Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@:2]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C@H:6]([S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[Cl-].[Li+]>CN(C=O)C>[C:26]([O:25][C:23]([NH:22][C@@H:2]([C@H:6]([S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1ccc(CS[C@H](c2ccccc2)[C@](C)(NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccc(CS[C@H](c2ccccc2)[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 90 °C

Procedure:
The methyl ester 18 (380 mg, 0.91 mmol) and anhydrous lithium chloride (376 mg, 8.89 mmol) were dissolved in dry DMF (10 mL). The reaction mixture was heated at 90° C. for 4 days. The reaction mixture was cooled to room temperature, quenched with diluted HCl and extracted several times with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. The crude product was purified by flash column chromatography (silica, step gradient: 20% ethyl acetate/hexane, 25% ethyl acetate/5% acetic acid/hexane) to produce recovered starting material 18 (75 mg, 20%), followed by the desired carboxylic acid as a white solid, which was recrystallized (341 mg, 77%). mp 107°-108° C. (ether-hexane); [α]20D =-143.7° (c=1.66, CHCl3); 1H NMR (CDCl3).δ1.379 (s, 9H), 2.300 (s, 3H), 3.460 (d, J=13.3 Hz, 1H), 3.588 (d, J=13.3 Hz, 1H), 4.242 (d,J=5.5 Hz, H-3), 4.646 (dd, J=8.7, 5.5 Hz, 1H, H-2), 5.273 (bd, J=8.7 Hz, 1H, H--N), 7.055 (s, 4H), 7.259-7.340 (m, 5H); 13C NMR (CDCl3).δ21.1, 28.2, 35.5, 50.8, 58.1, 80.5, 127.9, 128.6, 128.9, 129.2, 133.9, 136.9, 138.1, 155.3, 174.5; MS m/z 401 ([M+H]+ ; Anal. Calcd. for C22H27O4NS: C, 65.81; H, 6.78; N, 3.48. Found: C, 65.83; H, 6.92; N, 3.57.
Reaction SMILES: [I-].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:52][C:53]([F:64])([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=1)[CH:54](OC)O>C1COCC1>[C:2]([O:6][C:7]([N:9]1[CH2:10][CH2:11][CH:12]([CH:15]=[CH:54][C:53]([F:64])([F:52])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[CH2:13][CH2:14]1)=[O:8])([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: COC(O)C(F)(F)c1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C=CC(F)(F)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 0.1 %

Procedure:
A suspension of ((1-(t-butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide (5.29 g, 9.00 mmol, from Procedure 17, Step C) in THF (70 mL) was stirred at rt for 40 min. A toluene solution of potassium bis(trimethylsilyl)amide (18 mL, 0.5 M, 9.0 mmol) was added, giving an orange suspension. After 40 min., crude 2,2-difluoro-2-(2-pyridyl)-1-methoxyethanol (940 mg, 4.97 mmol) was added in THF (20 mL). After an additional 50 min., the mixture was quenched by the addition of saturated aq. NH4Cl (10 mL). The mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), and the aqueous layer was extracted with ethyl acetate (3×100 mL). The organic layers were washed in succession with saturated aq. brine (100 mL), dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 90:10 v/v to 80:20 v/v hexanes/ethyl acetate, gave 1.18 mg of the title compound (approximately 95:5 cis/trans mixture) as an oil which solidified upon standing. For the title compound:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:23](I)[CH3:24]>CN(C=O)C>[CH2:23]([N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=2)[CH:6]=[N:7]1)[CH3:24]
Reactant: COC(=O)c1cc([N+](=O)[O-])c2cn[nH]c2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ncc2c([N+](=O)[O-])cc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.9 %

