Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([CH3:14])[C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([CH3:14])[C:11]([NH2:13])=[O:12])=[CH:8][CH:9]=1
Reactant: C[C@@H](C(N)=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](C(N)=O)c1ccc(N)cc1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
(2R)-2-(4-Nitrophenyl)propanamide (4.9 g, 25.2 mmol) was dissolved in a mixture of THF (30 mL) and CH3OH (30 mL) and the resulting solution cooled at T=0-5° C. Ammonium formate (8 g, 126.mmol) was added and, then, also 10% Pd/C (1.6 g) was added portionwise and carefully. The resulting mixture was left stirring at room temperature overnight, until complete disappearance of the starting material (by TLC). After under vacuum filtration over a celite cake, and solvents evaporation at reduced pressure, the pure (2R)-2-(4-aminophenyl)propanamide was isolated as white powder (4 g, 24.24 mmol). Yield 96.2%. m.p. 110-112° C.; [α]D25 (c=0.6, CH3OH): −1.9°; 1H-NMR (CDCl3) δ 7.10 (d, 2H, J=7 Hz), 6.65 (d, 2H, J=7 Hz), 5.35 ((bs, 2H, CONH2), 3.52 (m, 1H), 1.50 (d, 3H, J=7 Hz).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:32][C:29]2[CH:28]=[CH:27][C:26]([O:25][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:31][CH:30]=2)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCOc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(OCCCCCC)cc2)cc1
Reaction time: 8 h
Yield: 50.4 %

Procedure:
In tetrahydrofuran were dissolved 1.0 g of p-octyloxybenzoic acid chloride and 800 mg of p-hexyloxyphenol, and 500 mg of triethylamine was added to the solution and reaction was carried out with stirring overnight. The precipitate was removed by filtration, and the filtrate was concentrated, purified by using a silica gel column and recrystallized from ethanol to obtain 800 mg of 4-hexyloxyphenyl 4-octyloxybenzoate. The phase transition temperatures of the so-obtained compounds are as follows. ##STR142##
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([Cl:36])[C:24]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].CCO.Cl>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:22]=[C:23]([Cl:36])[C:24]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)(=[O:27])=[O:28])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(S(=O)(=O)c4ccc(Cl)cc4)c(Cl)cc3n2COCCOC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3cc(S(=O)(=O)c4ccc(Cl)cc4)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
To a mixture of 1-[6-chloro-5-(4-chloro-benzenesulfonyl)-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (2.55 g, 4.61 mmol) and EtOH (11.5 mL) was added 4M HCl in dioxane (11.5 mL). The mixture was stirred for 3 h at 23° C. The reaction mixture was concentrated and Et2O was added. The solids were filtered and washed with Et2O to yield the titled compound (1.92 g, 89%). MS (ESI/CI): mass calcd. for C19H14Cl2N4O4S, 464.0; m/z found, 465.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 9.02 (s, 1H), 8.45 (s, 1H), 8.40 (s, 1H), 7.95-7.92 (m, 2H), 7.76 (br s, 1H), 7.70-7.67 (m, 2H), 4.30 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N+](C1C=C[C:7]([O:10][P:11]([CH3:23])(=[O:22])[O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=CC=1)([O-])=O.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33]1C2C(=CC=C(O)C=2)N[N:34]=1.N12CCCN=C1CCCCC2.CO>ClCCl>[CH3:7][O:10][P:11]([CH3:23])(=[O:22])[O:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:17][CH:18]=1)[NH:19][N:34]=[C:33]2[C:25]1[NH:24][C:32]2[C:27]([CH:26]=1)=[CH:28][CH:29]=[CH:30][CH:31]=2
Reactant: CP(=O)(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COP(C)(=O)Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Reaction time: 3 h
Yield: 26.3 %

