[C:21](=[O:22])[N:20]2[C@@H:16]1[CH2:17][C:18]([CH2:36][S:37]([CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=1)=[O:42])=[O:9])=[C:19]2[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])[CH3:14]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(CSCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)C[C@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(CS(=O)CCNC(=O)OCc3ccc([N+](=O)[O-])cc3)C[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A solution of 22 mg of m-chloroperbenzoic acid in 2 ml of methylene chloride was added dropwise to 60 mg of p-nitrobenzyl (5R,6S)-6-[1-(R)-hydroxyethyl]-3-(2-p-nitrobenzyloxycarbonylaminoethyl)thiomethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (53), prepared as described in step (g) of Example 6, in 3 ml of methylene chloride, whilst cooling with ice-water. When the addition was complete, the reaction mixture was stirred at 0°-5° C. for 30 minutes. The resulting mixture containing precipitated material was diluted with 100 ml of ethyl acetate and then the solution was washed successively with a 5% w/v aqueous solution of sodium hydrogen sulphite (once), a saturated aqueous solution of sodium bicarbonate (twice) and a saturated aqueous solution of sodium chloride (three times). The solution was then dried over sodium sulphate, after which the solvents were evaporated under reduced pressure at room temperature, to give a solid substance. This crude substance was dissolved in dimethyl sulphoxide and then reprecipitated by the addition of benzene, to give 55 mg of the title compound as an amorphous powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C@@H:8](O)[CH2:7][C@@H:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:20]([NH:23][CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>[Pd].CO>[OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]([OH:9])=[C:5]([C@@H:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH2:8][N:23]([CH:24]([CH3:26])[CH3:25])[CH:20]([CH3:22])[CH3:21])[CH:4]=1
Reactant: OCc1ccc2c(c1)[C@@H](c1ccccc1)C[C@H](O)O2
Reactant: CC(C)NC(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CO)ccc1O)C(C)C

Procedure:
A mixture consisting of methanol, Pd/C catalyst, (R)-6-hydroxymethyl-4-phenylchroman-2-(R)-ol, and an excess of diisopropyl amine will be hydrogenated at ambient temperature at a pressure of 4 bar. After at least 18 hours, the reaction mixture will be filtered and evaporated to dryness. Subsequently, it is treated with 1 molar equivalent of a solution of lithium aluminium hydride in tetrahydrofuran for cleaving any cyclic hemiaminal. The reaction is quenched with water, and the product will be extracted with ethyl acetate. Removal of the solvent and drying in vacuum provides (R)-4-hydroxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenol in the form of a colourless oil.
Reaction SMILES: F.F.F.C(N(CC)CC)C.C(N(CC)CC)C.[Si]([O:35][CH2:36][C@H:37]1[O:41][C@@H:40]([N:42]2[CH:49]=[C:48]([CH3:50])[C:46](=[O:47])[NH:45][C:43]2=[O:44])[C@H:39]([O:51][CH2:52][CH2:53][O:54][N:55]([CH3:57])[CH3:56])[C@@H:38]1[OH:58])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CO>C(Cl)Cl>[CH3:56][N:55]([CH3:57])[O:54][CH2:53][CH2:52][O:51][C@@H:39]1[C@H:38]([OH:58])[C@@H:37]([CH2:36][OH:35])[O:41][C@H:40]1[N:42]1[CH:49]=[C:48]([CH3:50])[C:46](=[O:47])[NH:45][C:43]1=[O:44]
Reactant: Cc1cn([C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Agent: F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
Triethylamine trihydrofluoride (3.91 mL, 24.0 mmol) was dissolved in dry TIIF and triethylamine (1.67 mL, 12 mmol, dry, kept over KOH). This mixture of triethylamine-2HF was then added to 5′-O-tert-butyldiphenylsilyl-2′-O—[N,N-dimethylaminooxyethyl]-5-methyluridine (1.40 g, 2.4 mmol) and stirred at room temperature for 24 hrs. Reaction was monitored by TLC (5% MeOH in CH2Cl2). Solvent was removed under vacuum and the residue placed on a flash column and eluted with 10% MeOH in CH2Cl2 to get 2′-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%).
