Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C(C)=C2C(CCC(CCCC(CCCC(CCCC(C)C)C)C)(C)[O:9]2)=C(C)C=1O.N1C=CC=CC=1.[CH3:38][O:39][C:40]1[CH:50]=[CH:49][C:43]([CH:44]=[CH:45][C:46](Cl)=[O:47])=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:38][O:39][C:40]1[CH:50]=[CH:49][C:43]([CH:44]=[CH:45][C:46]([OH:9])=[O:47])=[CH:42][CH:41]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)cc1
Yield: 88 %

Procedure:
4.3 g of dl-α-tocopherol (0.010 mol) and 1.34 g of pyridine (0.017 mol) are placed in 20 ml of CH2Cl2 while gassing with argon in a 100 ml 4-necked sulphonation flask provided with a temperature, a 20 ml dropping funnel, a magnetic stirrer and a reflux condenser. A solution of 0.95 g of 4-methoxycinnamic acid chloride (0.015 mol) in 15 ml of CH2Cl2 is added dropwise within 10 minutes. The reaction mixture is heated to reflux temperature for 3 hours. The solution is washed in succession with 10 ml of water, 10 ml of 5% HCl and 10 ml of 5% NaHCO3. After drying (Na2SO4) the solvent is concentrated on a rotary evaporator. The crude product (6.3 g) is chromatographed (toluene) on 150 g of silica gel (0.040-0.063 mm) under 0.5 bar pressure. There are obtained 5.2 g of yellowish d,l-α-tocopherol ester of p-methoxycinnamic acid (yield 88%).
Reaction SMILES: O=[C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:11][NH2:12]>C(O)C>[CH3:11][N:12]=[C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCCc2scnc21
Reactant: CN
Solvent: CCO
Product: CN=C1CCCc2scnc21
Yield: 86 %

Procedure:
6 g (0.039 mole) of the ketone obtained in step (d) are dissolved in 50 ml anhydrous ethanol and treated for 30 minutes with a gaseous methylamine stream. After evaporation to dryness, the residue is taken up into ether and filtered, to give 5.6 g (86%) of product, M.p. 233°-235° C.
Reaction SMILES: N1C=CC=CC=1.[Br:7][CH2:8][C:9](Br)=[O:10].[C:12]1([C:18]([OH:21])([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[Br:7][CH2:8][C:9]([O:21][C:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:20])[CH3:19])=[O:10]
Reactant: O=C(Br)CBr
Reactant: CC(C)(O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(OC(=O)CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
Pyridine (3.84 mL, 47.7 mmol) followed by bromoacetyl bromide (4.16 mL, 47.7 mmol) was added to a solution of 2-phenylpropan-2-ol (5.00 g, 36.7 mmol) in dichloromethane (100 mL) at 0° C., warmed to r.t. and stirred overnight. The reaction mixture was washed with water (3×100 mL), saturated aqueous sodium bicarbonate (3×100 mL), water (2×100 mL), dried (Na2SO4) and concentrated. The crude residue was purified by silica gel flash column chromatography (neutralized with TEA, heptanes) to afford the title compound (2.8 g (non-optimized), 30%) as a colorless oil. 1H NMR (300 MHz, ((CD3)2CO) δ: 7.44 (d, J=7.2 Hz, 2H), 7.34 (t, J=7.2 Hz, 2H), 7.25 (t, J=7.2 Hz, 1H), 4.01 (s, 2H), 1.78 (s, 6H).
Reaction SMILES: C([O:8][C:9]1([CH3:30])[CH2:18][CH2:17][C:16]2[NH:15][CH:14]=[C:13]3[C:19](=[O:29])[N:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[N:21]=[C:12]3[C:11]=2[CH2:10]1)C1C=CC=CC=1.[H][H]>CN(C=O)C.CCO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:20]2[C:19](=[O:29])[C:13]3=[CH:14][NH:15][C:16]4[CH2:17][CH2:18][C:9]([OH:8])([CH3:30])[CH2:10][C:11]=4[C:12]3=[N:21]2)=[CH:23][CH:24]=1
Reactant: CC1(OCc2ccccc2)CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1
Reactant: [H][H]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC1(O)CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1

