Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][N:37]1[CH2:41][CH3:42]>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH:8]([N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:34][CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH2:41][CH3:42])=[O:23])(=[O:16])=[O:15])[CH2:12]2)[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:28][CH:29]=1
Reactant: CCN1CCCC1CN
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Product: CCN1CCCC1CNC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.0396 cm3 of 2-(aminomethyl)-N-ethylpyrrolidine. 58 mg of 3-({-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide are thus obtained in the form of an ochre-colored foam.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9](OC)=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-:16].[NH4+:17]>CO>[ClH:16].[CH:1]1([CH:7]2[NH:8][C:9](=[NH:17])[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: COC1=NC(C2CCCCC2)CCCC1
Solvent: CO
Product: Cl
Product: N=C1CCCCC(C2CCCCC2)N1
Yield: 75.8 %

Procedure:
The product of EXAMPLE 94 (730 mg, 3.45 mmol) in 30 mL of MeOH was reacted with ammonium chloride (177 mg, 3.31 mmol) by the method of EXAMPLE 27 to yield 579 mg (75%) of the title material.
Reaction SMILES: [Br:1][CH:2]([C:4]1[N:5]=[C:6]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:7]2[C:8](=[O:10])[CH:9]=1)[CH3:3].[I:16]N1C(=O)CCC1=O>>[Br:1][CH:2]([C:4]1[N:5]=[C:6]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:7]2[C:8](=[O:10])[C:9]=1[I:16])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cccc2nc(C(C)Br)cc(=O)n12
Product: Cc1cccc2nc(C(C)Br)c(I)c(=O)n12
Yield: 98 %

Procedure:
The desired compound was prepared according to the procedure of Example 8, step 3, using 2-(1-bromoethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and N-iodosuccinimide as the starting materials in 98% yield. LCMS for C11H11BrIN2O (M+H)+: m/z=392.7, 394.7.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Br.Cl>C1C=CC=CC=1>[Br:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][N:2]([CH3:3])[CH3:1]
Reactant: CNC
Reactant: BrCc1cccc(Br)c1
Agent: Cl
Solvent: c1ccccc1
Product: CN(C)Cc1cccc(Br)c1
Yield: 79.9 %

Procedure:
Dimethylamine (51.4 g, 1.14 mol) was reacted with 3-bromobenzyl bromide (95 g, 0.38 mol) in benzene at 5° and the mixtue was acidified with hydrochloric acid and the mixture was extracted with aqueous 3N hydrochloric acid. The aqueous extracts were made alkaline with aqueous potassium hydroxide and the oil which separated out was distilled to give 3-bromo-N,N-dimethylbenzylamine (65 g, 80%) b.p. 118°/20 mmHg.
Reaction SMILES: [C:1]([Si:5]([CH3:35])([CH3:34])[O:6][CH:7]1[CH2:23][N:11]2[C:12](=[O:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=[C:10]2[N:9]([C:24]2[CH:29]=[CH:28][N:27]=[C:26](S(C)(=O)=O)[N:25]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:36]1([C@@H:42]([NH2:44])[CH3:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCOCC1.CCOC(C)=O>[C:1]([Si:5]([CH3:35])([CH3:34])[O:6][CH:7]1[CH2:23][N:11]2[C:12](=[O:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=[C:10]2[N:9]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:44][CH:42]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH3:43])[N:25]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CN(c2ccnc(S(C)(=O)=O)n2)c2nc(-c3ccccc3)cc(=O)n2C1
Reactant: C[C@H](N)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(Nc1nccc(N2CC(O[Si](C)(C)C(C)(C)C)Cn3c2nc(-c2ccccc2)cc3=O)n1)c1ccccc1
Temperature: 110 °C

Procedure:
A mixture of 7-(tert-butyl-dimethyl-silanyloxy)-9-(2-methanesulfonyl-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one, prepared from last step (0.6 mmol) and (S)-1-phenylethylamine (1.0 mL, 7.8 mmol) in dioxane (6 mL) was heated at 110° C. for 17 h. The brown solution was cooled to room temperature and was diluted with EtOAc (10 ML). The mixture was washed with H2O (2×), dried (Na2SO4), and concentrated to oil. Purification on silica (0-1% 2N NH3-MeOH in DCM) provided the product as a white solid. M+1: 555.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][C:16]=1[O:25][CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:22](=[O:23])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([OH:14])=[C:16]([O:25][CH3:26])[CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1cc(CC(=O)O)ccc1O
Product: COc1cc(CC(=O)NCCc2ccc(OC)c(OC)c2)ccc1O

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine and 4-hydroxy-3-methoxy-phenylacetic acid.
Reaction SMILES: [N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]([OH:17])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1C=CC=CC=1>[N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]([Cl:19])=[O:17])([O-:3])=[O:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(=O)O
Solvent: c1ccccc1
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(=O)Cl