Procedure:
Methylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester methyl ester is prepared according to procedure F using 150 mg of methylphosphonic acid bis-(4-nitrophenyl) ester, 4 ml of dichloromethane, 100 mg of 3-(1H-indol-2-yl)-1H-indazol-5-ol, 67 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene and 4 ml of dichloromethane. After stirring for 3 hours, a solution of 100 μl of methanol in 2 ml of dichloromethane is added dropwise. The reaction medium is stirred for approximately 16 hours and then concentrated to dryness under reduced pressure. The oil obtained is purified on a 5 g Interchim flash cartridge of silica with a particle size of 15-35 μ. Eluent: 30% of ethyl acetate in cyclohexane, then with 80% of ethyl acetate in methanol. The solvents are evaporated off under reduced pressure and the product obtained is crystallized from ethyl acetate. 36 mg of methylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester methyl ester are obtained in the form of white crystals.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1)=O.[N+]([O-])(O)=O.[F:19][C:20]([F:35])([O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH2:34])=[NH:33])[CH:28]=[CH:29][CH:30]=1)[CH:21]([F:23])[F:22].[OH-].[Na+]>CC(O)C>[F:19][C:20]([F:35])([O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[N:34]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=3)[CH:4]=[CH:3][N:33]=2)[CH:28]=[CH:29][CH:30]=1)[CH:21]([F:22])[F:23]
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: CN(C)C=CC(=O)c1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)O
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccc(Cl)nc3)n2)c1
Temperature: 25 °C

Procedure:
9.22 g (43.8 mmol)of 3-dimethylamino-1-(2-chloro-5-pyridyl)-2-propen-1-one is suspended in 88 ml of 2-propanol. 11 g (43.8 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate and 1.93 g (48.4 mmol) of sodium hydroxide are added and the reaction mixture is boiled under reflux for 19 h. After cooling to RT, the product is isolated by filtration, washed with 2-propanol and water and dried at 50° under HV. N[3(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-5-pyridyl)-2-pyrimidineamine is obtained; FAB-MS: 399 (M+ +H), m.p. 182°-184°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NCCc1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(NCCc2ccccn2)cc1
Temperature: 60 °C
Yield: 95.7 %

Procedure:
2 g of 4-fluoronitrobenzene, 2.07 g of 2-(2-aminoethyl)pyridine, and 2.35 g of K2CO3 were added to a solution of 20 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 18 hours and, after cooling to room temperature, was then poured into a water+ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 3.3 g of N-(4-nitrophenyl)-N-(2-pyrid-2-ylethyl)amine (5) were obtained.
Reaction SMILES: [CH2:1]([C:5]1[CH:14]=[C:13]([O:15]CC2C=CC(C3C(C(O)=O)=CC=CC=3)=CC=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].C(C1C=C(OCC2C=CC(C3C(C(OC)=O)=CC=CC=3)=CC=2)C2C(=CC=CC=2)N=1)CCC>CS(C)=O>[CH2:1]([C:5]1[CH2:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(OCc2ccc(-c3ccccc3C(=O)O)cc2)c2ccccc2n1
Agent: CCCCc1cc(OCc2ccc(-c3ccccc3C(=O)OC)cc2)c2ccccc2n1
Solvent: CS(C)=O
Product: CCCCC1=Nc2ccccc2C(=O)C1