Procedure:
8-Benzyloxy-2-p-chlorophenyl-8-methy-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one (4 g) is dissolved in 200 mL of a 1:1 mixture of DMF/EtOH and subjected to catalytic hydrogenation with 5% palladiium on carbon (1 g) for 24 hours under 1 atm. of hydrogen. After the reaction is over, the catalyst is filtered off, the filtrate is evaporated, and the dried residue is triturated with EtOH to yield 2-p-chlorophenyl-8-hydroxy-8-methyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=O)[NH:10][C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:8]2.O=P(Cl)(Cl)[Cl:22]>CC#N>[Cl:22][C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[N:4][C:3]=2[O:2][CH3:1])[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1
Reactant: COc1nccc2cc(-c3ccccc3)[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1nccc2cc(-c3ccccc3)nc(Cl)c12

Procedure:
8-Methoxy-3-phenyl-2,7-naphthyridin-1(2H)-one (80 mg, 0.32 mmol) is dissolved in CH3CN (2 mL) and POCl3 (59 uL, 0.64 mmol) The mixture is stirred at 80° C. for 3 hours. POCl3 is removed and neutralized with sat. NaHCO3. The compound is extracted with CHCl3 and the organic layer is dried (Na2SO4) and evaporated to yield the crude compound and used for the next step without any further purification. MS m/z 271.1 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(Cc3ccc(C(C)(C)C)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-bromomethyl-4-tert-butyl-benzene as described in Example 49 and isolated as a yellow solid (0.080 g, 53% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.36-7.40 (m, 3H), 7.26-7.30 (m, 1H), 7.20 (d, J=8 Hz, 2H), 6.82 (d, J=2 Hz, 1H), 6.09-6.14 (m, 1H), 5.31 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H), 1.30 (s, 9H); MS (M+H)+=445.9; Rt=1.47 min; HRMS (M+H)+=446.20.
Reaction SMILES: ClC1C=C[CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[C:12]([O:16][C:17]([NH:19]C=C(C)C)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[C:12]([O:16][C:17]([NH:19][CH:8]1[O:10][C:4]1([CH3:3])[CH3:5])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)=CNC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1OC1(C)C

Procedure:
A solution of 27.18 g of m-chloroperbenzoic acid in chloroform is cooled to circa 10° under argon and treated, by dropwise addition, with a chloroform solution of 17.1 g of 3-(N-tert.-butoxycarbonylamino)-2-methyl-prop-2-ene over a period of 1 hour maintaining the temperature below 15° with external cooling. About 30 minutes after the addition is complete and a white precipitate begins to form. Completeness of the reaction can be judged by chromatographic analysis. When the reaction is complete, the suspension is diluted with chloroform and washed with 3×300 ml of a 10% aqueous solution of sodium bisulphite followed by 3×300 ml of a 10% aqueous solution of sodium bicarbonate. Drying of the organic layer and removal of the solvent in vacuo afforded 3-(N-tert.-butoxycarbonylamino)-2-methyl-2,3-epoxypropane as a colourless oil; 1H-NMR (CDCl3): δ (ppm)=3.3 (2H, t, CH2N), 2.65 (2H, ABq, CH2) 1.43 (9H, s, tBu), 1.33 (3H, s, CH3).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([N:21]2[CH2:24][CH:23]([NH:25][S:26]([C:29]3[CH:34]=[C:33](F)[CH:32]=[C:31]([F:36])[CH:30]=3)(=[O:28])=[O:27])[CH2:22]2)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1>CS(C)=O.ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:21]2[CH2:22][CH:23]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:32]=[C:31]([F:36])[CH:30]=3)(=[O:27])=[O:28])[CH2:24]2)=[CH:11][CH:12]=1
Reactant: C1CCNC1
Reactant: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(N2CCCC2)c1
Temperature: 90 °C