Procedure:
Ten grams of 3,5-dinitro-4-chloro-o-toluic acid is warmed on a water bath with 9.2 grams of phosphorus pentachloride and 30 ml. of benzene. After the solids dissolve, the benzene is distilled and the phosphorus oxychloride is removed under reduced pressure. The desired product as a residual oil solidifies on chilling.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][C@H:33]([OH:36])[C@H:32]([OH:37])[CH2:31]2)[CH:27]=[N:26][CH:25]=1>Cl.CC(O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][C@H:33]([OH:36])[C@H:32]([OH:37])[CH2:31]2)[CH:27]=[N:26][CH:25]=1.[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH:32]([OH:37])[CH2:31]2)[CH:27]=[N:26][CH:25]=1
Reactant: O[C@@H]1CN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)CC[C@@H]1O
Agent: Cl
Solvent: CC(C)O
Product: OC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)CC1O
Product: O[C@@H]1CN(c2cncc(-c3n[nH]c4ccc(-c5c(F)cccc5F)cc34)n2)CC[C@@H]1O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 26.2 %

Procedure:
A slurry of racemic cis-1-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidine-3,4-diol (0.100 g, 0.197 mmol) in 3 mL 5-6 N HCl in IPA (acros organics) was sealed and the slurry was heated to 70° C. After 1.5 h, the reaction was cooled and concentrated in vacuo. This material was dissolved in DMSO and purified by shimadzu RPHPLC, 15-70% ACN/H2O with 0.1% TFA; product-containing fractions were concentrated in vacuo. The material was partitioned between sat'd aq NaHCO3 and DCM, and the aq. layer was extracted 3×10% MeOH/DCM. The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (0.024 g, 29% yield) as an off-white solid: MS (ESI, pos. ion) m/z: 424 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][Br:27])=[CH:15][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nsc(-c3ccc(F)cc3)n2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2nc(-c3ccc(CBr)cc3)ns2)cc1
Temperature: 25 °C
Yield: 106.8 %

Procedure:
To a solution of 5-(4′-fluorophenyl)-3-(p-tolyl)-1,2,4-thiadiazole (0.16 g, 0.59 mmol) in CCl4 (20 ml) is added NBS (0.11 g, 0.59 mmol) and the mixture is heated to reflux for 36 hours The mixture is cooled to room temperature and filtered through celite. The mother liquor is concentrated. The residue is taken up in chloroform (30 ml) and washed with water (30 ml). The organic layer is dried over MgSO4 and concentrated to yield 5-(4′-fluorophenyl)-3-(p-bromomethylphenyl)-1,2,4-thiadiazole, (0.22 g) as crude product which is used as is without further purification.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:19][C:17](=[O:18])[C@H:16]([CH3:20])[C@@H:15]([O:21][C@@H:22]2[O:27][C@@H:26]([CH3:28])[C@H:25]([OH:29])[C@@:24]([O:31][CH3:32])([CH3:30])[CH2:23]2)[C@H:14]([CH3:33])[C@@H:13]([O:34][C@@H:35]2[O:40][C@H:39]([CH3:41])[CH2:38][C@H:37]([N:42]([CH3:44])[CH3:43])[C@H:36]2[OH:45])[C@@:12]([O:47][CH3:48])([CH3:46])[CH2:11][C@@H:10]([CH3:49])/[C:7](=N\O)/[C@H:6]([CH3:50])[C@@H:5]([OH:51])[C@@:4]1([OH:53])[CH3:52].C(O)C.[OH-:57].[Na+]>O>[CH3:1][CH2:2][C@H:3]1[O:19][C:17](=[O:18])[C@H:16]([CH3:20])[C@@H:15]([O:21][C@@H:22]2[O:27][C@@H:26]([CH3:28])[C@H:25]([OH:29])[C@@:24]([O:31][CH3:32])([CH3:30])[CH2:23]2)[C@H:14]([CH3:33])[C@@H:13]([O:34][C@@H:35]2[O:40][C@H:39]([CH3:41])[CH2:38][C@H:37]([N:42]([CH3:43])[CH3:44])[C@H:36]2[OH:45])[C@@:12]([O:47][CH3:48])([CH3:46])[CH2:11][C@@H:10]([CH3:49])[C:7](=[O:57])[C@H:6]([CH3:50])[C@@H:5]([OH:51])[C@@:4]1([OH:53])[CH3:52]
Reactant: [OH-]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)/C(=N\O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 80 °C

