Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[CH:12]([OH:14])[CH3:13].[H-].[Na+].[CH2:17](Br)[CH3:18].CO>C1C=CC=CC=1.O>[CH3:17][CH2:18][O:14][CH:12](/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])[CH3:13]
Reactant: CC1=C(/C=C/C(C)O)C(C)(C)CCC1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: c1ccccc1
Product: CCOC(C)/C=C/C1=C(C)CCCC1(C)C
Temperature: 20 °C
Yield: 81.4 %

Procedure:
A solution of 350 g (1.8 mol) of β-ionol in 600 ml of benzene was allowed to flow in over a period of 15 minutes to a suspension of 97.5 g (2.34 mol) of sodium hydride (ca 55%-60%) in 3 liters of benzene and the mixture was subsequently stirred at reflux for 8 hours. The mixture was cooled to ca 50° C. and treated over a period of 10 minutes with 232 g (2.13 mol) of ethyl bromide. The mixture was stirred at reflux for 20 hours, cooled to 20° C., cautiously treated with 50 ml of methanol and, after 20 minutes, with 1.2 liters of water. The phases were separated, the organic phase was washed with water until neutral, dried and concentrated. Crude distillation of the crude product gave 326 g of crude ether 2 of boiling point 120°-128° C./10 mmHg. Fine distillation finally gave 274 g (68.3%) of pure and olfactorily good β-ionyl ethyl ether 2 of boiling point 121° C./10 mmHg; nD20 =1.4752.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:54][CH2:55][C@H:56]([OH:58])[CH3:57]>O.CN(C)C=O>[OH:58][C@H:56]([CH3:57])[CH2:55][NH:54][C:18](=[O:20])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[CH:4][C:3]=3[O:2][CH3:1])=[N:16][CH2:15]1
Reactant: C[C@@H](O)CN
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC[C@@H](C)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.3 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzotriazole (130 mg), (2R)-1-aminopropan-2-ol (100 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was washed with ethyl acetate-diethyl ether to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (220 mg, 65%) as colorless prisms. MS 519 (MH+). mp 185-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CCCC(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CCCC(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)ccc1F

Procedure:
Example 108 was prepared from bis(4-chlorophenyl) acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butan amide according to the procedures described in Scheme 10: ESMS m/e: 584.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]#[N:17])/[C:8]([O:10]CC)=[O:9])[N:6]=1.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+]>CN(C)C=O.O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]2[NH:17][N:20]=[N:19][N:18]=2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCC#N)c1csc(N)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(/C(=N/OCc2nnn[nH]2)C(=O)O)cs1
Reaction time: 1 h
Yield: 73.7 %

Procedure:
5.0 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetate are heated to 60° C. for 48 hours while stirring together with 1.95 g of sodium azide and 1.6 g of ammonium chloride in 50 ml of dimethylformamide. The mixture is taken up in water/ethyl acetate. The ethyl acetate phase is washed twice with a small amount of water. The combined aqueous phases are concentrated to dryness, the residue is dissolved in 50 ml of 1N aqueous sodium hydroxide solution and stored at room temperature for 1 hour. The mixture is subsequently diluted with 50 ml of water and the solution is concentrated to 50 ml. The product crystallizes after the addition of 50 ml of aqueous 1N hydrochloric acid. There are obtained 3.9 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-(1H-tetrazol-5-yl-methoxy)imino]-acetic acid of melting point 151°-152° C. The water content is 6.96%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]1[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=[CH:12]1)[CH3:2].[OH:19][CH2:20][CH2:21][N+:22]([CH3:25])([CH3:24])[CH3:23].C1(C)C=CC=CC=1>O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]1[C:15]([C:16]([O-:18])=[O:17])=[CH:14][N:13]=[CH:12]1)[CH3:2].[OH:19][CH2:20][CH2:21][N+:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CCc1cccc(CC)c1-n1cncc1C(=O)O
Agent: C[N+](C)(C)CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cccc(CC)c1-n1cncc1C(=O)[O-]
Yield: 97 %

