Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].Br[CH2:9][C:10]1[N:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:13]=[CH:12][C:11]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH:9]([C:10]1[N:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:13]=[CH:12][C:11]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:3]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1CBr
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)(C)C)c1C=O
Yield: 70.1 %

Procedure:
This reaction was conducted in accordance with the procedure described by H. B. Hass and M. L. Bender in J. Am. Chem. Soc., 71 1767 (1949). Sodium (1.6 grams, 0.07 mole) was dissolved in 50 ml. of absolute ethanol. Subsequently, 2-nitropropane (8.1 grams, 0.09 mole) and 5-(bromomethyl)-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester (20 grams, 0.07 mole) were added. The resulting reaction mixture was refluxed for two hours, then cooled and the solvent removed in vacuo. The residue was taken up in ether, washed with water, washed with 1N sodium hydroxide, washed with saturated brine, and dried using sodium sulfate and filter paper. The solvent was removed in vacuo and the residue was distilled at 110° C. at 1.6 mm mercury pressure, yielding 11 grams of the 5-formyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].CC([Si](C)(C)[O:32][C:33]1[CH:42]=[C:41]2[C:36]([CH2:37][CH2:38][NH:39][CH2:40]2)=[CH:35][C:34]=1[O:43][CH3:44])(C)C.C(N(CC)C(C)C)(C)C>C(#N)C>[CH:21]1([S:20][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:39]2[CH2:38][CH2:37][C:36]3[C:41](=[CH:42][C:33]([OH:32])=[C:34]([O:43][CH3:44])[CH:35]=3)[CH2:40]2)[C:8]#[N:9])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CNCC2
Reactant: COc1ccc(C(C#N)(CCCCCBr)SC2CCCCC2)cc1OC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1O)CN(CCCCCC(C#N)(SC1CCCCC1)c1ccc(OC)c(OC)c1)CC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 150.7 %

Procedure:
A mixture, under argon, of 2.17 g of product from Example 113, 1.8 g of product from Example 28, 13.0 ml of N,N-diisopropyl ethylamine and 80 ml of acetonitrile is heated under reflux temperature for 8 hours. The reaction is cooled and concentrated in vacuo and dried under high vacuum for 1 hour. The crude residue is dissolved in 70 ml of tetrahydrofuran and 10.0 ml of 1M tetrabutyl ammonium fluoride in tetrahydrofuran is added and the mixture is stirred at room temperature, under argon, for 2.5 hours. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried, filtered, and concentrated in vacuo to give 4.0 g of a brown oil. The oil is purified by chromatography (silica gel: 1%, 1.5% and 2% methyl alcohol/methylene chloride)to give 2.1 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.S(=O)(=O)(O)O.[Br:17]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[Br:17][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[CH3:8]
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 114.8 %

Procedure:
To a solution of 4-fluoro-2-nitrotoluene (3.44 g) in trifluoroacetic acid (13 mL) was added concentrated sulfuric acid (4 mL) followed by N-bromosuccinimide (5.92 g). The reaction mixture was stirred for 16 h and was then quenched with brine, extracted into ethyl acetate, and dried (MgSO4). The solvent was removed in vacuo to furnish crude 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (5.96 g).
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[OH-].[Na+].Cl[S:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=1)(=[O:32])=[O:31]>C(O)C(N)(CO)CO.C1COCC1>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][S:30]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=3)(=[O:32])=[O:31])=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(C(C)C)c3)c2c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Agent: NC(CO)(CO)CO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc2c(Br)c3ccccc3c(-c3ccc(OS(=O)(=O)c4ccc(C(=O)O)c(O)c4)c(C(C)C)c3)c2c1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
At ambient temperature, to a stirred suspension of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenol (0.306 g, 0.744 mmol) in 0.05 M Tris buffer pH 9: THF (10:3, 3.56 mL, 0.2 M) was added 2.5N NaOH (0.285 mL, 0.713 mmol) followed by a minimal amount of THF to form a solution. After 0.5 h, the reaction was cooled to 5° C. To the reaction was added dropwise, a solution of 4-chlorosulphonyl-2-hydroxybenzoic acid (0.338 g, 1.43 mmol) in THF (2.85 mL, 0.5M) while maintaining the pH at 10 with the simultaneous addition of 2N NaOH. After the addition was completed, the reaction was allowed to warm to ambient temperature and stirred for 1.5 h. At 5° C. additional 4-chlorosulphonyl-2-hydroxybenzoic acid (0.338 g, 1.43 mmol) in THF (2.85 mL, 0.5 M) was added in the exact same manner as above and the reaction was stirred for 1.5 h. The reaction was quenched with 2N HCl (40 mL) and extracted with EtOAc. The combined organic extracts were washed with 2N HCl (3×), dried (MgSO4) and concentrated. Purification on 2% H3PO4 /MeOH treated Biotage KP-Sil eluting with a 15 & 25% EtOAc/Hexane step gradient gave 0.294 g, (66%) of the title compound as a yellow solid, mp >225° C.; 1H NMR (DMSO-d6): δ 0.96 (d, 3 H), 1.02 (d, 3 H), 1.48 (s, 3 H), 2.50 (s, 3 H), 3.08 (heptet, 1 H), 7.26-7.39 (m, 5 H), 7.43 (dd, 1 H), 7.50 (t, 1 H), 7.66 (t, 1 H), 8.05 (d, 1 H), 8.21 (d, 1 H). IR (KBr) 3425, 2950, 1675, 1400 and 1190 cm-1. mass spectrum (-ESI), m/z 623/625 (M-H). Anal. Calcd. for C30H25BrO6S2 : C, 57.60; H, 4.03; N, 0.00. Found: C, 57.88; H, 4.29 N, 0.09.
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][C@@H:19]1/[CH:20]=[CH:21]/[CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78.5 %