Procedure:
0.104 cm3 of pyrrolidine is added, at room temperature, to 0.24 g of N-{-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-(3,5-difluorophenyl)sulfonamide in solution in 6 cm3 of dimethyl sulfoxide and then the mixture is heated for 18 hours at 90° C. The reaction mixture is diluted with 30 cm3 of dichloromethane and washed with three times 30 cm3 of distilled water. The organic phased is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography on silica gel, eluting with dichloromethane. 50 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3-fluoro-5-pyrrolidin-1-ylphenyl)sulfonamide are thus obtained in the form of a white powder [1H NMR spectrum (600 MHz, CDCl3 with addition of a few drops of CD3COOD d4, δ in ppm): 2.04 (mt: 4H); from 3.20 to 3.35 (mt: 6H); 3.60 (t, J=8.5 Hz: 2H); 4.14 (mt: 1H); 4.57 (s: 1H); 6.31 (broad d, J=11.5 Hz: 1H); 6.70 (broad d, J=8.5 Hz: 1H); 6.72 (broad s: 1H); from 7.20 to 7.35 (mt: 8H)].
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]#[CH:6])[CH3:2].Cl[C:8]([O:10][CH2:11][CH3:12])=[O:9]>>[CH2:11]([O:10][C:8](=[O:9])[C:6]#[C:5][CH2:4][S:3][CH2:1][CH3:2])[CH3:12]
Reactant: CCOC(=O)Cl
Reactant: C#CCSCC
Product: CCOC(=O)C#CCSCC

Procedure:
The title compound was prepared from 3-ethylsulfanyl-propyne and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, (5697-5708).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][C:13](=[O:15])[CH2:12][CH2:11][N:10]2[C:16]([N:18]2[CH2:24][C:23]3[CH:25]=[C:26]([C:29]4[CH:30]=[CH:31][C:32]5[N:36]=[C:35]([NH:37]C(=O)OCC6C=CC=CC=6)[NH:34][C:33]=5[CH:48]=4)[CH:27]=[CH:28][C:22]=3[O:21][CH2:20][CH2:19]2)=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]>C(O)(=O)C.[Pd]>[NH2:37][C:35]1[NH:34][C:33]2[CH:48]=[C:29]([C:26]3[CH:27]=[CH:28][C:22]4[O:21][CH2:20][CH2:19][N:18]([C:16]([N:10]5[CH2:11][CH2:12][C:13](=[O:15])[CH2:14][CH:9]5[C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=5)=[O:17])[CH2:24][C:23]=4[CH:25]=3)[CH:30]=[CH:31][C:32]=2[N:36]=1
Reactant: O=C1CCN(C(=O)N2CCOc3ccc(-c4ccc5nc(NC(=O)OCc6ccccc6)[nH]c5c4)cc3C2)C(c2ccc(F)c(F)c2)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCC(=O)CC3c3ccc(F)c(F)c3)CCO4)cc2[nH]1
Yield: 8 %

Procedure:
A solution of phenylmethyl [6-(4-{[2-(3,4-difluorophenyl)-4-oxopiperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-yl]carbamate (0.11 g, 0.17 mmol) in acetic acid (5 mL) was hydrogenated at 1 atm over 10% Pd—C (0.1 g) for 2 h. The catalyst was filtered off and the filtrate was concentrated. The resulting brown residue was dissolved in methanol and purified by preparative reverse phase HPLC to afford 1-{[7-(2-amino-1H-benzimidazol-6-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-2-(3,4-difluorophenyl)piperidin-4-one (0.007 g, 8% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): 7.02-7.29 (m, 8H), 6.98 (d, 1H), 6.94 (d, 1H), 5.27 (t, 1H), 4.43-4.46 (m, 2H), 4.16-4.30 (m, 2H), 3.70-3.85 (m, 3H), 3.21-3.31 (m, 1H), 2.79-2.99 (m, 2H), 2.51-2.61 (m, 1H), 2.32 (d, 1H); MS (EI) for C28H25F2N5O3: 518 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[N:12]([CH3:13])[N:11]=[C:10]([CH3:14])[C:9]=2[CH:15]=[N:16]O)=[CH:5][CH:4]=1.[C:20]([NH:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][CH:27]=1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:20]([NH:24][C:25](=[O:34])[C:26]1[CH:27]=[CH:28][C:29]([CH2:32][N:16]=[CH:15][C:9]2[C:10]([CH3:14])=[N:11][N:12]([CH3:13])[C:8]=2[O:7][C:6]2[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:30][CH:31]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(Oc2c(C=NO)c(C)nn2C)cc1
Reactant: CC(C)(C)NC(=O)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Oc2c(C=NCc3ccc(C(=O)NC(C)(C)C)cc3)c(C)nn2C)cc1
Yield: 84.8 %