Procedure:
25 pbw (0.10 mole) of 1-(2,6-diethylphenyl)imidazole-5-carboxylic acid and 27.0 pbw (0.11 mole) of a 50% aqueous solution of choline are heated in 100 pbv of toluene in a water separator, until the water has been completely removed. The mixture is allowed to cool and is then evaporated in vacuo. 34.5 pbw (97% of theory) of 2-hydroxyethyltrimethylammonium 1-(2,6-diethylphenyl)imidazole-5-carboxylate, a high-viscosity oil, are obtained; identification is carried out by 1H-NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:13]CBr.[CH2:16]1[CH2:20]O[CH2:18][CH2:17]1>>[Br-:13].[Br-:13].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]2[CH:12]=[CH:11][N:10]([CH2:5][N:8]3[CH:12]=[CH:11][N+:10]([C:16]4[CH:20]=[CH:1][C:2]([CH3:3])=[CH:18][CH:17]=4)=[CH:9]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-n2ccnc2)cc1
Reactant: BrCBr
Reactant: C1CCOC1
Product: Cc1ccc(-[n+]2ccn(Cn3cc[n+](-c4ccc(C)cc4)c3)c2)cc1
Product: [Br-]
Reaction time: 9 h

Procedure:
0.013 mol of 1-(4-methylphenyl)imidazole (2.000 g), 0.0063 mol of dibromomethane (1.099 g; 0.45 ml) and 5 ml of THF are stirred in a pressure tube at room temperature overnight and then at 120° C. for 9 hours. The precipitated solid is filtered off and washed repeatedly with a little tetrahydrofuran.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[O:18][C:19]5[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:31]1([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[O:18][C:19]5[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2.[N:31]1([CH2:37][CH2:38][CH2:39][NH-:40])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: NCCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: [NH-]CCCN1CCOCC1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
To solution of 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (73.9 mg, 0.18 mmol) and 3-morpholine-4-yl-propylamine (0.053 ml, 0.37 mmol) in DMF 4.0 mL was added HATU (54.8 mg, 0.37 mmol) and DIPEA (0.064 ml, 0.37 mmol). After stirring at room temperature, the mixture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=10:1) to give 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (3-morpholine-4-yl-propylamide as a white foam (11.9 mg, 13% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1COCC1.C(OCC)(=O)C>[CH3:10][OH:11].[O:16]1[CH2:17][CH2:18][N:13]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][C:10]([OH:12])=[O:11])[CH2:14][CH2:15]1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1ccccc1CCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CO
Product: O=C(O)Cc1ccccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 174.7 %

Procedure:
To a suspension of 2-(2-(chloromethyl)phenyl)acetic acid (2.00 g, 10.8 mmol) in THF (20 mL) was added morpholine (1.89 g, 21.7 mmol) and the solution was stirred at room temperature for 3 hours. The reaction mixture was then diluted with ethyl acetate and extracted with H2O (2×). The aqueous phase was lyophilized and the residue was purified by silica gel chromatography (Biotage/0-10% methanol-CH2Cl2) to give the title compound 2-(2-(Morpholinomethyl)phenyl)acetic acid as a colorless solid (2.22 g, 87%). 1H NMR (400 MHz, CD3OD) δ 7.37-7.44 (m, 3H), 7.29-7.33 (m, 1H), 4.24 (s, 2H), 3.83 (br s, 4H), 3.68 (s, 2H), 3.14 (br s, 4H). LCMS: Anal. Calcd. for C13H12NO3: 235; found: 236 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)#[N:2].CO.[ClH:18]>C1COCC1>[Cl-:18].[N+:13]([C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH2:1][NH3+:2])([O-:15])=[O:14]
Reactant: COC(=O)c1ccc(C#N)cc1[N+](=O)[O-]
Reactant: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C[NH3+])cc1[N+](=O)[O-]
Product: [Cl-]

