Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.O.[C:4]([C:7]1[CH:8]=[C:9]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)=[O:16])[CH:10]=[CH:11][CH:12]=1)(=[O:6])[NH2:5].[OH:30][CH2:31][S:32]([O-:35])(=[O:34])=[O:33].[Na+:36]>O>[OH2:6].[OH2:30].[C:4]([C:7]1[CH:8]=[C:9]([N:13]([CH2:31][S:32]([O-:35])(=[O:34])=[O:33])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)=[O:16])[CH:10]=[CH:11][CH:12]=1)(=[O:6])[NH2:5].[Na+:36]
Reactant: COc1ccc(CCNC(=O)CNc2cccc(C(N)=O)c2)cc1OC
Reactant: O=S(=O)([O-])CO
Agent: [Na+]
Solvent: O
Product: COc1ccc(CCNC(=O)CN(CS(=O)(=O)[O-])c2cccc(C(N)=O)c2)cc1OC
Yield: 47.8 %

Procedure:
200 g of 2-(3-carbamoylphenylamino)-N-(3,4-dimethoxyphenethyl)acetamide trihydrate and 65.2 g of sodium hydroxymethanesulfonate were suspended in 400 ml of water, and the suspension was refluxed over night. After cooling, the reaction mixture was washed with chloroform, and an insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The residue was dissolved in a mixture of 500 ml of water and 500 ml of ethanol under heating, and then the solution was cooled. The precipitate formed was collected by filtration and recrystallized from a mixture of water and ethanol to give 59.2 g of sodium N-(3-carbamoylphenyl)-N-(2-((2-(3,4-dimethoxyphenyl)ethyl)amino)-2-oxoethyl)aminomethanesulfonate dihydrate as colorless crystals with m.p. 253° to 255° C. (decomposition).
Reaction SMILES: C1COCC1.[C:6]([NH:10][S:11]([C:14]1[S:15][C:16]([Cl:19])=[CH:17][CH:18]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7].C([Li])CCC.C1(S(N(S(C2C=CC=CC=2)(=O)=O)[F:35])(=O)=O)C=CC=CC=1>CCCCCC>[C:6]([NH:10][S:11]([C:14]1[S:15][C:16]([Cl:19])=[CH:17][C:18]=1[F:35])(=[O:12])=[O:13])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)s1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1sc(Cl)cc1F
Temperature: 23 °C
Reaction time: 1 h
Yield: 108.2 %

Procedure:
A THF solution (1.5 mL) of 128 mg (0.50 mmol) of (tert-butyl)[(5-chloro(2-thienyl))sulfonyl]amine was cooled to −78° C. and treated with 954 μL (1.5 mmol) of a 1.6 M solution of butyl lithium in hexane. After 1 h, 159 mg (0.5 mmol) of bis(phenylsulfonyl)fluoroamine was added and the solution was allowed to warm to 23° C. The reaction was quenched with 1 mL of sat. NH4Cl, extracted 3 times with diethyl ether, dried (MgSO4), concentrated in vacuo to afford a quantitative yield (147 mg) of the desire product. 19F-NMR (CDCl3) δ (ppm): −113.4.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:7]OC[CH2:4]1.[C:8]1([CH:14]=[CH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(I)(C)C>CN(P(N(C)C)(N(C)C)=O)C>[CH:3]([CH:16]([CH:15]=[CH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH3:7])[CH3:4]
Reactant: C1CCOC1
Reactant: CCOC(=O)CC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)I
Product: CCOC(=O)C(C=Cc1ccccc1)C(C)C

Procedure:
To sodium hydride (2.84 g, 57% in oil, washed with pentane), 110 ml dry THF and 20 ml HMPT, cooled to 0° and under nitrogen, is added 12.7 g ethyl 4-phenyl-3-butenoate slowly with stirring. Then 6.5 ml of isopropyliodide is added and the reaction mixture is stirred for about 60 hrs. The reaction is worked up by extracting into water/ether mixture. The aqueous phase is extracted with ether. The organic phases are combined, washed with brine, dried over calcium sulfate and rotoevaporated to give ethyl 2-isopropyl-4-phenyl-3-butenoate, which is hydrolyzed (potassium hydroxide, water-methanol) to the acid, 2-isopropyl-4-phenyl-3-butenoic acid. The acid is reacted with m-phenoxybenzyl alcohol following the procedure of Example 4 to yield m-phenoxybenzyl ester of 2-isopropyl-4-phenyl-3-butenoic acid. NMR (CDCl3) δ0.91 [d, 3, J=Hz, --CH(CH3)2 ], 0.94 [d, 3, J=Hz, --CH(CH3)2 ], 5.13 (s, 2, benzyl), and 6.0-6.5 ppm (complex, 2, vinyl). IR (CCl4) 1745 cm-1 (C=O).
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]3[O:20][CH2:21][O:22][C@H:17]3[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C@:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1)#[CH:24].C(N(CC)CC)C.N>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:24]#[C:23][C@:25]2([OH:33])[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]3[O:20][CH2:21][O:22][C@H:17]3[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc(N2C[C@@H]3OCO[C@@H]3C2)nc1Cc1ccccc1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O[C@]1(C#Cc2ccc(N3C[C@@H]4OCO[C@@H]4C3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 75 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
A mixture of 116 mg of 2-benzyl-6-(cis-3,4-methylenedioxypyrrolidine-1-yl)-3-iodopyridine, 47 mg of (3R)-3-ethynyl-3-quinuclidinol, 33 mg of tetrakis(triphenylphosphine)palladium (0), 3 mg of cuprous iodide, 0.12 ml of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring at 75° C. for 4 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, and then extracted with ethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (20:1), to give 38 mg of the target compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([NH2:21])=[S:20])[CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:23]I>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[NH:21])[S:20][CH3:23])[CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(NC(N)=S)c2)CCC1
Reactant: CI
Product: CSC(=N)Nc1cccc(C2(NC(=O)OC(C)(C)C)CCC2)c1
Yield: 96 %