Reaction SMILES: NC1C=C2C(=CC=1)NC=C2.ClCCNCCCl.[NH:18]1[C:26]2[C:21](=[C:22]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1>>[NH:18]1[C:19]2[C:24](=[CH:23][C:22]([N:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)=[CH:21][CH:20]=2)[CH:25]=[CH:26]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: ClCCNCCCl
Agent: Nc1ccc2[nH]ccc2c1
Product: c1cc2cc(N3CCNCC3)ccc2[nH]1

Procedure:
This piperazine was prepared by treatment of 5-aminoindole with and bis(2-chloroethyl)amine by a procedure analogous to the procedure described above for the preparation of 1-(1H-indol-4-yl)piperazine.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1.[CH3:16]O>>[OH:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:9][CH2:8]1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.95 liters of methanol and 9.7 ml of conc. sulfuric acid are initially charged, and 175.0 g (1.21 mol) of cis-4-hydroxycyclohexanecarboxylic acid are added a little at a time at RT. The mixture is stirred at RT for 16 h. Almost all of the solvent is then removed on a rotary evaporator and the residue is taken up in 2 liters of a 1:1 mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate. The phases are separated, and the organic phase is washed with 1 liter of 10% strength aqueous ammonium chloride solution and then dried over magnesium sulfate. After removal of the solvent on a rotary evaporator the residue is purified chromatographically on silica gel 60 (mobile phase: gradient ethyl acetate/petroleum ether 3:7→1:1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[NH:24][NH2:25]>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:25][NH:24][C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
A suspension of 7-bromo-4-chloro-3-nitroquinoline (75.00 g, 260.9 mmol) in 350 mL of dichloromethane was cooled to 0° C. under an atmosphere of nitrogen. The suspension was treated with triethylamine (43.25 mL, 326.1 mmol), which dissolved most of the material. A solution of tert-butyl carbazate (37.93 g, 287.0 mmol) in 250 mL of dichloromethane was added to the reaction mixture over 20 min. The reaction was allowed to slowly come to ambient temperature. After 15 h, the reaction mixture was washed with 5% Na2CO3 solution (2×100 mL) and water (100 mL). The combined aqueous washes were back-extracted with CHCl3 (50 mL). The combined organic portions were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 99.98 g of tert-butyl N′-(7-bromo-3-nitroquinolin-4-yl)hydrazinecarboxylate as a dark red solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:15][O:14]3)=[CH:7][C:5]=2[N:6]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(O)C>[C:25]([O:24][C:22]([N:16]1[CH2:21][CH2:20][N:19]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH2:18][CH2:17]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1nc2cc(OCC3CO3)ccc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Product: Cc1nc2cc(OCC(O)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Temperature: 85 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To 2-methyl-5-(oxiran-2-ylmethoxy)benzothiazole (2.21 g, 10 mmol), a compound of formula (3), was added tert-butyl 1-piperazinecarboxylate (1.86 g, 10 mmol), a compound of formula (4), and ethanol (30 ml). The resulting solution was heated to 85° C. and stirred for 8 hours. The solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield 4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazine-1-carboxylic acid tert-butyl ester as a clear oil (2.9 g, 7.1 mmol).
