Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH:6](N1CCCCC1)=[O:7].Br[C:15]1[C:24]([CH3:25])=[CH:23][C:22]2[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1.[Cl-].[NH4+]>O1CCCC1>[CH:6]([C:15]1[C:24]([CH3:25])=[CH:23][C:22]2[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1)=[O:7]
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: O=CN1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
22.2 mL (35.2 mmol) of n-butyl lithium (1.6 M in hexanes) was added. After 1 hours, a solution of 3.95 mL (35.5 mmol) of N-formylpiperidine was added to a solution of 5 g (17.8 mmol) of 2-bromo-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 50 mL of tetrahydrofuran, cooled in a dry ice/acetone bath. After 30 minutes 30 mL of saturated aqueous ammonium chloride was added to the reaction mixture. The reaction mixture was warmed to room temperature and extracted with ethyl acetate. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with gradient elution (hexane-10% ethyl acetate/hexane) to provide 3.5 g (85%) of 2-formyl-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (m.p.: 82.4-84.1° C.).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][CH3:29])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN=C=NCCCN(C)C.Cl>C1COCC1.ClCCl>[O:26]=[C:25]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:28][CH3:29]
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)Nc1ccccc1
Temperature: 55 °C
Yield: 64.3 %

Procedure:
2.0 g (9.94 mmol) of 1-amino-N-phenyl-1H-pyrrole-2-carboxamide, 2.45 g (12.05 mmol) of (S)-2-(tert-butoxycarbonylamino)butanoic acid (purchased from Aldrich®, cat. no. 15533) and 1.90 g (12.24 mmol) of EDC.HCl were dissolved in a mixture of 90 mL of THF and 30 mL of dichloromethane. The resulting solution was heated at 55° C. overnight. Then the solvents were evaporated and the crude residue was taken up in dichloromethane and washed with an aqueous solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulphate, filtered and the solvent was evaporated. The solid obtained was triturated in diethyl ether to furnish 2.47 g (64% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[BrH:17].BrBr.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C(Cl)Cl>[Br:17][CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:16]
Reactant: Br
Reactant: O=C(Cc1ccccc1)c1ccc(F)cc1
Agent: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)C(Br)c1ccccc1
Temperature: 19 °C
Reaction time: 0.08 h

Procedure:
Methylene chloride (1 L) is taken in a 4 necked RB flask equipped with mechanical strring rod, pressure equalization funnel and a CaCl2 guard tube. 100 g (0.466 mol) of 1-(4-Fluorophenyl)-2-phenyl ethanone is introduced in to the above flask and stirred for 5 minutes to obtain a clear solution.2 ml of a 30% hydrobromic acid in acetic acid is then added, followed by gradual addition of a cold solution of bromine (73 g, 0.456 mole) in 200 ml of methylene chloride at 26±2° C. Bromine solution is added in such a manner that it is consumed instantly as indicated by colouration of reaction mixture. After addition of bromine solution the reaction mixture is cooled to 19±1° C., treated with 5% aqueous sodium sulphite (200 ml) and stirred for about lhr at 21.5±3.5° C. The organic layer is then separated and is subjected to the above operation twice with 5% aqueous sodium sulphite (2×200 ml). The organic layer is then stirred with 5% aqueous sodium bicarbonate (200 ml) for about 1 hr at 21.5±3.5° C. and separated. The organic layer is finally stirred with 5% aqueous sodium chloride(200 ml) and separated. The organic layer is dried over sodium sulphate and filtered. Methylene chloride is removed by distillation and the syrup thus obtained solidified on standing in to a pale orange coloured solid. Yield 129 g (94.8%)
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:11])[CH2:6][CH2:7][CH2:8][CH2:9]Cl)(=[O:3])[CH3:2].[I-:12].[Na+]>>[C:1]([O:4][C@H:5]([CH3:11])[CH2:6][CH2:7][CH2:8][CH2:9][I:12])(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)O[C@H](C)CCCCCl
Agent: [Na+]
Product: CC(=O)O[C@H](C)CCCCI
Yield: 96.4 %