Procedure:
1.0 Gram (0.0038 mole) of 5-(4-methoxyphenoxy)-1,3-dimethylpyrazole-4-carbaldehyde oxime, 0.86 g (0.0038 mole) of N-tert-butyl-4-chloromethylbenzamide and 1.0 g (0.0072 mole) of potassium carbonate were added to 20 ml of acetonitrile, and the resulting mixture was heated under reflux for 6 hours. After completion of the reaction, acetonitrile was removed by evaporation under reduced pressure, after which water was added to the residue and extraction was carried out with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 1.4 g of the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Si:12]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NS(=O)(=O)c1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(S(N)(=O)=O)cc1
Reaction time: 20 h

Procedure:
4-Hydroxyphenylsulfonamide (3.46 g, 20 mmol) is dissolved in DMF (40 mL) and treated with tert-butyl-dimethylsilylchloride (3.31 g, 22.0 mmol) and imidazole (1.50 g, 22.0 mmol) at room temperature. After 20 hr, the reaction mixture is diluted with EtOAc (100 mL) and washed with 1.0 N HCl (2×50 mL). The organic phase is dried (MgSO4), filtered, and concentrated to yield an oil. The crude oil is purified by Biotage column chromatography (40M SiO2 column, eluted at 75 mL/min with 1:1 hexanes:EtOAc). A white solid is obtained (4.24 g, 15.4 mmol, 77%). ESI-MS m/e 288.1 (M++H); mp 117–118° C.; 1H NMR (CDCl3) δ 7.78 (d, 2H), 6.89 (d, 2H), 4.86 (br s, 2H), 0.97 (s, 9H), 0.20 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:21]([O:23][CH2:24][C:25](Cl)=O)[CH3:22]>>[CH2:21]([O:23][CH2:24][C:25]1[N:12]([CH2:13][C:14]2([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:22]
Reactant: CCOCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCOCC1
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCOCC1
Yield: 80.2 %

Procedure:
4-{[(3-Aminoquinolin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol (7.50 g, 27.4 mmol) was reacted with ethoxyacetyl chloride (3.70 g, 30.1 mmol) and the resulting product was cyclized according to the method described in Part E of Example 9 to provide 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol as pale tan crystals (7.50 g, 76%) after crystallization from ethanol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13]([NH2:15])[CH:14]=1)=[O:8])[CH3:5].N([O-])=O.[Na+].[N-:27]=[N+:28]=[N-].[Na+]>FC(F)(F)C(O)=O.O>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[CH:12]=[C:13]([N:15]=[N+:27]=[N-:28])[CH:14]=1)=[O:8])[CH3:5]
Reactant: COCC(C)NC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COCC(C)NC(=O)c1cc(N=[N+]=[N-])cc(-c2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-amino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (500 mg, 1.68 mmol) in trifluoroacetic acid (10 mL) was added a solution of NaNO2 (21.47 mmol, 1.49 g) in water (10 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and a solution of NaN3 (44.43 mmol, 2.89 g) in water (10 mL) was added. The solution was stirred at room temperature for 16 hours. Solvent was removed under reduced pressure and the residue was extracted with ethyl acetate, washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 5-azido-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide. (80%). MS (M+H)=325.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16](=[O:42])[C:17]([C:20]1[N:21]=[C:22]([N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[S:23][CH:24]=1)([CH3:19])[CH3:18])[CH3:14].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:53])(=O)=O)=CC=1.[NH4+].[Cl-]>C1COCC1>[CH2:13]([O:15][C:16](=[O:42])[C:17]([C:20]1[N:21]=[C:22]([N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[S:23][C:24]=1[F:53])([CH3:19])[CH3:18])[CH3:14]
Reactant: CCOC(=O)C(C)(C)c1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)c1nc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)sc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
Under anhydrous condition n-BuLi (3.6 M solution in hexane, 2.55 mL, 9.20 mmol) was added to stirred solution of N,N-Diisopropyl amine (1.29 mL, 9.20 mmol) in 10 mL dry THF at −78° C. and reaction mixture was stirred for 1 hr. A solution of 2-{2-[tert-Butoxycarbonyl-(4-methoxy-benzyl)-amino]-thiazol-4-yl}-2-methyl-propionic acid ethyl ester (synthesized as per preparation 44; 2.0 g, 4.60 mmol) in 10 mL of dry THF was added dropwise to above reaction mixture and continued to stir for an additional 1 hr at −78° C. N-Fluorobenzenesulfonimide (2.17 g, 6.90 mmol) dissolved in 10 mL dry THF was added to reaction mixture dropwise and resulted reaction mixture was allowed to warm 0° C. within 3 hrs. Reaction mixture was poured on aq. saturated solution of NH4Cl (50 mL), mixture was then extracted with (3×50 mL) ethyl acetate; organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and washed with ethyl acetate and solvent was removed under reduced pressure. The crude material was purified by silica-gel column chromatography (4% ethyl acetate in hexane) to afford pure compound (0.5 g).
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[C:35](C2C=CC=CC=2CSCCO)=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:29]([O:31][C:32]([C:34]1[C:39]([C:14]2[CH:13]=[CH:12][CH:17]=[CH:16][C:15]=2[CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Reactant: CCOC(=O)c1ccccc1-c1ccccc1CSCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccccc1-c1ccccc1CSCCOc1ccccc1

