Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[C:27](=[O:28])[N:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[N:25]=[CH:24][C:23]=3[N:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>CN(C1C=CN=CC=1)C.ClCCl.N1C=CC=CC=1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[C:27](=[O:28])[N:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[N:25]=[CH:24][C:23]=3[N:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)=[O:6]
Reactant: Cc1ccc(-n2ncc(N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccc(-c4ccc(O)cc4)cc3)c2=O)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-n2ncc(N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccc(-c4ccc(OC(=O)C(C)(C)C)cc4)cc3)c2=O)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
0.66 ml of pivaloyl chloride are added dropwise to a suspension of 728 mg (1.18 mmol) of tert-butyl 4-[5-[(4′-hydroxy-1,1′-biphenyl-4-yl)oxy]-1-(4-methyl-phenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-1-piperazinecarboxylate (Example 46) and a catalytic amount of 4-DMAP in a mixture of dichloromethane (4.0 ml) and pyridine (0.4 ml) at room temperature. The heterogeneous reaction mixture is stirred at about 40° C. overnight. The slightly cloudy suspension is diluted with dichloromethane and washed with 0.2 N hydrochloric acid solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product is purified by chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[NH:15][CH:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]3([C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[CH:12]2[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])=[O:10])=[C:4]([O:39][CH3:40])[CH:3]=1.C(N(CC)CC)C.[C:48](Cl)(=[O:50])[CH3:49]>C1COCC1>[C:48]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[NH:15][CH:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]3([C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[CH:12]2[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])=[O:10])=[C:4]([O:39][CH3:40])[CH:3]=1)(=[O:50])[CH3:49]
Reactant: COc1cc(N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-amino-2-methoxy-phenyl)-amide (17 mg, 0.029 mmol) and triethylamine (4 mg, 0.044 mmol) in THF (2 mL) was acetyl chloride (2.3 mg, 0.029 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer, was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-acetylamino-2-methoxy-phenyl)-amide as a off white solid (17 mg, 93%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:18][O:17][C:16]3[CH:19]=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:26]1[CH2:31][CH:30]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:28][CH2:27]1.C(OCC)(=O)C>CS(C)=O>[O:14]1[C:15]2[C:22]3[CH2:23][CH2:24][O:25][C:21]=3[CH:20]=[CH:19][C:16]=2[O:17][CH2:18][CH:13]1[CH2:12][N:26]1[CH2:27][CH:28]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:30][CH2:31]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CCO4)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4c(c3O2)CCO4)C1
Temperature: 25 °C