Procedure:
A solution of 4.80 g (R)-5-acetoxy-1-chlorohexane (26.89 mmol) (prepared in accordance with procedures set forth in U.S. Pat. No. 5,629,423) was added to 5.39 g sodium iodide (36 mmol) in a round bottomed flask fitted with magnetic stirrer bar and a reflux condenser and refluxed for 12 h with stirring. Acetone was removed under reduced pressure. The crude product was partitioned between 60 ml ethyl acetate and 60 ml water layer. The organic layer was washed with 10% sodium thiosulphate solution followed by 20 ml water and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield 7 g (96%) (R)-5-Acetoxy-1-iodohexane.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:3]1[CH:4]=[CH:5][C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CNc2cccc(F)n2)cc1
Solvent: CC#N
Product: COc1ccc(CNc2ccc(Br)c(F)n2)cc1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To (6-fluoro-pyridin-2-yl)-(4-methoxy-benzyl)-amine (61, 151 g, 650 mmol) in 4 L of acetonitrile under an atmosphere of nitrogen, N-bromosuccinimide (116 g, 650 mmol) was added in portions. After reacting for 2 hours, the solvent was removed under vacuum and the residue taken up in ethyl acetate, then poured into aqueous sodium thiosulfate. The organic layer was washed with warm water, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was crystallized from heptane to provide the desired compound (62, 172 g, 553 mmol, 85% yield).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2.N1C=CC=CC=1>C(Cl)Cl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2)(=[O:3])=[O:2]
Reactant: Oc1ccc2ncccc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2ncccc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.6 %

Procedure:
A solution of triflic anhydride (42.8 g, 0.15 mol) in CH2Cl2 (100 mL) was added dropwise to a 0° C. solution of 6-hydroxyquinoline (20.00 g, 0.138 mol) and pyridine (23 g, 0.277 mol) in CH2Cl2 (500 mL). The cooling bath was removed and the resulting solution was stirred at RT for 4 h. The reaction mixture was washed with water (3×300 mL) and the organic phase was dried (MgSO4) and concentrated under vacuum to afford crude quinolin-6-yl trifluoromethanesulfonate (40 g, >100% yield) as an oil. 1H-NMR (400 MHz, DMSO-d6) δ 9.00 (d, 1H, J=2.8 Hz), 8.50 (d, 1H, J=8.0 Hz), 8.21 (d, J=2.8 Hz, 1H), 8.18 (d, J=9.2 Hz, 1H), 7.80 (m, 1H), 7.64 (m, 1H); MS (ESI) m/z: 277.9 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:3]#[CH:4].I[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1>>[CH3:1][C:2]1([CH3:14])[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=2)[C:13]2[CH:12]=[C:9]([C:10]#[N:11])[CH:8]=[CH:7][C:6]=2[O:5]1
Reactant: O=[N+]([O-])c1ccc(I)nc1
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Product: CC1(C)C=C(c2ccc([N+](=O)[O-])cn2)c2cc(C#N)ccc2O1

Procedure:
2,2-Dimethyl-4-(5-nitro-2-pyridyl)-2H-1-benzopyran-6-carbonitrile was prepared from 4-(1,1-dimethyl-2propynyloxy)benzonitrile and 2-iodo-5-nitropyridine in an analogous manner to that described in Example 6(A).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:14]([CH2:16][N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:20][CH:19]([NH2:34])[C:18]1=[O:35])=[O:15])([CH3:13])([CH3:12])[CH3:11]>O1CCCC1>[C:10]([C:14]([CH2:16][N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:20][CH:19]([NH:34][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[C:18]1=[O:35])=[O:15])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)C(=O)CN1C(=O)C(N)CN(C2CCCCC2)c2ccccc21
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CN1C(=O)C(NC(=O)Nc2ccccc2)CN(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
Phenyl isocyanate (110 mg) was added to a solution of 1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (300 mg) in anhydrous tetrahydrofuran (10 ml), the mixture was stirred for 10 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, etanol was added to the residue for crystallization, collected by filtration, to thereby obtain 336 mg of the title compound (Yield 83.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:23])[CH:3]=1.[CH2:24]=O.C[O-].[Na+].[BH4-].[Na+]>CO.O>[Cl:23][C:4]1[CH:3]=[C:2]([NH:1][CH3:24])[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:11])([F:12])[F:13]
Reactant: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNc1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 36.6 %