Reaction SMILES: [C:1]([Cl:4])(Cl)=O.C(P(=O)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]CO)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:1][Cl:4])=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(CCO)cc1
Agent: CCCCP(=O)(CCCC)CCCC
Product: COc1ccc(CCCl)cc1

Procedure:
11 g (0.11 mole) of phosgene were added to 4.4 g (0.02 mole) of tri-n-butylphosphine oxide during the course of 15 minutes at a temperature of 80° C. The temperature was then held at 90°-100° C. while 108 g (1.09 moles) of phosgene and 152 g (1.00 mole) of 2-(4-methoxyphenyl)ethanol were added over 1 hour. To complete the reaction, the mixture was kept at this temperature for another hour.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH:28]=[CH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:16][N:17]3[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:36]OS(OC)(=O)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:36][N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:28]=[CH:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[N:16][N:17]2[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:25])[CH3:26])=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(Nc3cccc([N+](=O)[O-])c3)cc21
Reactant: COS(=O)(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(c1cccc([N+](=O)[O-])c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1

Procedure:
To (3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amine (434 mg, 0.89 mmol) in THF (5 mL) cooled to −5° C. under an atmosphere of argon, was added dimethylsulfate (0.42 mL, 4.5 mmol) followed by LiHMDS (1M in THF) (1.8 mL, 1.8 mmol). After 20 min the reaction was quenched with saturated NH4Cl(aq) (2 mL), then extracted 3×20 mL EtOAc. The pooled organic material was washed with brine (10 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (eluting with hexane:EtOAc 9:1) gave methyl-(3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amine, as an oil (367 mg, 82%): TLC (Hexane:EtOAc 7:3) Rf sm 0.29, Rf p 0.39 (ethyl acetate: hexane 3:7); FTIR (KBr) 2951, 2894, 1611, 1528, 1485, 1348, 1248, 1077 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.99 (d, 1H, J=8.67 Hz) 7.77 (t, 1H, J=2.25 Hz), 7.72 (dd, 1H, J=0.79, 2.09 Hz), 7.60, (d, 2H, J=7.22 Hz), 7.26-7.54 (m, 7H), 7.19 (dd, 1H, J=0.78, 2.41 Hz) 7.07 (dd, 1H, J=1.85, 8.69 Hz), 5.70 (s, 2H), 3.63 (t, 2H, J=8.10 Hz), 3.48 (s, 3H), 0.92 (t, 2H, J=8.10 Hz), −0.04 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 150.2, 149.6, 147.1, 143.5, 142.5, 137.3, 131.9, 129.8, 129.0, 128.2, 126.8, 123.1, 122.6, 120.2, 120.0, 119.7, 114.4, 111.4, 104.5, 78.0, 66.8, 41.1, 18.0, −1.2; LCMS (ESI) [M+H]/z Calc'd 501, Found 510.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:20][C:21](O)=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C1C=CC2N(O)N=NC=2C=1.O.C(Cl)CCl.Cl>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH2:20][C:21](=[O:22])[N:33]1[CH2:34][CH2:35][CH:30]([C:27]2[CH:26]=[CH:25][N:24]=[CH:29][CH:28]=2)[CH2:31][CH2:32]1
Reactant: c1cc(C2CCNCC2)ccn1
Reactant: COc1ccccc1C1(CC(=O)O)C(=O)Nc2ccc(Cl)cc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccccc1C1(CC(=O)N2CCC(c3ccncc3)CC2)C(=O)Nc2ccc(Cl)cc21
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
To a solution of 720 mg of [5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetic acid, which is the compound described in Preparation 1.1 of the brochure WO03/008407 and 350 mg of 4-piperidin-4-yl pyridine obtained in Step 51-1 in CHCl3 (15 ml) was added 500 mg of HOBt/H2O, stirred for 15 minutes, then, 500 mg of EDC/HCl was added. The solution was stirred for 11 hours, then, water was added and the resulting mixture was extracted with CHCl3. The organic layer was washed with water saturated brine, dried over Na2SO4, then, the drying agent was separated by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (first time: silicagel 60; mobile phase: CHCl3/MeOH=9/1 to 5/1; second time: silica gel NH; mobile phase: CHCl3/MeOH=19/1) to obtain 850 mg of the title compound (colorless amorphous).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[N:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1c2cc3c(n2CCN1c1nccc(Cl)c1CO)CCCC3