Procedure:
Using the compound obtained in Example 158 as a starting material and also using methyl iodide as a reagent, reaction was performed as in Example 29 to give 150 mg of the titled compound (yield, 96%).
Reaction SMILES: [CH3:1][N:2]1[C@@H:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=[O:30]>[O-][V]([O-])([O-])=O.[Na+].[Na+].[Na+]>[OH:30][CH:4]1[CH2:3][N:2]([CH3:1])[CH:11]2[C:10]3[C:5]1=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[C:9]=3[C:18]1[C:13]([CH2:12]2)=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=1
Reactant: COc1ccc(C[C@H]2c3cc(OC)c(OC)cc3CCN2C)cc1OC
Reactant: O=C(O)C(F)(F)F
Agent: O=[V]([O-])([O-])[O-]
Agent: [Na+]
Product: COc1cc2c(cc1OC)-c1c(OC)c(OC)cc3c1C(C2)N(C)CC3O

Procedure:
2 g. (+)-laudanosine (Eur. J. Med. Chem., 9, 237/1974) is reacted, in the manner described in Example 1, with 1.73 g. vanadyl (V) fluoride in trifluoroacetic acid. After analogous working up and crystallisation from diethyl ether, there is obtained (+)-4-hydroxy-1,2,9,10-tetramethoxyaporphine (cataline) in the form of colourless crystals; m.p. 180° - 182° C.;
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([CH:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=2[CH2:8]1)[CH3:6]>CC(O)=O>[CH2:5]([CH:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([OH:17])[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]=2[CH2:8]1)[CH3:6]
Reactant: CCC1CCc2cc(O)ccc2C1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCC1CCc2cc(O)c([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of HNO3 (65%, 1.05 mL, 23.0 mmol) in AcOH (10 mL) at 0° C. is added 6-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol (2.02 g, 11.5 mmol) in AcOH (33 mL) dropwise. It is allowed to warm to ambient temperature and stirred for 1.5 h and then at 40° C. until starting material is completely consumed. Water is added, followed by EtOAc. The organic layer is concentrated and purified by column chromatography to give the title compound as a yellow oil: 1H NMR (CDCl3) δ 0.91 (t, J=7 Hz, 3H), 1.28-1.36 (m, 3H), 1.51-1.56 (m, 1H), 1.85-1.90 (m, 1H), 2.24-2.31 (m, 1H), 2.72-2.64 (m, 3H), 6.77 (s, 1H), 7.73 (s, 1H), 10.29 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH3:7])[S:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:23](OC(C)=C)(=[O:25])[CH3:24]>>[C:23]([O:1][C:2]1[CH:6]([CH3:7])[S:5][CH2:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:25])[CH3:24]
Reactant: C=C(C)OC(C)=O
Reactant: COC(=O)C1CSC(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)C1=C(OC(C)=O)C(C)SC1
Reaction time: 22 h

Procedure:
Methyl 4-keto-5-methyl-2,3,4,5-tetrahydrothiophene-3-carboxylate (90.83 g) and p-toluenesulphonic acid (1 g) were refluxed for 6 hours in isopropenyl acetate (214 ml) and then stood at room temperature for 22 hours.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[CH2:16][OH:17])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)C>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[C:8]([CH2:16][OH:17])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(CO)c1
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)c(CO)c1
Reaction time: 4 h
Yield: 84.2 %