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester (5.0 g, 15.80 mmol, 1 eq.) in anhydrous THF was treated with phenol (2.08 g, 22.12 mmol, 1.4 eq.), triphenylphosphine (5.80 g, 22.12 mmol, 1.4 eq.), and diisopropyl azidocarboxylate (4.47 g, 22.12 mmol, 1.4 eq.). When complete, the reaction was worked up as described leaving an orange oil.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)=[N+:2]=[N-:3].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.C(OC(=O)C)(=O)C>O1CCOCC1>[N:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[C:10](=[O:11])[C:5]=12)=[O:9])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cccc2c1C(=O)OC2=O
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(c1ccc(C(=O)O)cc1)C2=O
Temperature: 85 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
A solution of 3.78 g (0.02 mol) of 3-azidophthalic anhydride in 50 ml of dioxan is mixed with a solution of 2.74 g (0.02 mol) of p-aminobenzoic acid in 50 ml of dioxan and the mixture is left to stand for 3 hours. 5 ml of acetic anhydride are then added and the reaction mixture is heated for 1 hour at 85° C. After concentrating to dryness, the residue is mixed with water and the resulting crystals are filtered off with suction. 4.8 g (78% of theory) of 4-(3-azidophthalimidyl)-benzoic acid are obtained; melting point 300° C. (with decomposition).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1([CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH3:25][C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: Cc1ccccc1C1(C)c2ccccc2CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccccc1C1(C)NCCc2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-Benzyl-1-methyl-1-o-tolyl-1,2,3,4-tetrahydro-isoquinoline (164 mg, 0.50 mmol) and 10% Pd/C (16 mg) in acetic acid (6 ml) is stirred for 5 hours at room temperature under 1 atm of H2. The mixture is filtered through celite and the filtrate concentrated. The residue is diluted with methylene chloride and basified with saturated NaHCO3 to pH 8. The layers are separated and the aqueous layer extracted with methylene chloride. The combined organic layers are washed with brine, dried over sodium sulfate, and concentrated to give 1-Methyl-1-o-tolyl-1,2,3,4-tetrahydro-isoquinoline. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=7.2 Hz, 1H), 7.28-6.97 (m, 7H), 6.69 (d, J=8.0 Hz, 1H), 3.43-3.36 (m, 1H), 3.21-3.03 (m, 2H), 2.79 (d, J=16.4 Hz, 1H), 1.99 (s, 3H), 1.91 (s, 3H). C. 2-(1-Ethyl-1-o-tolyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2-fluoro-benzyl)-N-indan-2-yl-acetamide
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCCCCO)cc1
Temperature: 100 °C

Procedure:
2.44 g (0.02 mol) of 4-hydroxybenzaldehyde, 2.73 g (0.02 mol) of 6-chlorohexanol, 1.66 g (0.012 mol) of potassium carbonate and 20 ml of N,N-dimethylformamide were put in a three-neck 50 ml-flask equipped with a stirrer and a thermometer and heated at 100° C. for 2 hours with stirring. The reaction mixture was cooled to room temperature, poured into water containing ice and extracted with ethyl acetate. The resulting extract was dried with anhydrous sodium sulfate, and ethyl acetate was removed therefrom by distillation. The oily residue was allowed to stand at room temperature, whereupon it gradually crystallized. By silica gel thin layer chromatography (using a developer of ethyl acetate), the purity of the crystals was high. The yield of the product was 4.4 g (99.0%).