Procedure:
700 ml of a 1 M BH3 solution in THF (0.7 mol) are metered in the course of one hour at 40-50° C. into a solution of 144 g (0.7 mol) of methyl 4-cyano-2-nitrobenzoate in 250 ml of THF and the mixture is subsequently refluxed for a further 1.5 hours. The reaction mixture is then treated with 600 ml of methanol saturated with hydrogen chloride gas, with ice-cooling, and refluxed for one hour. The mixture is concentrated completely under atmospheric pressure and reevaporated with 700 ml of methanol. The residue which remains is stirred with 500 ml of ethyl acetate and filtered, and the product is dried. This gives 115 g (67%) of 3-nitro-4-methoxycarbonylbenzyl-ammonium chloride of melting point 247-248° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:26]([CH:27](OCC)OCC)=[CH:25][N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(OC(C)=O)=O.[N:41]1[CH:46]=CC=C[CH:42]=1.CNC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:26]([CH2:27][N:41]([CH3:46])[CH3:42])=[CH:25][N:24]=[N:23]2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccncc1
Reactant: CCOC(OCC)c1cnnn1-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CNC
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CN(C)Cc1cnnn1-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 30 mL scintillation vial was charged with 4-tert-butyl-N-[4-chloro-2-(5-diethoxymethyl-[1,2,3]triazol-1-yl)-phenyl]-benzenesulfonamide (synthesized according to general procedure Q, 1.0 g, 2.0 mmol) and Ac2O/pyridine (1:2 v/v, 6 mL), and stirred at room temperature for 4 hours. The reaction mixture was subsequently diluted with Et2O and washed with 1 M HCl, saturated NaHCO3, and brine. The combined organics were then dried over Na2SO4 and concentrated in vacuo. The resultant product (35 mg, 0.075 mmol) and dimethyl amine (80 μL, 2.0 M in THF) were combined in a 4 mL scintillation vial and stirred for 30 minutes. NaBH(OAc)3 (32 mg, 0.17 mmol) was then added and the reaction was stirred for 12 hours at room temperature. The reaction mixture was subsequently diluted with Et2O, washed with 1 M HCl, and the combined organics were purified by preparative TLC to generate 4-tert-butyl-N-[4-chloro-2-(5-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-benzenesulfonamide: MS (ES) M+H expected 448.2, found 448.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:25]=[CH:24][C:12]([C:13]([NH:15][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])=[O:14])=[CH:11][C:10]=2[NH:26][C:27]2[C:28]3[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[N:33][C:29]=3[N:30]=[CH:31][N:32]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C1COCC1.C(OCC)(=O)C>[CH:37]([C:34]1[CH:35]=[CH:36][C:28]2[C:27]([NH:26][C:10]3[CH:11]=[C:12]([CH:24]=[CH:25][C:9]=3[S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:48]([CH3:47])(=[O:50])=[O:49])=[CH:3][CH:4]=3)[C:13]([NH:15][C@H:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])=[O:14])=[N:32][CH:31]=[N:30][C:29]=2[N:33]=1)([CH3:39])[CH3:38]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(NS(C)(=O)=O)cc3)ncnc2n1

Procedure:
A solution of the product of Example 385G (50 mg, 0.094 mmol) and triethylamine (0.030 mL, 0.215 mmol) in THF (1.0 mL) at 0° C. under N2 was treated with methanesulfonyl chloride (0.008 mL, 0.103 mmol) added dropwise then reacted at room temperature for 1 hour. The reaction was recooled to 0° C., followed by additional methanesulfonyl chloride (0.004 mL, 0.052 mmol) added dropwise and reaction at room temperature for 0.5 hours. The mixture was diluted with ethyl acetate (20 mL) and the organic layer was washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with dichloromethane and ending with ethyl acetate (25 mg, 44%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J=6.99 Hz, 6 H) 1.46 (d, J=6.99 Hz, 3 H) 3.03 (s, 3 H) 3.15-3.28 (m, 1 H) 5.04-5.31 (m, 1 H) 7.09 (d, J=8.09 Hz, 2 H) 7.13-7.27 (m, 3 H) 7.26-7.45 (m, 7 H) 7.62 (d, J=8.46 Hz, 1 H) 7.77 (dd, J=8.27, 1.65 Hz, 1 H) 7.95 (s, 1 H) 8.57 (s, 1 H) 8.82 (d, J=8.46 Hz, 2 H) 10.00 (s, 1 H) 10.20 (s, 1 H).
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([O:24]C)=[O:23])[CH:17]=[CH:18][C:19]=1[OH:20]>CO.O>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([OH:24])=[O:23])[CH:17]=[CH:18][C:19]=1[O:20][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: CC(C)Cc1ccc(CCl)cc1
Solvent: O
Solvent: CO
Product: CC(C)Cc1ccc(COc2ccc(CC(=O)O)cc2Cl)cc1