Procedure:
(Example 4): 4'-[(2-Butylquinolin-4-yloxy)methyl]biphenyl-2-carboxylic acid, m.p. 148° C.; NMR (d6 -DMSO): 0.93(t,3H), 1,38(m,2H), 1.8(m,2H), 2.95(t,2H), 5.5(s,2H), 7.25(s,1H), 7.33-7.68(complex m,8H), 7.7-7.85(m,2H), 7.98(d,1H), 8.2(d,1H); mass spectrum (-ve FAB, DMSO/GLY): 410 (M-H)-, 200; microanalysis found: C,77.1; H,6.1; N,3.1%; C27H25NO3.0.5H2O requires: C,77.1; H,6.2; N,3.3%; starting from methyl 4'-[(2-butylquinolin-4-yloxy)methyl]biphenyl-2-carboxylate obtained as viscous oil; NMR: 0.97(t,3H), 1.45(m,2H), 1.78(m,2H), 2.94(t,2H), 3.68(s,3H), 5.35(s,2H), 6.76(s,1H), 7.35-7.6(complex m,8H), 7.69(dt,1H), 7.88(dd,1H), 8.0 (d,1H), 8.25(dd,1H); mass spectrum (+ve CI): 426 (M+H)+, 225, 202; itself obtained from 2-butyl-4-quinolone using analogous procedures to those described in Example 1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]=[CH:10][C:9]([CH:12]([OH:16])[CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=2)=[CH:2]1.[CH:17]1[N:21]=[CH:20][N:19]([C:22](N2C=NC=C2)=[O:23])[CH:18]=1>C(#N)C>[N:19]1([C:22]([O:16][CH:12]([C:9]2[CH:10]=[N:11][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[CH:7][CH:8]=2)[CH:13]([CH3:14])[CH3:15])=[O:23])[CH:18]=[CH:17][N:21]=[CH:20]1
Reactant: CC(C)C(O)c1ccc(-c2ccoc2)nc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)C(OC(=O)n1ccnc1)c1ccc(-c2ccoc2)nc1

Procedure:
Synthesized using compound 49a (73.0 mg, 0.36 mmol), CDI (291 mg, 1.80 mmol) and acetonitrile (4 mL) according to Method E. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (1:1) as eluent. Green oil. Yield: 62 mg, 67%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=0.92 (d, J=6.9 Hz, 3H), 1.11 (d, J=6.3 Hz, 3H), 2.25-2.44 (m, 1H), 5.63 (d, J=7.9 Hz, 1H), 6.88 (s, 1H), 7.08 (s, 1H), 7.41-7.58 (m, 3H), 7.66 (dd, J=7.9, 1.9 Hz, 1H), 8.03 (s, 1H), 8.16 (s, 1H), 8.60 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=18.6, 18.8, 33.5, 83.8, 108.7, 117.2, 120.0, 126.8, 131.1, 131.4, 135.4, 137.2, 141.7, 144.2, 148.2, 148.8, 152.5; MS (ESI): m/z=312.32 [M+H]+.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:9])[NH:7][NH:6][C:5](=O)[CH2:4]1.O=P(Cl)(Cl)[Cl:12]>>[ClH:12].[Cl:1][C:5]1[CH2:4][C:3]([CH3:9])([CH3:2])[NH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)CC(=O)NN1
Agent: Cl
Product: CC1(C)CC(Cl)=NN1
Temperature: 90 °C
Yield: 100 %

Procedure:
A round 50 mL round bottom flask equipped with stir bar, Vigreux column and nitrogen inlet was charged with 5,5-dimethyl-pyrazolidin-3-one.Hydrochloride (300 mg, 2.0 mmol) and POCl3 (4 mL). The mixture was heated at 90° C. for 3 h. LC-MS showed consumption of SM. The POCl3 was evaporated under reduced pressure and trace POCl3 was removed under high vacuum for 30 min. Amount obtained: 336 mg, 2.0 mmol, 100% yield. The material was used as in the next step. Step 4
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[H-].[Na+]>CN(C=O)C>[O:12]=[C:8]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:11][CH2:10][N:9]1[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NCCN1c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCN(c2ccccn2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 1-pyridin-2-ylimidazolidin-2-one from Step A (150 mg, 0.92 mmol) and tert-butyl bromoacetate (197 mg, 1.01 mmol) in DMF (2 mL) at 0° C. was added sodium hydride (40 mg of a 60% dispersion in mineral oil, 1.00 mmol). The mixture was stirred at 0° C. for 30 min, then quenched with saturated aqueous NaHCO3 and extracted with CHCl3 (2×35 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 70:30, to give the title compound. MS: m/z=278 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1
Reactant: O=C1COc2ccc(CO)cc2N1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C1COc2ccc(COC3CCCCO3)cc2N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The solution of 5.0 g of 6-hydroxymethyl-4H-benzo[1,4]oxazin-3-one in 60 ml of dichloromethane is admixed successively with 5.20 ml of 3,4-dihydro-2H-pyran and 0.236 g of p-toluenesulphonic acid monohydrate. The reaction mixture is stirred at room temperature over 14 hours. The solution is poured onto 1M sodium hydrogencarbonate solution (300 ml) and extracted with tert-butyl methyl ether (2×400 ml). The organic phase is washed with brine (300 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of crystallization (EtOAc/heptane). Rf=0.25 (1:1 EtOAc-heptane); Rt=3.45.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][CH2:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:21]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH:22]=2)=[CH:14][C:13]=1[CH3:34]>>[N:5]1[C:4]2[NH:8][CH2:9][CH2:10][C:3]=2[C:2]([N:31]2[CH2:30][CH2:29][CH:28]([C:20]3[N:21]([CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])[CH:22]=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([F:11])=[C:13]([CH3:34])[CH:14]=4)[N:19]=3)[CH2:33][CH2:32]2)=[N:7][CH:6]=1
Reactant: Cc1cc(-c2cn(CCN(C)C)c(C3CCNCC3)n2)ccc1F
Reactant: Clc1ncnc2c1CCN2
Product: Cc1cc(-c2cn(CCN(C)C)c(C3CCN(c4ncnc5c4CCN5)CC3)n2)ccc1F