Procedure:
A solution of 0.65 g (1.8 mmole) of (2R)-2,3,8,9-tetrahydrofuro[3,2-f]-[1,4]benzodioxin-2-ylmethyl 4-methylbenzenesulfonate and 1.0 g (5.0 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 10 mL of DMSO was heated under nitrogen at 80° C. for 4 hours. After the reaction had cooled to room temperature, 400 mL of ethyl acetate was added and the solution was washed with 250 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 2% methanol in chloroform to give 0.32 g of the (S)-enantiomer of the title compound as a gold solid, m.p. 207-209° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[O:10][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[C:27]([Cl:40])[CH:26]=2)=[CH:12][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[C:27]([Cl:40])[CH:26]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
(5-(4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl)-furan-2-ylmethyl)-carbamic acid tert-butyl ester (0.0218 g, 0.0379 mmol) is dissolved in DCM (2 ml) and TFA (2 ml) is added dropwise. The reaction mixture is stirred at room temperature for 1 hour. The solvent is removed under a nitrogen stream and to the residue are added consecutively saturated aqueous potassium carbonate solution and DCM. The resulting mixture is extracted with DCM containing 5% THF, the combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to yield 17.6 mg (0.037 mmol, 98%) of the clean desired product.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]([F:21])([F:20])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][C:13]2=O)=[CH:8][CH:7]=1.Cl>N1C=CC=CC=1>[F:4][C:5]([F:21])([F:20])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][C:13]2=[N:2][OH:3])=[CH:8][CH:7]=1
Reactant: NO
Reactant: O=C1CCC(=O)C(c2ccc(C(F)(F)F)cc2)N1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(=NO)C(c2ccc(C(F)(F)F)cc2)N1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
Pyridine (47 ml) and hydroxylamine hydrochloride (8.18 g) were added to a stirring solution of 6-(4-trifluoromethyl-phenyl)piperidin-2,5-dione (5.04 g) under nitrogen. The mixture was heated at reflux for 21 h, cooled to room temperature, poured into aqueous hydrochloric acid (2M, 100 ml) and extracted with ethyl acetate (100 ml). The organic extract was washed with aqueous hydrochloric acid (3×100 ml) and the combined aqueous solution was extracted with ethyl acetate (2×50 ml). The combined organic solution was dried (MgSO4) and evaporated in vacuo to give the crude product (5.84 g) which was azeotroped with toluene (3×50 ml). FCC (dichloromethane: methanol, 12:1) gave the title compound (3.26 g) as an inseparable mixture of geometrical isomers (2:1).δ(d6 -DMSO) for the major isomer 2.0-2.4 (m,4H), 5.15 (d,1H, J=3.5 Hz), 7.49 and 7.75 (2d,4H, J=8 Hz for both). 8.39 (d,1H, J=3.5 Hz), 11.08 (s,1H). 1 H-NMR signals for the minor isomer includes 5.77 (d,1H, J=2.5 Hz), 7.59 and 7.72 (2d,4H, J=8 Hz for both), 8.10 (d,1H, J=2.5 Hz),11.14 (s,1H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:9][N:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[N:19]=[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([N:29]([CH2:37][C:38]([F:41])([F:40])[F:39])C(=O)OC(C)(C)C)[CH:24]=4)[O:21][CH:22]=3)=[O:17])=[CH:13][N:12]([CH3:42])[N:11]=2)[C:7](=[O:43])[CH2:6]1)[CH3:3].C(OC(=O)C)C.Cl>CO>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:9][N:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[N:19]=[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH2:37][C:38]([F:39])([F:41])[F:40])[CH:24]=4)[O:21][CH:22]=3)=[O:17])=[CH:13][N:12]([CH3:42])[N:11]=2)[C:7](=[O:43])[CH2:6]1)[CH3:1]
Reactant: CN(C)CC1CC(=O)N(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)CC1CC(=O)N(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of tert-butyl (4-(4-((3-(4-((dimethylamino)methyl)-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (71 mg) in methanol (2.0 mL) was added 4M hydrogen chloride ethyl acetate solution (2.0 mL). The reaction mixture was stirred at room temperature for 16 hr, and the solvent was evaporated under reduced pressure. The residue was suspended in methanol, the suspension was basified with sodium methoxide, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (51 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].F[C:13]1[C:18]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[N:20]=2)=[CH:17][CH:16]=[CH:15][N:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:13]2[C:18]([C:19]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[CH2:36][C:37]4[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=4)[N:20]=3)=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(N)cc1OC
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(OC)c(OC)c3)n2)cc1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 3,4-dimethoxyaniline (Aldrich) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine, and isolated as a brown oil (100%). 1H NMR (400 MHz, CDCl3) δ 11.69 (s, 1H); 8.82 (dd, J=7.8, 2.0 Hz, 1H); 8.30 (dd, J=4.7, 1.8 Hz, 1H); 7.31 (d, J=2.2 Hz, 1H); 7.20 (d, J=8.2 Hz, 4H); 6.98 (dd, J=8.6, 2.3 Hz, 1H); 6.78-6.91 (m, 5H); 6.72 (dd, J=7.8, 4.7 Hz, 1H); 4.83 (s, 4H); 3.86 (s, 3H); 3.81 (s, 6H); 3.79 (s, 3H); 2.57 (s, 3H). m/z (ESI, +ve ion) 579.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=1)[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][C:35]=1[C:43]([F:46])([F:45])[F:44].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.C(#N)C.CCOC(C)=O>[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:1][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:20])([F:21])[F:19])[CH:12]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:30])([F:31])[F:32])[CH:23]=2)[C@@H:3]([OH:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:39])=[CH:36][C:35]=1[C:43]([F:44])([F:45])[F:46]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: NC(c1cccc(OC(F)(F)F)c1)(c1cccc(OC(F)(F)F)c1)[C@@H](O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(NC(c1cccc(OC(F)(F)F)c1)(c1cccc(OC(F)(F)F)c1)[C@@H](O)c1ccccc1)c1ccc(F)c(C(F)(F)F)c1
Yield: 15 %