Procedure:
To a solution of (2-morpholin-4-yl-5-nitro-phenyl)-methanol (870 mg) in ethanol (40 mL) palladium hydroxide (87 mg) is added and the mixture is stirred in a Parr-apparatus under hydrogen pressure (10 bars) for 4 hours. The reaction mixture is filtrated over Celite 521, washed with ethanol and concentrated in vacuo to give the title compound (640 mg, 83%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:36])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][C:31]1[CH:30]=[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:36])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:34]=[CH:33][N:32]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M69) (0.41 g, 0.80 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (172 mg, 54%).
Reaction SMILES: O[C@@H:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:4]=2[C@H:3]1[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:18][C:17]1=[O:31].[H-].[Na+].O>O1CCCC1>[C:14]([C:12]1[CH:11]=[CH:10][C:5]2[O:6][C:7]([CH3:9])([CH3:8])[CH:2]=[C:3]([N:16]3[CH:21]=[CH:20][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:25])[CH3:26])=[CH:18][C:17]3=[O:31])[C:4]=2[CH:13]=1)#[N:15]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2ccc(CO[Si](C)(C)C(C)(C)C)cc2=O)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C=C(n2ccc(CO[Si](C)(C)C(C)(C)C)cc2=O)c2cc(C#N)ccc2O1
Yield: 82.1 %

Procedure:
In 50 ml of anhydrous tetrahydrofuran, is dissolved 1.32 g of trans-3-hydroxy-6-cyano-3,4-dihydro-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran obtained is Example 1. Then, 0.12 g of 60% oily sodium hydride is added to the solution at room temperature and reacted under reflux for 4 hours. After stopping the reaction by adding water, the reaction mixture is extracted with ether. The organic layer is successively washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/7 mixture of ethyl acetate/methylene chloride as a developing solvent. Thus, 1.04 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran is obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Product: Cc1oc2c(C)c(C)c(NC(=O)c3ccccc3)c(C)c2c1-c1ccc(C(C)C)cc1
Yield: 91 %

Procedure:
By using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine and benzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 91%. Melting point: 225-227° C. (Ethyl acetate).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:36])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH:19]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11](Br)[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].COC(C)(C)C.[CH3:43][N:44](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:36])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH:19]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:43]#[N:44])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)Cc2ccc(Br)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: COC(C)(C)C
Product: CCOC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)Cc2ccc(C#N)cc2C1
Reaction time: 2 h

Procedure:
The compound of step 1 (50 mg, 0.091 mmol) was added to a mixture of zinc cyanide (10.6 mg, 0.091 mmol) and tetrakis(triphenylphosphine)palladium(0) (5.2 mg, 0.004 mmol) in DMF (0.16 ml) at 150° C. and stirred for 2 h. After cooling, tert-butyl methyl ether was added and the mixture was filtered over celite. The filtrate was washed with water, the organic phase dried over magnesium sulfate, filtered and evaporated to dryness to yield the title compound which was used without further purification.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH2:9])[CH2:2]2.[C:10]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][CH:13]=[C:12]([C:16](O)=[O:17])[CH:11]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:16]([C:12]1[CH:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)=[O:17])[CH2:2]2
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: NC1CN2CCC1CC2
Product: O=C(NC1CN2CCC1CC2)c1cccc(-c2ccccc2)c1
Yield: 68 %

Procedure:
Using general procedure I, 1-aza-bicyclo[2.2.2]oct-3-ylamine (200 mg, 1.00 mmol) and biphenyl-3-carboxylic acid gave the title compound as a white solid (211 mg, 68%). 1H NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.40 (d, J=7.6 Hz, 2H), 7.28 (t, J=7.6 Hz, 1H), 7.19 (t, J=7.6 Hz, 2H), 7.11 (t, J=7.6 Hz, 1H), 4.21 (br s, 1H), 3.56 (t. J=11.6 Hz, 1H), 3.11-3.22 (m, 1H), 3.05-3.10 (m, 4H), 2.10 (q, J=3.2 Hz, 1H), 1.95 (br s, 1H), 1.79-1.83 (m, 2H), 1.59-1.20 (m, 1H) ppm. 13C NMR (400 MHz, CD3OD) δ 169.6, 141.6, 140.2, 134.5, 130.3, 129.0, 127.7, 126.9, 126.3, 125.9, 51.9, 46.4, 46.0, 45.6, 24.6, 21.6, 17.3 ppm. Purity: 99.8% HPLCMS (210 nm); retention time 1.60 min; (M+1) 307.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([C:32](Cl)=[O:33])[NH:26]2.C(N(C(C)C)CC)(C)C>ClCCl.O>[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([C:32]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]3[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=3)[C:4]=1[F:20])=[O:33])[NH:26]2
Reactant: O=C(Cl)c1cc2c(Cl)cc(Cl)cc2[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4c(Cl)cc(Cl)cc4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.4 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.16 mmol) in dichloromethane (1.5 mL) was added 4,6-dichloro-1H-indole-2-carbonyl chloride (0.060 g, 0.24 mmol) and diisopropylethylamine (0.031 g, 0.24 mmol). The resulting suspension was stirred at RT for 45 min. The reaction mixture was diluted with dichloromethane and water. A solid precipitated which was filtered and dried under vacuum to give the title compound (0.069 g, 82%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.12 (br. s., 1H), 9.20 (br. s., 1H), 7.77-7.78 (m, 1H), 7.41-7.52 (m, 3H), 7.33-7.41 (m, 2H), 7.23-7.32 (m, 1H), 7.19-7.20 (m, 1H), 4.54 (s, 2H). ES-LCMS: m/z 522 (M−H).
Reaction SMILES: C([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[CH3:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[C:28]1([O:27][C:25]([N:8]2[CH2:22][CH2:21][C:20]3[C:11](=[N:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]=3[CH3:23])[CH2:10][CH2:9]2)=[O:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1c2c(nc3ccccc13)CCN(Cc1ccccc1)CC2
Reactant: O=C(Cl)Oc1ccccc1
Product: Cc1c2c(nc3ccccc13)CCN(C(=O)Oc1ccccc1)CC2
Yield: 63 %