Procedure:
The title compound was prepared according to the procedure described for the preparation of A4 by using 4-chloro-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine coupling with 2-(4-(4-fluoro-3-methyl-phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine. LC-MS (M+H=450, obsd.=450);
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]#[N:12].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>C(Cl)(Cl)Cl.ClCCl>[C:11]([CH2:10][NH:9][C:18]([C:14]1[O:13][CH:17]=[CH:16][CH:15]=1)=[O:19])#[N:12]
Reactant: O=C(Cl)c1ccco1
Reactant: N#CCN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCNC(=O)c1ccco1
Yield: 49.3 %

Procedure:
A 20.2-g (0.2 mol) sample of triethylamine was added dropwise over 20 minutes to a stirred and cooled (ice bath) mixture of 9.3 g (0.1 mol) aminoacetonitrile hydrochloride in 150 ml chloroform. A solution of 13.2 g (0.1 mol) 2-furoyl chloride in 25 ml dichloromethane was then added dropwise over 20 minutes. The ice bath was removed and the reaction mixture stirred for 25 minutes. The reaction mixture was then washed with water, dried over magnesium sulfate and evaporated to give 7.4 g of crude N-cyanomethyl-2-furamide, as a beige solid, m.p. 85°-93° C. Recrystallization from benzene gave the furamide as a white solid, m.p. 101°-102° C. Elemental analysis for C7H6N2O showed: %C, calc. 56.0, found 56.0; %H, calc. 4.06, found 4.11; %N, calc. 18.7, found 19.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9])=[O:17]
Reactant: O=C(Cl)CCCCCBr
Reactant: Nc1ccc(O)cc1F
Product: O=C(CCCCCBr)Nc1ccc(O)cc1F
Yield: 98 %

Procedure:
The 10.9 g (0.09 mol) of 4-amino-3-fluorophenol from above was reacted with 8.96 g (0.04 mol) of 6-bromo-hexanoyl chloride according to the procedure of Example 3, part a. 6-Bromo-N-(2-fluoro-4-hydroxyphenyl) hexanamide was obtained in 98% yield after crystallization from acetonitrile, mp 66°-69° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:53])[C@@H:11]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si](C(C)(C)C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])[CH:16]=[CH:17][CH:18]=1)[OH:12]>ClCCl>[CH3:8][O:9][C:10](=[O:53])[C@@H:11]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:26][CH3:27])([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([OH:43])[C:39]([CH3:41])([CH3:42])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)[CH2:28][CH3:29])=[CH:21][C:20]=2[CH3:52])[CH:16]=[CH:17][CH:18]=1)[OH:12]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cccc([C@@H](O)C(=O)OC)c2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cccc([C@@H](O)C(=O)OC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Trifluoroacetic acid (0.04 mL) was added to a solution of (R)-[4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2′-methyl-biphenyl-3-yl]-hydroxy-acetic acid methyl ester (Example 156-(2); 3.6 mg, 0.0056 mmol) in dichloromethane (0.20 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 7 to 8 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (2.6 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([NH2:8])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17].[CH2:30]([O:32][C:33](=[O:39])[CH:34](Cl)[C:35]([CH3:37])=O)[CH3:31]>C(Cl)(Cl)Cl>[CH2:30]([O:32][C:33]([C:34]1[S:17][C:6]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=2)=[N:8][C:35]=1[CH3:37])=[O:39])[CH3:31]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: COc1cc(C(N)=O)cc(OC)c1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1sc(-c2cc(OC)c(OC)c(OC)c2)nc1C
Yield: 84 %