Procedure:
A solution of 3-(4-amino-2-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (Example 68 step 4, 50 mg) in MeOH (14 ml) and paraformaldehyde (21 mg) was added to a suspension of NaOMe (44 mg) in MeOH (1 ml). The mixture was heated for 2 h under reflux and then cooled to 0° C. NaBH4 (29 mg) was added and the mixture was stirred for 1.5 h at room temperature. Additional NaBH4 (78 mg) was added and the mixture heated 30 min under reflux. Water (30 ml) was added and extracted with DCM. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 30% EtOAc/heptane) to give the title compound (19 mg) as a light yellow foam. MS (m/e)=379.1 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:35][CH2:36]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:36][CH2:35][C:21]3[N:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=4)[S:24][C:20]=3[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol [PCT Int. Appl. (2001), WO 01/00603 A1] in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield (6-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([Br:14])=[C:7]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:6]=1)C.O.[OH-].[Na+].Cl>O1CCOCC1>[Br:14][C:8]1[C:9]([O:11][CH2:12][CH3:13])=[CH:10][C:5]([C:4]([OH:26])=[O:3])=[CH:6][C:7]=1[O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25]
Reactant: CCOC(=O)c1cc(OCC)c(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc(C(=O)O)cc(OCCc2ccc(Cl)cc2Cl)c1Br
Temperature: 60 °C
Reaction time: 16 h

Procedure:
0.21 g (0.47 mmol) of 4-Bromo-3-[2-(2,4-dichlorophenyl)-ethoxy]-5-ethoxy-benzoic acid ethyl ester was dissolved in 6 ml of dioxan. 6 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1-2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][CH:18]=1>>[N:17]1([C:2]2[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccccc1
Reactant: c1ccc2[nH]cnc2c1
Product: C[C@H](Nc1cncc(-n2cnc3ccccc32)n1)c1ccccc1
Yield: 37.5 %

Procedure:
In a procedure analogous to example 12, reaction of 6-chloro-N-[(1S)-1-phenylethyl]pyrazin-2-amine (140 mg, 0.60 mmol) and benzimidazole (78 mg, 0.66 mmol) furnished the product (71 mg, 38%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.[NH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CN1CCN(N)CC1
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Product: CN1CCN(Nc2cc(Nc3ccc(P(C)(C)=O)cc3)ncn2)CC1

Procedure:
The compound is prepared as in Example 59 by reacting 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with 1-Amino-4-methyl-piperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=O.Cl>O>[C:18]1([C:15]2[CH:14]=[CH:13][C:12]([C:10]3[NH:1][C:2]4[C:7]([CH:9]=3)=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:17][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccccc1
Reactant: O=C(CCl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: O
Product: c1ccc(-c2ccc(-c3cc4ccccc4[nH]3)cc2)cc1
Yield: 24.9 %

Procedure:
A mixture of 372 g (4 mols) of aniline and 230 g (1 mol) of ω-chloroparaphenyl-acetophenone was refluxed for 105 minutes. After cooling to about 50°-80° C, the mixture was poured into iced-water containing 50 ml of concentrated hydrochloric acid to give a precipitate which was filtered out, washed with water, dried and then recrystallized from N,N-dimethylformamide. The pure substance was then filtered out and washed with ethanol to give 67.2 g of 2-(4'-phenyl-phenyl)-indole.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:3]2[C:2]([Cl:1])=[CH:13][C:6]([C:7](=[O:8])[N:9]([O:11][CH3:12])[CH3:10])=[CH:5][N:4]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CON(C)C(=O)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CON(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1

Procedure:
5,6-Dichloro-N-methoxy-N-methyl-nicotinamide from step (a) above (3.2 g, 1.36 mmol) reacted with piperazine-1-carboxylic acid tert-butyl ester (2.53 g, 1.36 mmol, Aldrich) under the conditions of Example 3a to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 385 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][CH2:8][C:9]3[C:10]([C:16](=[O:17])[C:5]=2[CH:4]=1)=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=3)#[N:2].S(Cl)(C1C=CC(C)=CC=1)(=O)=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12](=[O:21])[NH:11][C:10]=3[C:16](=[O:17])[C:5]=2[CH:4]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc2c(c1)C(=O)c1c(ccc[n+]1[O-])CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ccc2c(c1)C(=O)c1[nH]c(=O)ccc1CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.85 gram (0.0034 mole) of the N-oxide thus obtained and 0.77 gram (0.0043 mole) of tosyl chloride in 37.5 milliliters of chloroform was added a solution of 0.58 gram (0.0042 mole) of potassium carbonate in 5.8 milliliters of water and the resulting mixture was stirred vigorously at room temperature for two days and the reaction mixture washed with alkali to obtain an 11-oxo-5,6-dihydrobenzo[5,6]-cyclohepta[1,2-b]pyrid-2(1H)one product which is recovered and purified by conventional procedures.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([C@H:26]([NH2:28])[CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+]>CO>[C:16]1([C@H:26]([NH:28][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C[C@@H](NCc1ccc(Oc2ccccc2)cc1)c1cccc2ccccc12
Reaction time: 48 h
Yield: 77 %