Procedure:
3-chloro-4-(4'-isobutylbenzyloxy) phenylacetic acid was prepared in accordance with the procedure designated (f) above by reacting 4-isobutylbenzyl chloride and methyl 3-chloro-4-hydroxyphenylacetate. The resultant product evidenced a melting point of 97°-99° C. (methanol-water 4:1), the yield being 61%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].CCN(CC)CC.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>C1COCC1>[CH3:17][O:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:34]([NH:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]([F:25])([F:36])[F:37])=[O:35]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.9 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methoxyphenylacetate (1.11 g, 4.68 mmol) and Et3N (720 ml 5.17 mmol) in THF (10 ml) was added 2-trifluoromethylphenyl isocyanate (707 ml, 4.68 mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to a small volume and diluted with n-hexane. Resulting precipitate was collected under a reduced pressure and washed with n-hexane to give tert-butyl 3-methoxy-4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.11 g, 56%) as a white crystalline powder. mp 131-133° C.; 1H-NM (CDCl3) δ1.44 (s, 9 H), 3.49 (s, 2 H), 3.85 (s, 3 H), 6.83-6.88 (m, 3 H), 6.98 (br s, 1 H), 7.17-7.21 (m, 1 H), 7.52-7.59 (m, 2 H), 7.89-7.91 (m, 1 H), 8.04-8.06 (m, 1 H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].[CH3:34][CH2:35][C@H:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)C>[CH3:34][C@H:35]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH2:36][CH3:37]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: CC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Yield: 84.2 %

Procedure:
A solution of DIAD (16.6 mL, 84.0 mmol) in dry THF (100 mL) was added dropwise to a cooled (ice bath) stirred mixture of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (14.5 g, 56.2 mmol); R-(−)-sec-butanol (5 g, 67.0 mmol) and solid-supported triphenylphosphine (28 g, of 3 mmol per g loading, 84.0 mmol) in dry THF (400 mL) whilst maintaining the temperature below 10° C. The mixture was allowed to stir for 3 hours, then diluted with diethyl ether (800 mL) and filtered. Removal of the solvent gave a pale coloured oil, which was purified by column chromatography on silica, eluting with 25% ethyl acetate in hexane; to give the desired product (14.87 g).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: CN(C)CCCOc1ccccc1C=O
Solvent: CCO
Product: CN(C)CCCOc1ccccc1C=Nc1ccccc1
Yield: 83.2 %

Procedure:
A solution of 15 g of 2-(3-dimethylaminopropoxy)benzaldehyde and 8.0 g of aniline (distilled over zinc dust) in 300 ml of ethanol is kept at room temperature for 22 hours, refluxed for 2 hours, and the solvent removed on a rotary evaporator. The residue (21.3 g) is distilled to give 17 g of an oil; boiling point 171°-175° C/0.2 mm of Hg.
Reaction SMILES: [CH2:1]([N:8]([CH3:20])[CH2:9][C:10](=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:21]#[N:22].[Na+].[NH4+:24].[Cl-]>N.CO.C(Cl)Cl>[NH2:24][C:10]([CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:20])([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:21]#[N:22]
Reactant: [NH4+]
Reactant: CN(CC(=O)CCc1ccccc1)Cc1ccccc1
Reactant: [C-]#N
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN(Cc1ccccc1)CC(N)(C#N)CCc1ccccc1