Procedure:
In the present method, acid is added to the mixture of protected silylated clarithromycin oxime, ethanol, water and deoximating agent and the mixture is heated at reflux (about 80° C.) Heating is then continued and the suspension is stirred for an amount of time sufficient to finish the reaction. The mixture is then cooled to about 20° C. and sodium hydroxide solution having a concentration of from about 20% to about 47%, preferably 47%, is added at this temperature until the pH of the reaction mixture reaches about 10 to about 11, preferably about 10.2 to about 10.5. Crystalline clarithromycin is then isolated, preferably by filtration, with no further water addition. The obtained clarithromycin may subsequently be further purified and/or isolated and the crystalline form of clarithromycin may be altered to the desired form (such as crystal form 0, I, II, or IV) for use.
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[NH:22][N:21]=[C:20]([CH:23]5[CH2:25][CH2:24]5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[C@:34]([OH:38])([C:36]#[CH:37])[CH3:35].C(NC(C)C)(C)C>CN(C=O)C>[CH:23]1([C:20]2[N:19]=[C:18]([C:12]3[N:8]4[CH2:9][CH2:10][O:11][C:5]5[CH:4]=[C:3]([F:27])[C:2]([C:37]#[C:36][C@@:34]([OH:38])([C:29]6[N:30]=[CH:31][CH:32]=[CH:33][N:28]=6)[CH3:35])=[CH:26][C:6]=5[C:7]4=[N:14][C:13]=3[C:15]([NH2:17])=[O:16])[NH:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: C#C[C@@](C)(O)c1ncccn1
Reactant: NC(=O)c1nc2n(c1-c1nc(C3CC3)n[nH]1)CCOc1cc(F)c(Br)cc1-2
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: C[C@@](O)(C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1-c1nc(C2CC2)n[nH]1)c1ncccn1
Yield: 40 %

Procedure:
3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-9-fluoro-10-[(3R)-3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with (2R)-2-pyrimidin-2-ylbut-3-yn-2-ol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford 47 mg of the titled compound (40% yield). M+1=501.2. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J=4.8 Hz, 2H), 8.64 (d, J=8.4 Hz, 1H), 8.35 (br s, 1H), 7.74 (br s, 1H), 7.50 (t, J=4.8 Hz, 1H), 7.03 (d, J=10.5 Hz, 1H), 6.21 (s, 1H), 5.04-4.80 (m, 2H), 4.63-4.54 (m, 2H), 2.13-2.04 (m, 1H), 1.89 (s, 3H), 1.03-0.95 (m, 2H), 0.93-0.87 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:39][CH:40]1[CH2:42][O:41]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH:40]4[CH2:42][O:41]4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCC3CO3)cc2)c2ccccc21
Temperature: 80 °C
Yield: 98.3 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.5 g, 1.14 mmol) was dissolved in DMF at room temperature and K2CO3 (1.26 g, 9.13 mmol) was added. 2-Chloromethyl-oxirane (0.42 g, 4.57 mmol) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (50% EtOAc/50% Hexane) to afford (2S,4R)-N-(4-chloro-phenyl)-N-[2-methyl-1-(4-oxiranylmethoxy-benzoyl)-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.55 g, 77%), which was further elaborated to the product following ref. (Tetrahedron Lett 2002, 43(46), 8327).
Reaction SMILES: [CH:1]([N:4]([CH:25]([CH3:27])[CH3:26])[CH2:5][CH2:6][C:7]([CH2:16][CH2:17][N:18]([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9])([CH3:3])[CH3:2].[OH-:28].[Na+]>S(=O)(=O)(O)O>[CH:22]([N:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][C:7]([CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:25]([CH3:27])[CH3:26])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]([NH2:9])=[O:28])([CH3:24])[CH3:23]
Reactant: [OH-]
Reactant: CC(C)N(CCC(C#N)(CCN(C(C)C)C(C)C)c1ccccc1)C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)N(CCC(CCN(C(C)C)C(C)C)(C(N)=O)c1ccccc1)C(C)C
Temperature: 0 °C

Procedure:
2 Parts of α,α-bis[2-(diisopropylamino)ethyl]-α-phenylacetonitrile is dissolved in 20 parts by volume of concentrated sulfuric acid and the resulting solution heated on a steam bath for about 90 minutes. The solution is then cooled to about 0° C. and made alkaline by the addition of dilute sodium hydroxide. The alkaline solution is extracted with ether, the ether extract dried over calcium sulfate and stripped of solvent to afford α,α-bis[2-(diisopropylamino)ethyl]-α-phenylacetamide, melting at about 102°-103° C. after crystallization from hexane. This compound has the following structural formula ##STR14## cl EXAMPLE 4
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Cl)cc2Cl)CC1
Temperature: 100 °C
Yield: 85.9 %