Procedure:
A solution of (S)-2-amino-1-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)ethanol (44 mg, 0.096 mmol), 4-fluoro-3-(trifluoromethyl)benzoic acid (20 mg, 0.096 mmol), EDCI (28 mg, 0.14 mmol), HOBT (14 mg, 0.096 mmol) and a catalytic amount of DMAP in acetonitrile (3 mL) was stirred for 24 h at rt. The reaction mixture was diluted with EtOAc and washed successively with 1 N HCl, 1 N NaOH, sat. NaCl, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC Shimadzu-YMC Sunfire 5μ column, 30×100 mm eluting with 50-100% MeOH (90% in H2O, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm. (S)-4-Fluoro-N-(2-hydroxy-2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamide (Example 311) was isolated as a colorless film (10 mg, 15% yield). HPLC: RT=4.143 minutes (Phenomenex Luna C18 5 u column eluting with 10-90% aqueous methanol containing 0.1% phosphoric acid over a 4 minute gradient monitoring at 220 nm). LCMS: [M+H] 648.0 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 8.23 (m, 1H), 7.37-6.9 (m, 15H), 5.41 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=[O:12])[O:11][CH2:10][CH2:9]1>C(#N)C>[C:2]1([NH:1][CH2:10][CH2:9][C:8]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCO1
Solvent: CC#N
Product: O=C(O)CCNc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aniline (9.11 mL, 100 mmol) was dissolved in acetonitrile (100 mL) and heated to reflux while β-propiolactone (Sigma, 6.29 mL, 100 mmol) in acetonitrile (20 mL) was added dropwise for 30 minutes. The mixture was refluxed for 3 hours and then stirred overnight at ambient temperature. The mixture was concentrate under reduced pressure, and chromatographed on silica gel eluting with 40-to-100% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 2.69 (t, J=6.27 Hz, 2H), 3.48 (t, J=6.44 Hz, 2H), 6.66 (dd, J=8.81, 1.02 Hz, 2H), 6.75 (t, J=7.46 Hz, 1H), 7.20 (dd, J=8.65, 7.29 Hz, 2H). MS (DCI) m/z 166.05 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([OH:12])([CH3:11])[CH3:10].[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:13](=[O:14])[O:12][C:9]([CH3:10])([CH3:11])[C:3]=2[CH:4]=1
Reactant: CC(C)(O)c1cc(Br)ccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)Nc2ccc(Br)cc21
Temperature: 50 °C

Procedure:
To a solution of 2-(2-amino-5-bromophenyl)propan-2-ol (18 g, 78 mmol) in dry THF (150 mL) was added 1,1′-carbonyldiimidazole (15.5 g, 94 mmol) under nitrogen. The reaction solution was heated at 50° C. overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 mL). The solution was washed with 1N aqueous hydrochloride solution (2×40 mL), brine (20 mL), and dried with MgSO4. After removal of the solvent in vacuo, 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was obtained as a white solid (20 g, 100%): mp 199-200° C.; 1H-NMR (DMSO-d6) δ10.32 (s, 1H, D2O exchangeable), 7.48 (d, 1H, J=2.1 Hz), 7.43 (dd, 1H, J=8.5, 2.1 Hz), 6.84 (d, 1H, J=8.4 Hz), 1.61 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:21][NH2:22]>C(O)C>[CH3:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:21][NH2:22])=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN1CCN(Cc2ccc(C)cc2)CC1
Reactant: NN
Solvent: CCO
Product: Cc1ccc(CN2CCN(CC(=O)NN)CC2)cc1

Procedure:
Synthesized according to General Procedure C: 6{13} (7.66 g, 27.7 mmol, 1 equiv.), anhydrous hydrazine (2.6 mL, 83.2 mmol, 3 equiv.), ethanol (55.4 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{13} (6.10 g, 84%) as a beige solid. 1H-NMR (500 MHz, CDCl3): δ 8.14 (br s, 1H), 7.18 (d, 2H, J=8.0 Hz), 7.12 (d, 2H, J=8.0 Hz), 3.84 (br s, 2H), 3.46 (s, 2H), 3.06 (s, 2H), 2.52 (br s, 4H), 2.45 (br s, 4H), 2.33 (s, 3H). 13C-NMR (125 MHz, CDCl3): δ 170.5, 136.7, 134.6, 129.1, 128.9, 62.5, 60.5, 53.6, 52.9, 21.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([C:8]#[N:9])=O)=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:25])[N:18]([CH2:22][CH2:23]Cl)[CH2:19][CH2:20]Cl)([CH3:15])([CH3:14])[CH3:13].[H-].[Na+]>CN(C)C=O>[C:12]([O:16][C:17]([N:18]1[CH2:22][CH2:23][C:6]([C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)([C:8]#[N:9])[CH2:20][CH2:19]1)=[O:25])([CH3:15])([CH3:14])[CH3:13]
Reactant: N#CC(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Temperature: 60 °C
Yield: 53.6 %

Procedure:
To 1.26 g (8.37 mmol) 4-chloro-benzoylcyanide was added bis-(2-chloroethyl)-carbamic acid tert-butyl ester (2.02 g, 8.37 mmol) in 25 ml N,N-dimethylformamide. The resulting mixture was stirred and cooled in an ice bath, then sodium hydride (60% suspension in mineral oil) (1.1 g, 42 mmol) was added portionwise. The reaction was brought to room temperature and then heated in an oil bath at 60° C. for 16 hours. The reaction mixture was quenched by addition of ice water and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed twice with water, once with brine, dried with magnesium sulfate and concentrated in vacuo. The residual brown oil was purified by silica gel chromatography eluting with hexane-ethyl:acetate (9:1) to give the title compound (1.44 g, 54%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)[CH3:2].Cl.[NH2:18][OH:19]>>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=[N:18][OH:19])[CH2:12][CH2:11]1)[CH3:2]
Reactant: NO
Reactant: CCOCCCCCCN1CCC(=O)CC1
Agent: Cl
Product: CCOCCCCCCN1CCC(=NO)CC1