Procedure:
1,2,4,5-Tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid phenyl ester was prepared from 3-benzyl-1,2,4,5-tetrahydro-11-methyl- 3H-azepino[4,5-b]quinoline and phenyl chloroformate analogous to Example 59.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:9]#[N:10])=[C:5]([C:7]#[N:8])[N:6]=1.Cl[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13].CC(C)=O.[OH-].[Na+]>O>[CH2:15]([O:14][C:12]([N:3]1[C:4]([C:9]#[N:10])=[C:5]([C:7]#[N:8])[N:6]=[C:2]1[NH2:1])=[O:13])[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)Cl
Reactant: N#Cc1nc(N)[nH]c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOC(=O)n1c(N)nc(C#N)c1C#N
Temperature: 0 °C

Procedure:
2 g of 2-amino-4,5-dicyanoimidazole and 2 g of allyl chloroformate were added to 20 ml of acetone and further 3 ml of water solution containing 20% of sodium hydroxide was added dropwise to it under stirring at a temperature of 15° to 20°C. After the resulting solution was stirred during an hour at a room temperature, it was poured into ice-water and thereby white crystal was separated out.
Reaction SMILES: C([O:8][C:9](=[O:42])[C@@H:10]([NH:24][CH2:25][P:26]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27])[CH2:11][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)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]([CH2:11][C@H:10]([NH:24][CH2:25][P:26]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:27])[C:9]([OH:42])=[O:8])=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1

Procedure:
(S)-3-(Biphenyl-4-yl)-2-[(diphenylphosphonomethyl)-amino]-propionic acid benzyl ester (0.8 g, 1.38 mmol) is dissolved in ethyl acetate (25 mL) and treated with hydrogen (50 lbs) in a Parr apparatus in the presence of 10% palladium on carbon (0.8 g). After uptake of 1 mole, the catalyst is filtered off and the solvent is evaporated in vacuo. The solid residue is recrystallized at 0° from ethyl acetate/hexane. After being dried under high vacuum at 50°, (S)-3-(biphenyl-4-yl)-2-[(diphenylphosphonomethyl)-amino]-propionic acid is obtained as a white solid, m.p. 118°-119°; [α]405 =+9.49 (c 1.01, CHCl3)
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Cl-].[CH2:13]([O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:24])=[CH:4][CH:3]=1
Reactant: Fc1cccc2ccccc12
Reactant: CCOC(=O)CCCCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)CCCCC(=O)c1ccc(F)c2ccccc12
Temperature: 0 °C
Yield: 69.8 %

Procedure:
To a mixture of 1-fluoronaphthalene (20.0 g) and adipic acid monoethyl ester chloride (27.5 g) was added gradually aluminum chloride (38.5 g) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (500 ml) and extracted with diethyl ether (200 ml×2). The organic layer was washed with a 10% aqueous solution of sodium hydrogen carbonate (200 ml), dried over anhydrous magnesium sulfate, and concentrated to give ethyl 6-(4-fluoro-1-naphthyl)-6-oxohexanoate as an oil (27.7 g, 67%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[CH:3][CH:4]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:21][CH:20]=1)([CH3:23])[CH3:24]
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCCOC2CCCCO2)cc1)Oc1ccc(C(C)C)cc1
Yield: 100.1 %

Procedure:
In a similar manner to that described in Reference example 3(e), a reaction was carried out using ethyl 3-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)propionate (14.8 g), which is the product of Reference example 5(d), 2-(2-bromoethoxy)tetrahydropyran (28.2 g) and potassium carbonate (24.9 g) in dimethylformamide and the reaction mixture was treated to afford the desired compound (20.6 g) as a syrup.