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of 4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 103b (1.0 g, 3.0 mmol) in methanol (50 mL) was added sodium borohydride (380 mg, 9.0 mmol) at 10° C. and the mixture was stirred for another 30 minutes. Then the reaction mixture was quenched with water (1 mL) and concentrated. The residue was dissolved in dichloromethane (50 mL) and washed with water (10 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 113g as a yellow solid (900 mg, 90%). MS: [M+H]+ 332.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:14]([NH:24][CH3:25])=[CH:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]([F:53])([F:52])[C:36]1[CH:37]=[C:38]([C:46]([CH3:51])([CH3:50])[C:47](Cl)=[O:48])[CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1>ClCCl.C(N(C(C)C)C(C)C)C>[CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:14]([N:24]([C:47](=[O:48])[C:46]([C:38]2[CH:37]=[C:36]([C:35]([F:34])([F:52])[F:53])[CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:39]=2)([CH3:51])[CH3:50])[CH3:25])=[CH:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(N(Cc2ccccc2)C(=O)OCc2ccccc2)cc1-c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(N(Cc2ccccc2)C(=O)OCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a solution of 1.075 g (2.5 mmol) benzyl-(5-methylamino-4-o-tolyl-pyridin-2-yl)-carbamic acid benzyl ester in 10 ml dichloromethane and 1 ml N-ethyldiisopropylamine was added dropwise at 0° C. a solution of 1.15 g (3.5 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionic acid chloride in 2 ml dichloromethane and the mixture was stirred for 3 h at room temperature. The solution was washed with water (20 ml), saturated aqueous sodium hydrogencarbonate solution (20 ml) and brine (20 ml), dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 1.15 g (62%) of the title compound as a yellow oil. MS m/e (%): 720 (M+H+, 100).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[Br:14]Br.Br>C(Cl)(Cl)(Cl)Cl>[Br:14][C:2]([CH3:13])([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11][CH3:12])=[CH:9][CH:10]=1)=[O:4]
Reactant: CSc1ccc(C(=O)C(C)C)cc1
Reactant: BrBr
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(C(=O)C(C)(C)Br)cc1
Temperature: 25 °C

Procedure:
369.2 g (1.9 mols) of 2-methyl-1-[4-(methylthio)phenyl]-propan-1-one are dissolved in 400 ml of carbon tetrachloride. 303.7 g (1.9 mols) of bromine, diluted with 270 ml of carbon tetrachloride, are added dropwise slowly to this solution, with cooling, at room temperature. The dissolved HBr gas is then driven off by blowing with nitrogen. The solution is concentrated and is then reacted further as described below.
Reaction SMILES: [OH-].[Li+].BrC1C=C(C=CC=1)C[O:8][C:9](=[O:27])[C:10]1[CH:15]=[C:14]([I:16])[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=2)=[C:12]([I:26])[CH:11]=1.Cl>C1COCC1>[I:16][C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([I:26])[C:13]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)[C:9]([OH:27])=[O:8]
Reactant: O=C(OCc1cccc(Br)c1)c1cc(I)c(OCc2cccc(Br)c2)c(I)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(I)c(OCc2cccc(Br)c2)c(I)c1
Reaction time: 17 h
Yield: 96.6 %

Procedure:
A 1.2 M solution of lithium hydroxide (0.5 mL, 0.6 mmol) was added to a solution of 4-(3-bromo-benzyloxy)-3,5-diiodo- benzoic acid 3-bromo-benzyl ester (as prepared in Example 1, 363 mg, 0.5 mmol) in 4 mL THF. The biphasic solution was stirred for 17 hours, after which time the reaction mixture was poured into 1 M HCl (15 mL). The resulting white precipitate was isolated by filtration, rinsed with water, and dried in vacuo, yielding the title compound as a white powder (270 mg, 97%). 1H NMR (400 MHz, DMSO-d6): δ 13.39 (br. s, 1H), 8.33 (s, 2H), 7.81 (s, 1H), 7.63-7.61 (m, 2H), 7.44 (appar. t, J=7.8 Hz, 1H), 5.00 (s, 2H). HPLC (30-90), 17.20 min. LRMS (EI−) calc'd for [C14H9BrI2O3—H] 556.8, found 556.6.