Procedure:
To 2,3,5-trichloropyridine (25 g) were added 1-BOC-piperazine (28.13 g), potassium carbonate (37.86 g), N,N-dimethylformamide (25 mL) and toluene (50 mL), and the mixture was stirred at 100° C. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (39.13 g). To 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (6.35 g) were added palladium (II) acetate (0.46 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.71 g), potassium fluoride (9.556 g), methylboronic acid (5 g) and tetrahydrofuran (202 mL), and the mixture was refluxed under a nitrogen stream for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g). To 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g) were added 4N hydrogen chloride/ethyl acetate (18.2 mL) and chloroform (45.5 mL), and the mixture was stirred at room temperature. After completion of the reaction, to the reaction mixture were added water and potassium carbonate, and the mixture was extracted with ethyl acetate. The solvent was evaporated to give the title compound (3.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:22])[C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([C:5]([N:44]2[CH2:45][CH2:46][CH:41]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:42][CH2:43]2)=[O:6])=[C:8]([CH3:22])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[N:11]=1
Reactant: COc1nc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1nc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
A suspension of 0.200 g (0.64 mmol) 2-methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid in 5 ml of CH2Cl2 was treated at RT with one drop of DMF; then, 0.06 ml=0.09 g (0.71 mmol) of oxalyl chloride was added to this solution drop by drop below 25° C. and the reaction mixture was stirred for 0.5 hour. After removal of the solvents by evaporation in a high vacuum, the residue was dissolved again in 10 ml of CH2Cl2 and 0.36 ml=0.26 g (2.57 mmol) of Et3N was added while stirring, followed by 0.099 g (0.64 mmol) of 4-pyrrolidin-1-yl-piperidine. The reaction mixture was stirred at RT. After 16 hours, it was poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 98:2 to 4:1) to give 0.278 g (97%) of the title compound as yellow amorphous solid. MS: 448.1 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C@@H:6]([CH3:17])[C@@H:7]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)[OH:8])[CH3:4].[NH2:18][S:19]([C:22]1[C:23]([Cl:44])=[CH:24][C:25]([NH:37][CH2:38][C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)=[C:26]([CH:36]=1)[C:27]([O:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])=[O:28])(=[O:21])=[O:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1.C1(C)C=CC=CC=1>[NH2:18][S:19]([C:22]1[C:23]([Cl:44])=[CH:24][C:25]([NH:37][CH2:38][C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)=[C:26]([CH:36]=1)[C:27]([O:29][CH2:30][CH2:31][CH2:32][C:33]([O:1][CH2:2][C@H:3]([NH:5][C@H:6]([CH3:17])[C@H:7]([C:9]1[CH:10]=[C:11]([F:16])[CH:12]=[C:13]([F:15])[CH:14]=1)[OH:8])[CH3:4])=[O:34])=[O:28])(=[O:20])=[O:21]
Reactant: NS(=O)(=O)c1cc(C(=O)OCCCC(=O)O)c(NCc2ccco2)cc1Cl
Reactant: C[C@H](CO)N[C@@H](C)[C@H](O)c1cc(F)cc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](COC(=O)CCCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1)N[C@H](C)[C@@H](O)c1cc(F)cc(F)c1

Procedure:
The free base of (rac)-(R*,S*)-2-((2-hydroxy-(R)-1-methylethyl)amino)-1-(3,5-difluorophenyl)propanol (21) (0.023 mole) and benzene (30 mL) (or toluene) is added to a round-bottomed flask. 4-(5-(Aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoic acid (0.025 mole), benzene (30 mL), and p-toluenesulfonic acid (0.026) catalyst is added to the flask. A Dean-Stark trap is filled with benzene, and the contents of the flask is refluxed with stirring for several hours or until no additional water is collected in the trap. The reaction is cooled, extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give (rac)-(R*,S*)-2-((2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl)amino)-(R)-2-methylethyl 4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoate. See eg., Sandler et al., Organic Functional Group Preparations, p. 249 (1968).
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1.[F:30][CH:31]([CH3:35])[C:32](Cl)=[O:33].Cl>C1C=CC=CC=1>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:32](=[O:33])[CH:31]([F:30])[CH3:35])=[CH:21][CH:22]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CC(F)C(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCc1cnc(-c2ccc(OC(=O)C(C)F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5 %

Procedure:
5.4 g (173 mmol) of p-(5-decyl-2-pyrimidyl)-phenol and 1.4 g (177 mmol) of pyridine were dissolved in 30 ml of benzene, and a benzene solution of the above 2-fluoropropanoic acid chloride was added dropswise thereto at 5° C. in 15 minutes. Then, the mixture was stirred overnight at room temperature, and after the completion of the reaction, the reaction solution was poured into ice water. Then, the system was acidified with the addition of 6N-HCl and subjected to extraction with benzene. The extract benzene solution was washed with water and saline water, dried with anhydrous magnesium sulfate, and the solvent was distilled to leave 3.2 g of a crude product. The product was purified by column chromatography (eluent: hexane/acetone=10/1) to obtain 330 mg of 2-fluoropropanoic acid-p-(5-decyl-2-pyrimidyl)phenyl-ester. Yield: 5.0%.