Procedure:
In a round bottom flask, 21.1 g (0.1 mol) of 3,4,5-trimethoxybenzamide, 4.4 g (0.02 mol) of diphosphorus pentasulfide and 250 ml of chloroform were introduced and after attaching a reflux condenser to the flask, the content was heated for 2 hours while refluxing. Then, 19.8 g (0.12 mol) of alphachloroacetoacetic ethyl ester was added to the content of the flask, and the mixture was heated for 5 hours while refluxing. After filtering the reaction mixture while hot and condensing the filtrate to dryness, activated carbon was added to the residue and the mixture was recrystallized from ethanol. The product consisting of needle-like crystals light cream in colour amounting to 28.2 g was thus obtained at a yield of 84%. The crystals melted at 118° to 119° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Mg].[CH2:14]([SiH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:15][CH3:16].[CH2:23]1[CH2:27]O[CH2:25][CH2:24]1>[Cu](Cl)Cl>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:25][CH2:24][C@H:23]2[CH2:27][CH2:6][C@H:5]([C@H:20]3[CH2:21][CH2:22][Si@H:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]3)[CH2:4][CH2:9]2)=[CH:6][CH:5]=1
Reactant: CCC[SiH]1CCCCC1
Reactant: C1CCOC1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: Cl[Cu]Cl
Agent: [Mg]
Product: CCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(OC(F)(F)F)cc3)CC2)CC1

Procedure:
4.8 g (20 mmol) of p-trifluoromethoxybromobenzene was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 10 mg of copper chloride (I), 10 mg of copper chloride (II) and 7.3 g (20 mmol) of trans-4-(2-bromoethyl) cyclohexyl)-1-n-propyl-1-silacyclohexane. After a conventional after treatment, 6.6 g (yield 80%) of trans-4-(trans-4-(2-(4-trifluoromethoxyphenyl) ethyl) cyclohexyl)-1-n-propyl-1-silacyclohexane was obtained.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.8 %

Procedure:
To a cooled and stirred solution of 3′-[4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.24 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.081 g, 34%). MS (ISP) 471.2 [(M+H)+]; mp 220° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]([NH2:32])=[O:31]>CC(C)=O>[F:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][N:14]([CH2:29][C:30]([NH2:32])=[O:31])[CH2:15][CH2:16][C:10]=2[CH:9]=1
Reactant: NC(=O)CCl
Reactant: Fc1cccc(COc2ccc3c(c2)CCNCC3)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)CN1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Yield: 50.3 %

Procedure:
A solution of 70 mg (0.23 mmol) of 7-(3-fluoro-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride [Example 1c)] in 1 ml of acetone was successively treated with 69 mg (0.5 mmol) of potassium carbonate and 24 mg (0.25 mmol) of 2-chloroacetamide. The reaction mixture was heated to reflux during 18 h. For the working-up, 1 g of silica gel was added to the cooled reaction mixture, which was then evaporated under reduced pressure. For purification, the crude material obtained was chromatographed on silica gel using a 95:5:0.1-mixture of dichloromethane, methanol and ammonium hydroxide as the eluent. There were obtained 38 mg (51% of theory) of 2-[7-(3-fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-acetamide as a white solid; MS: m/e 329 (M+H)+.