Procedure:
To a solution of methyl 4-nitro-1H-indazole-6-carboxylate (D197) (500 mg, 2.3 mmol, 1 equiv) in DMF (10 ml) at room temperature was added K2CO3 (346 mg, 2.5 mmol, 1.1 equiv) then ethyl iodide (200 μl, 2.5 mmol, 1.1 equiv). The resulting suspension was stirred at room temperature for 15 min then at 40° C. for 30 min, cooled to room temperature and partitioned between AcOEt and a 2N aqueous HCl solution. The two layers were separated and the organic phase dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 2/1) gave methyl 1-ethyl-4-nitro-1H-indazole-6-carboxylate (D198) (200 mg, 35%) as a pale yellow solid. [M+H]+=250.1, RT=3.11 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][NH:25][CH2:26][C@@H:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:28])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>C(N(CC)CC)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][N:25]([CH2:26][C@@H:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:28])[C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[O:11])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: COc1ccc(CCNC[C@H](C)c2ccccc2)cc1OC
Solvent: CCN(CC)CC
Product: COc1ccc(CCN(C[C@H](C)c2ccccc2)C(=O)c2ccc3c(c2)OCO3)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.5 %

Procedure:
A stirring solution of benzo[1,3]dioxole-5-carbonyl chloride (151 mg, 0.82 mmol) in MDC (5 ml) was treated with a pre-mixed solution of (R)-[2-(3,4-dimethoxy-phenyl)-ethyl]-(2-phenyl-propyl)-amine (D12, 245 mg, 0.75 mmol) and triethylamine (0.17 ml) in MDC (2 ml). After stirring under argon at room temperature for 72 h the solvent was removed in vacuo and the residue was chromatographed (silica gel, 0–40% EtOAc-pentane) to afford the title compound as a colourless gum (250 mg, 68%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:17]O>>[CH3:17][O:11][C:10](=[O:12])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)COCc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of benzyloxy-acetic acid (5 g, 30.12 mmol) in methanol (100 mL) was added SOCl2 (2.66 mL, 35.8 mmol) at 0° C. The mixture was stirred for 30 min at 0° C., finally at room temperature for 2.5 h. After completion of the reaction, the solvent was evaporated and the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The separated organic part was dried over sodium sulfate and concentrated under reduced pressure to get benzyloxy-acetic acid methyl ester (3) as a crude colorless oil (4.98 g).
Reaction SMILES: C(O[CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8])C.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14]>C(Cl)Cl>[C:12]([N:8]1[CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7]1)(=[O:15])[CH:13]=[CH2:14]
Reactant: C=CC(=O)Cl
Reactant: CCOC(CCCN)OCC
Solvent: ClCCl
Product: C=CC(=O)N1CCCC1OCC
Temperature: 15 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
4-Aminobutyraldehyde diethyl acetal (AmBDA, 75 g, 1.09 mol, Aldrich Chemical) was combined with a two phase mixture of 955 mL of CH2Cl2 and 160 mL of 14N NaOH in a 3 neck flask equipped with a thermometer and an efficient mechanical stirrer. This was cooled to 15° C. with an ice bath. Acryloyl chloride (98.3 g, 1.09 mol, Aldrich) was added via an addition funnel at a rate slow enough to maintain the reaction temperature below 30° C. Reaction monitoring by capillary glpc revealed essentially complete AmBDA consumption when the acryloyl chloride addition was complete. Agitation was continued for 1 h. The layers were separated (water may be added to dissolve precipitated salt and improve phase separation) and the organic phase was washed with saturated brine. The brine was combined with the aqueous layer and back extracted with CH2Cl2. The combined organic layers were neutralized with saturated aqueous NaH2PO4, dried over anhydrous MgCl2 and concentrated on a rotary evaporator at 40° C. to give 99% pure ABDA (by glpc) in 87% yield. The product can be freed of any high molecular weight by-products by kugelrohr distillation (120°-125° C. at 0.2 torr), but this produces significant yield losses and partial isomerization to N-acryloyl-5-ethoxy pyrrolidine (AEP) and related products. The pot temperature should not exceed 60° C. during these operations. The yield loses are minimized by adding a basic reagent, such as Na2CO3, and a radical inhibitor, such as methylene blue, to the distillation vessel.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]Br>C(O)(=O)C>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Br:18])=[CH:12][C:11]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: COc1ccccc1OC(=O)c1ccccc1
Solvent: CC(=O)O
Product: COc1cc(Br)ccc1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 2-methoxyphenyl benzoate (29.1 g) in glacial acetic acid (150 mL) is treated with a solution of bromine (7.2 mL) in glacial acetic acid (25 mL) during a period of 20 minutes, and the solution is then stirred for a further period of 30 minutes at room temperature. The mixture is concentrated in vacuo, and the resulting residue is dissolved in methyl t-butyl ether (200 mL), washed with water (100 mL) and saturated aqueous sodium bicarbonate solution (3×100 mL), dried over magnesium sulphate and evaporated. The resulting residue is recrystallized from cyclohexane, to give 4-bromo-2-methoxyphenyl benzoate (22.7), m.p. 73°-75° C. [Elemental analysis: C,55.0; H,3.6; Br, 25.5%; calculated: C,54.6; H,3.9; Br, 25.9%].
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([OH:14])[C:8]([C:11](N)=[O:12])=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-:15].[Na+]>O>[CH2:1]([C:5]1[N:6]=[C:7]([OH:14])[C:8]([C:11]([OH:15])=[O:12])=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCc1cnc(C(N)=O)c(O)n1
Agent: [Na+]
Solvent: O
Product: CCCCc1cnc(C(=O)O)c(O)n1