Procedure:
4-Phenoxybenzaldehyde (2.34 g, 11.8 mmol) and (2R)-2-(1-naphthyl)eth-2-ylamine (2.02 g, 11.8 mmol) were dissolved in methanol (39 mL) under a nitrogen at room temperature. Sodium cyanoborohydride (742 mg, 11.8 mmol) was added, and stirring was continued for 48 hours. The solvent was evaporated and the residue was suspended in ether, washed with brine, and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 3.21 g (77%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz), δ 1.52 (d, J=6 Hz, 3H), 1.64 (s, 1H), 3.7 (dd, J=13.5 Hz, 7.5 Hz, 2H), 4.7 (q, J=7.5 Hz, 1H), 6.95 (m, 4H), 7.08 (m, 1H), 7.3 (m, 4H), 7.5 (m, 3H), 7.75 (m, 2H), 7.9 (m, 1H), 8.15 (m, 1H). MS (DCl/NH3) m/e 354 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:27])[N:10]([CH3:26])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[C:29]1[CH:41]=[CH:40][C:32]([CH:33]=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=1.CN(C)C=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH2:1]([NH:8][C:9](=[O:27])[N:10]([C:11]1[CH:12]=[C:13]([C:29]2[CH:41]=[CH:40][C:32]([CH:33]=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)C=Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C=CC(=O)OCC)cc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
308 mg (0.26 mmol, 5 mol %) of tetrakis(triphenylphosphine)palladium are added to a solution of 2 g (5.34 mmol, 1.0 eq) of 3-heptyl-1-methyl-1-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]urea and 1.6 g (6.4 mmol, 1.2 eq) of ethyl 4-bromocinnamate in 20 mL of an 8/2 mixture of dimethylformamide and of 2M potassium phosphate solution. The reaction mixture is stirred for 3 hours at 90° C. The reaction is stopped by addition of 50 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 1.69 g of ethyl 3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate in oil form are obtained. Yield=75%
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([OH:11])([C:7]([F:10])([F:9])[F:8])[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[CH:41]=[CH:40][C:30]([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])=[O:32])=[CH:29][CH:28]=1>O1CCCC1>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:31]([C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:4](=[O:6])[C:3]([OH:11])([C:2]([F:1])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8])=[CH:41][CH:40]=1)=[O:32]
Reactant: Nc1ccc(C(=O)c2ccccc2F)cc1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)cc1)c1ccccc1F
Temperature: 25 °C
Yield: 40.6 %

Procedure:
To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanoic acid (1.17 g, 5.5 mmol) in dry tetrahydrofuran (35 mL) was added 1,1'-carbonyldiimidazole (0.89 g, 5.5 mmol). The mixture was heated at reflux for 45 minutes, then cooled to room temperature. 4-Amino-2'-fluorobenzophenone (1.08 g, 5.0 mmol) was added in one portion and the reaction mixture heated at reflux for 48 hours. Tetrahydrofuran was removed from the reaction mixture in vacuo, and the residue dissolved in ethyl ether and filtered. The filtrate was washed with 3 N HCl (50 mL) and water. The ether extract was dried (MgSO4) and concentrated in vacuo to an off-white solid which was purified by flash column chromatography (5% v/v ethyl ether/methylene chloride). Recrystallization of the resulting solid from hexane yielded the title propanamide as a tan solid (0.83 g, 40%); mp 137°-139° C. 1H-NMR (300 MHz, d6 -DMSO): 7.36-7.42 (m, 2H, aromatic) 7.54-7.60 (m, 1H, aromatic) 7.63-7.69 (m, 1H, aromatic) 7.76-7.79 (m, 2H, aromatic) 7.92-7.96 (m, 2H, aromatic) 9.84 (s, 1H, NH) 10.86 (bs, 1H, OH). MS (CI, CH4): 410 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCN1CCCCC1
Reactant: O=C(NC1(c2ccc(O)cc2)CC1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(NC1(c2ccc(OCCCN3CCCCC3)cc2)CC1)OCc1ccccc1

Procedure:
{1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-cyclopropyl}-carbamic acid benzyl ester is prepared from [1-(4-Hydroxy-phenyl)-cyclopropyl]-carbamic acid benzyl ester (1.21 g, 4.28 mmol), Cs2CO3 (2.78 g, 8.55 mmol), KI (71 mg, 0.43 mmol), and N-(3-chloropropyl)piperidine (0.86 g, 5.34 mmol) in dioxane (50 mL) in a manner substantially analogous to Procedure A to give the product((1.16 g, 66%). MS (ES+) 409.3.