Procedure:
1-(6-Ethoxyhexyl)-4-piperidone oxime is prepared from 1-(6-ethoxyhexyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [C:1]([O:4][C@H:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[C:19]([O:23][C:24](=[O:44])[NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[CH2:34][NH:35][C:36]([C@@H:38]1[CH2:43][O:42][CH2:41][CH2:40][NH:39]1)=[O:37])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][C@H:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([N:39]1[CH2:40][CH2:41][O:42][CH2:43][C@H:38]1[C:36](=[O:37])[NH:35][CH2:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:44])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1COCCN1
Reactant: CC(=O)O[C@@H](C(=O)O)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H](C(=O)N1CCOC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.2 %

Procedure:
To a solution of (R)-2-acetoxy-3,3-dimethylbutanoic acid (0.14 g, 1.04 mmol) in CH2Cl2 (2 mL) was added oxalyl chloride (1.10 mL, 1.30 mmol) at 0° C. under nitrogen atmosphere and the resulting mixture was stirred at room temperature for 40 min. The reaction mixture was concentrated to dryness and the residue was dissolved in CH2Cl2 (4 mL). A solution of (S)-tert-Butyl-4-chloro-2-{(morpholine-3-carboxamido)methyl}benzylcarbamate (0.20 g, 0.52 mmol) and triethylamine (0.70 mL, 2.08 mmol) in CH2Cl2 (2 mL) was added dropwise at 0° C. and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed sequentially with saturated NaHCO3 solution (10 mL) and 1M aqueous HCl (10 mL). The organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 50% EtOAc/hexanes) to afford the title compound as a pale yellow oil (0.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([Cl:15])=[N:10][CH:11]=[N:12][C:13]=2[Cl:14])=[CH:4][CH:3]=1.[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1CCCCC1>CCOCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([Cl:14])=[N:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:10][C:9]=2[Cl:15])=[CH:6][CH:7]=1
Reactant: [Li]c1ccccc1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: Cc1ccc(-c2c(Cl)nc(-c3ccccc3)nc2Cl)cc1

Procedure:
A solution of 5-(4-methylphenyl)-4,6-dichloropyrimidine in ether is cooled at -30° C., and thereto is added dropwise a 1.8M phenyl lithium/cyclohexane solution. The reaction mixture is treated in the same manner as in Reference Example 20-(1) to give 5-(4-methylphenyl)-4,6-dichloro-2-phenylpyrimidine as crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([OH:35])=[CH:30][C:29]=3[CH3:36])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].[CH3:44][S:45](Cl)(=[O:47])=[O:46].O>N1C=CC=CC=1>[CH3:36][C:29]1[CH:30]=[C:31]([O:35][S:45]([CH3:44])(=[O:47])=[O:46])[CH:32]=[C:33]([CH3:34])[C:28]=1[C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:8]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]2[CH:5]=[CH:4][C:3]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:2]([F:1])[CH:7]=2)[CH:23]=1
Reactant: CCOC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cc(O)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cc(OS(C)(=O)=O)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To an ice-cooled solution of ethyl 3-(2-fluoro-4-{[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methyl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (600 mg, 0.989 mmol) in pyridine (10 mL) was added dropwise methanesulfonyl chloride (227 mg, 1.98 mmol). The mixture was stirred at room temperature for 16 hr. To the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-1/1) to give the title compound (670 mg, yield 98%) as a colorless oil.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[N:4]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>ClCCl>[CH3:10][S:11]([O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][S:11]([CH3:10])(=[O:13])=[O:12])[N:4]=1)(=[O:13])=[O:12]
Reactant: Oc1cccc(O)n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1cccc(OS(C)(=O)=O)n1

Procedure:
2,6-dihydroxypyridine hydrochloride (3 g) was suspended in dichloromethane (250 cm3) under an atmosphere of nitrogen at 0° C. The mixture was treated with methanesulphonyl chloride (3.5 cm3). The suspension was stirred and triethylamine (9.4 cm3) was added in aliquots over 15 minutes. The resulting mixture was stirred for 17 hours and poured onto brine. The organic layer was separated, washed twice with brine, dried over anhydrous magnesium sulphate, and the solvent evaporated under reduced pressure.