Procedure:
2-Oxohexanal (F. Ballistreri, et al., J. Organic Chem., 53, 830 (1988) is reacted (according to the method described by F. L. Muehlmann and A. R. Day in J. American Chem. Soc., 78, 242-4(1956) substituting 2-oxohexanal for the 2-oxopropanal used in the synthesis of 5-methyl-3-hydroxypyrazine-2-carboxamide) with aminomalonamide to give 5-n-butyl-3-hydroxypyrazine-2-carboxamide. The amide is hydrolyzed with sodium hydroxide in water at 95° C. to give 5-n-butyl-3-hydroxypyrazine-2-carboxylic acid. The acid is converted to the corresponding ester with methanol and hydrochloric acid and the ester is chlorinated with phosphorous oxychloride (according to the method described by G. Dick and H. Wood in J. Chem. Soc., 1955, 1379-82) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:11].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl.[OH-].[Na+]>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][N+:7]([O-:20])=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1sc2cnccc2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1sc2c[n+]([O-])ccc2c1Br
Reaction time: 4 h

Procedure:
3-Bromo-2-methylthieno[2,3-c]pyridine (0.500 g, 2.19 mmol) was dissolved in DCM (10 ml) and cooled down to 0° C. m-Chloroperbenzoic acid (0.737 g, 3.29 mmol) was added to the reaction portionwise while stirring. After 4 hours, the reaction wad diluted with 1N NaOH (10 ml) and DCM (10 ml). The layers were separated and the organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate, reduced in vacuo and dried to give the title compound as a yellow solid. MS (M+H)+ 245
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.[CH3:21][C:22]1([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:24]3[CH2:25][C:22]([CH3:21])([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:23]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CC1(NC(=O)C(F)(F)F)CNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(C)(NC(=O)C(F)(F)F)C3)c(F)c21
Yield: 37.5 %

Procedure:
A solution of 1.1 g (4 mmoles) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.32 g (6 mmoles) of 3-methyl-3-trifluoroacetamidoazetidine hydrochloride and 0.8 g (8 mmoles) of triethylamine in 10 ml of pyridine is heated under reflux for 3 hours. Cooling, filtering and washing with water acidified with a little acetic acid yields 0.65 g (37%) of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-methyl-3-trifluoroacetamido-1-azetidinyl)-3-quinolinecarboxylic acid, melting at 196°-210° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([CH3:17])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)Cl>[Br:20][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH:4]([CH:3]([CH3:17])[C:2]([F:18])([F:19])[F:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(c1ccc(C)cc1)C(C)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(c1ccc(CBr)cc1)C(C)C(F)(F)F