Procedure:
1-(Benzyl-methyl-amino)-4-phenyl-butan-2-one (2.4 g, 9.0 mmol, 1.0 equiv) was mixed in 36 mL of 2.0 M NH3 in MeOH. To the solution was added NaCN (0.484 g, 9.9 mmol, 1.1 equiv) and NH4Cl (0.528 g, 9.9 mmol, 1.1 equiv). The resulting mixture was refluxed for 2 h at which time an addition 15 mL of 2.0 M NH3 in MeOH was added and the mixture was refluxed another 4 h. Though TLC (5% MeOH in CH2Cl2) still showed the presence of the ketone, the reaction was cooled and filtered. The filtrate was concentrated and the crude product was purified by flash chromatography on SiO2 using 60% hexanes in CH2Cl2 then 1.5% MeOH to 3% MeOH was added. The desired product was isolated pure (0.561 g, 21%) as a yellow oil that crystallized upon standing at −20° C.; MS, m/z 294=M+1.
Reaction SMILES: [C:1]1([S:7]([Cl:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Cl-].[CH2:13]([N:20]([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:21][CH2:22][CH2:23][NH2:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-:29].[Na+]>CCOCC>[ClH:10].[CH2:13]([N:20]([CH2:21][CH2:22][CH2:23][NH:24][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:8])=[O:29])[CH2:25][CH2:26][CH2:27][NH:28][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCCN(CCCN)Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: [OH-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: Cl
Product: O=S(=O)(NCCCN(CCCNS(=O)(=O)c1ccccc1)Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Into a 1-L round-bottomed flask equipped with an addition funnel, a stirring bar and a nitrogen inlet, were added 40.2 g(0.23 mol) of benzenesulfonyl chloride, 150 mL of ether and 175 mL of a saturated aq. NaCl solution. The addition funnel was charged with a solution of 25.4 g (0.12 mol) of N-benzylbis(3-aminopropyl)amine and 175 mL of 1.3 N aq. NaOH. The amine was added dropwise with vigorous stirring over 2 h. The mixture was poured into a separatory funnel and the aqueous portion (bottom layer) removed. The two organic layers were diluted with 100 mL of chloroform and the resulting solution concentrated by rotary evaporation to a pale yellow oil. The residue was dissolved in 150 mL of dichloromethane. A solution of 2 N aq. HCl (60 mL) and 60 mL of saturated aq. NaCl was added and the mixture was stirred vigourously for 1 h. The layers were separated and the organic (lower) layer was washed with a saturated aq. NaCl solution (3×50 mL) and concentrated by rotary evaporation. The residue was recrystallized by bringing an ethanol solution of the residue to a boil and adding ethyl acetate to induce precipitation. The mixture was cooled to room temperature then to −25° C. for 2 weeks. Vacuum filtration of the precipitate gave 55.9 g (90%) of N-benzylbis(3-benzenesulfonamidopropyl)amine hydrochloride as a white solid. An analytical sample was prepared by drying at 65° C. (1 mm) for 13 h, mp 135-136° C. 1H NMR (DMSO-d6) δ11.0 (br, 1 H, BnNH), 7.89 (t, 2 H, J=5.7 Hz, SO2NH), 7.79 (d, 4 H, J=7.2 Hz,SO2ArH2,6), 7.59(m, 8 H. SO2ArH3,4,5, BnArH3,5), 7.41 (m, 3 H, BnArH2,4,6) 4.23 (d, 2 H, J=4.2 Hz, PhCH2N), 2.93 (m, 4 H, ArSO2NCH2CH2), 2.74 (m, 4 H, BnNCH2CH2), 1.88 (m, 4 H, NCH2CH2CH2N), 13C NMR (DMSO-d6) (140.3, 132.6, 131.5, 129.8, 129.6, 129.4, 128.9, 126.6, 56.0, 49.4, 40.1, 23.3. IR (KBr, cm−1) 3242 (br), 3073 (s), 2976 (m), 2855 (m), 2609 (s), 1470 (m), 1446 (s), 1330 (s), 1163 (s), 1092 (s), 740 (s), 689 (s). Anal. calc. for C25H31N3S2O4 HCl; C, 55.80; H, 5.99; N, 7.81; S, 11.92; Cl, 6.59. Found: C, 55.47; H, 6.13; N, 7.63; S, 11.63; Cl, 6.92%.