Procedure:
2.25 g (8.2 mmol) of ethyl 4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate, 1.53 g (8.6 mmol) of N-bromosuccinimide and 67 mg (0.41 mmol) of 2,2′-azobis-(2-methylpropanenitrile) in 36 ml of trichloromethane were stirred under reflux overnight. After the reaction had gone to completion, the succinimide was filtered off, the filter residue was washed with dichloromethane and the filtrate was concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 40:1). This gave 2.667 g (7.5 mmol, 92% of theory) of a yellowish oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22].C([N+](CCCC)(CCCC)CCCC)CCC>CC(C)CC(=O)C>[Cl:3][C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:19][CH2:20][CH2:21][Cl:22])[C:6]=2[CH:5]=1
Reactant: ClCCCBr
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: ClCCCN1c2ccccc2Sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
40 ml of a sodium hydroxide solution (50% by weight) are added to a solution of 2.34 g (10 mmol) of 2-chloropheno-thiazine, 4.73 g (30 mmol) of 1-bromo-3-chloropropane and 0.34 g (1 mmol) of tetrabutylammonium hydrogenosulfate in 40 ml of 4-methylpentan-2-one. The mixture is stirred at ambient temperature for 48 hours. After customary treatment of the organic phase, drying over sodium sulfate, evaporation of the solvent and purification by chromatography on silica gel, 2.17 g of pure product are obtained (eluant: petroleum ether).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[OH:14])[NH:10][CH:9]=[CH:8]2.Br[CH2:16][CH2:17][CH2:18][Cl:19].O>CN(C)C=O>[Cl:19][CH2:18][CH2:17][CH2:16][O:14][C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: COc1cc2cc[nH]c2cc1O
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2cc[nH]c2cc1OCCCCl
Temperature: -5 °C
Reaction time: 0.75 h
Yield: 108.6 %

Procedure:
To a stirred suspension of sodium hydride (0.94 g, 19.6 mmol of a 50% oil dispersion) in dimethylformamide (20 ml) under nitrogen and cooled to -5° C. was added, dropwise, 5-methoxy-6-hydroxyindole (3.2 g, 19.6 mmol) dissolved in dimethylformamide (60 ml) so that the temperature did not exceed -2° C. After complete addition, the reaction was stirred for 45 minutes at 0° C. While maintaining the reaction temperature between -5° C. and 0° C., a solution of 1-bromo-3-chloropropane (3.1 g, 19.6 mmol) dissolved in dimethylformamide (15 ml) was slowly added. The mixture was stirred at ambient temperature under nitrogen for 21 hours. The reaction was cooled in an ice bath, and water was added to destroy the excess sodium hydride, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO4 and concentrated to yield 5.3 g of a dark, oily liquid. This was combined with an additional sample, for a total of 10.0 g, and purification by preparative HPLC (Waters Associates prep LC/System 500) provided 5.1 g of a brown solid. A 2.5 g sample was recrystallized from isopropyl alcohol to yield 1.1 g (30%) of 6-(3-chloropropoxy)o5-methoxyindole as beige crystals, m.p.=73°-75° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:28][C:29]([CH3:31])=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:29]([CH3:31])[CH3:28])[CH2:18][CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OC3CCNCC3)ccc2n1-c1cncnc1
Reactant: CC(C)=O
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)ccc2n1-c1cncnc1

Procedure:
In analogy to the procedure described for the synthesis of example 43, step 7, the title compound was synthesized from 5-(piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indole-2-carboxylic acid ethyl ester (example 44, step 2) and acetone. The title compound was obtained in 46% yield as light brown foam. MS (m/e): 409.4 (MH+, 100%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][O:7][C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C=O)C>[C:17]1(=[O:27])[N:21]([CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[C:5]([C:6]([OH:7])=[O:16])=[CH:4][CH:3]=[CH:2][CH:1]=2)[C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12
Reactant: O=C1OCc2ccccc2-c2ccccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O
Temperature: 170 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
A mixture of 35 g (0.17 mol) of 7H-dibenzo[c,e]oxepin-5-one and 30.8 g (0.17 mol) of potassium phthalimide in 330 ml of DMF was heated at 170° C. for 18 h. After cooling, the deposited precipitate was filtered off with suction and introduced into 160 ml of glacial acetic acid. After stirring for 1 h, the mixture was diluted with 650 ml of ice water and the deposited product was filtered off with suction and dried in vacuo. 44.8 g of 2′-phthalimidomethylbiphenyl-2-carboxylic acid were obtained; m.p. 198° C.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[CH2:23]([O:20][C:9]1[CH:8]=[CH:7][C:6]2[CH:5]3[CH:14]([CH2:13][CH2:12][C:11]=2[CH:10]=1)[CH:15]1[C:2]([CH3:1])([C:18](=[O:19])[CH2:17][CH2:16]1)[CH2:3][CH2:4]3)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC12CCC3c4ccc(OCc5ccccc5)cc4CCC3C1CCC2=O
Temperature: 80 °C

Procedure:
A solution of 15 g (55 mmol) of estrone in DMF (110 mL) was cooled to 0° C. and 2.44 g (61 mmol) of NaH (60% in oil) were added slowly. The mixture was stirred at 0° C. under N2 for 1 h before addition of 13.2 mL (111 mmol) of benzyl bromine dropwise at 0° C. The reaction was then heated to 80° C. for 4 h. After cooling, the mixture was poured into water. The suspension was extracted by diethyl ether (5 times). The mixed organic layer were washed with 2N HCl (3 times) and brine, dried over Na2SO4 and concentrated in vacuo. Recrystallisation of the solid residue in ethanol gave 12.33 g (62%) of JAC01002 as beige solid. 1H NMR (400 MHz, CDCl3) δ 0.92 (s, 3H, CH3); 1.49-1.63 (m, 6H); 1.99-2.05 (m, 3H); 2.17 (dAB, J=18.9, 8.9 Hz, 1H); 2.23 (m, 1H); 2.40 (m, 1H); 2.51 (dAB, J=18.9, 8.9, 1H); 2.85 (m, 2H, CH26); 5.05 (s, 2H, OH2Ph); 6.74 (d, J=2.8 Hz, 1H, H4); 6.80 (dd, J=8.5, 2.8 Hz, 1H, H2); 7.21 (d, J=8.5 Hz, 1H, H1); 7.30-7.45 (m, 5H); Acq. Mass (FAB+) calcd 360.2089, obsd 360.21675 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].[B:10](OC)([O:13]C)[O:11]C>C1COCC1>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([B:10]([OH:13])[OH:11])=[CH:3][CH:4]=1
Reactant: COB(OC)OC
Reactant: Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)cc1
Temperature: -78 °C

Procedure:
Under nitrogen, a solution of 94.1 g (0.55 mol) of 4-bromotoluene in 400 mL of anhydrous THF was treated with 14.5 g (0.60 mol) of magnesium turnings. The reaction was stirred at reflux for 2 h, cooled to -78° C. treated with a solution of 156 mL (1.38 mol) of trimethyl borate in 475 mL of THF, stirred for 1 h, and allowed to warm to ambient temperature. The reaction mixture was concentrated in vacuo and partitioned between aqueous base and methylene chloride. The pH of the aqueous phase was adjusted to one with hydrochloric acid and extracted with methylene chloride. The organic phase was dried (MgSO4) and concentrated in vacuo to give 4-tolylboronic acid: NMR (CDCl3) δ2.45 (s, 3H), 7.31 (d, J=8 Hz, 2H), 8.13 (d, J=8 Hz, 2H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C:37](=[N:39]O)[NH2:38]>>[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C:37]1[N:39]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:38]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1ccc(F)cc1F
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccc(F)cc3F)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 38 mg (0.22 mmol, 1.1 eq.) of 2,4-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 52 mg (48% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][NH:19][CH2:18][CH2:17]2.C(N(CC)CC)C>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][N:19]([C:7]([C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:8])[CH2:18][CH2:17]2
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2c(c1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCc3cc(OC)ccc3C2)cc1
Reaction time: 18 h
Yield: 69.5 %

Procedure:
4-Methoxy-benzoyl chloride (2.35 g) was added dropwise to a solution of 6-methoxy-1,2,3,4-tetrahydro-isoquinoline (0.75 g) and triethylamine (1.54 mL) in dichloromethane (40 mL) at 0° C. After 18 h at room temperature, the reaction was washed with 1N NaOH (2×50 mL), then water (2×50 mL). The organic extract was dried over sodium sulfate, filtered through celite and concentrated. The (6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(4-methoxy-phenyl)-methanone (0.95 g) product was obtained after purification by chromatography on silica gel (eluant: methylene chloride).