Procedure:
Sodium borohydride (4 mg, 0.11 mmol), followed by MeOH (0.25 mL), was added to a solution of {4-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-butoxy}-acetic acid methyl ester (28 mg, 0.072 mmol) in CH2Cl2 (0.75 mL) at 0° C. The mixture was allowed to warm to rt. After 40 min at rt, the reaction was quenched with aqueous HCl (0.5 M) and extracted with EtOAc (3×7 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford 22 mg (78%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[S:25]1[CH2:29][CH2:28][NH:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:27]1[CH2:28][CH2:29][S:25][CH2:26]1)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: C1CSCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCSC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, thiazolidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.51 minutes; C19H16Cl2N4O2S (435.33); mass spectrum: (M+H)+=435.1.
Reaction SMILES: C(O[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH3:14])[N:5]=1)C.Cl.[NH2:16][NH2:17]>>[NH:16]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH3:14])[N:5]=1)[NH2:17]
Reactant: CCOC1=NC(C)Cc2ccccc21
Reactant: NN
Agent: Cl
Product: CC1Cc2ccccc2C(NN)=N1

Procedure:
In a manner similar to that of Step B of Example 1, condensation of 1-ethoxy-3-methyl-3,4-dihydroisoquinoline (1.0 g.) and hydrazine monohydrochloride (0.36 g.) and three recrystallizations of the resulting product from ethanol-ether afforded 1-hydrazino-3-methyl-3,4-dihydroisoquinoline (V: Y=CH3, Y'= Z=Z'=H) hydrochloride (m.p. 174°-176° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[N:13]=1>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:13]=1
Reactant: Clc1cccc(Cl)n1
Reactant: Fc1ccccc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccccc1Sc1cccc(Cl)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
2-Fluorothiophenol (Aldrich, St. Louis, Mo., Cat. No. 275379; 1.6 mL, 15 mmol) was dissolved in DMF (10 mL), and then NaH (0.45 g, 19 mmol) was added slowly to the mixture. After 1 hour, 2,6-dichloropyridine (Aldrich, St. Louis, Mo., Cat. No. 073707; 2.00 g, 14 mmol) was added and the mixture was heated in a pre-heated (70° C.) bath, and allowed to stir under inert atmosphere for 3 hours. The mixture was quenched with 1N NaOH and diluted with DCM. The organic layer was extracted with 4:1 DCM/MeOH (3×25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by ISCO Silica-Gel Chromatography (Teledyne ISCO, Lincoln, Nebr.) on a 120 gm column eluting with a solvent gradient of 1-30% DCM/Hexanes over 35 minutes to give 2-chloro-6-(2-fluorophenylthio)pyridine (1.13 g, 35% yield) as colorless oil. MS (ESI pos. ion) m/z: 240 (MH+). Calculated exact mass for C11H7ClFNS: 239.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=O)[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.Cl.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:32]4[CH2:35][CH:34]([OH:36])[CH2:33]4)=[O:30])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: OC1CNC1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Agent: Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N5CC(O)C5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and azetidin-3-ol hydrochloride (Aldrich, Cat. No. 680079). LCMS (M+H)+=503.1/505.3.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CCN(C(C)C)C(C)C.[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:6]=1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])=[O:36]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: COc1ccc(-c2csc(N)c2C(=O)OC(C)(C)C)cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-c2csc(NC(=O)c3cccc(F)c3)c2C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 16 (31 mg 0.1 mmol) in DCM (5 ml) was added DIEA (0.052 ml, 0.3 mmole), 3-fluorobenzoyl chloride (0.018 ml, 0.15 mmol) and catalytic amount of DMAP. The mixture was stirred at rt for 17 hrs, diluted with DCM (15 ml), washed with water, saturated sodium bicarbonate (aq.), water, 10% citric acid (aq.) and brine, dried over anhydrous sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under vacuum. The crude product was used in the next step without further purification. LC-MS for C22H21FN2O4S: 428; found: 429.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[C:11](Cl)(=[O:13])[CH3:12]>C1(C)C(C)=CC=CC=1>[C:11]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Cc1ccccc1C
Product: CC(=O)Nc1nc(C(Cl)(Cl)Cl)ns1
Yield: 86 %

Procedure:
A solution of 10.9 grams (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 14.0 grams (0.18 mole) acetyl chloride in 200 milliliters xylene was refluxed at about 140° C. for 15 hours. The product precipitated (11.2 grams, 86% yield) after concentration in vacuo to approximately 50% of the original volume. A pure product of m.p. 193° C. was obtained by recrystallization from ethanol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[CH3:14][C:15]([C:18]1[CH:19]=[C:20]([S:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[S:35][CH2:36][C:37](N(C)CCC2C=CC=CN=2)=[O:38])[CH:21]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)([CH3:17])[CH3:16]>>[CH3:27][C:24]([C:22]1[CH:21]=[C:20]([S:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[S:35][CH2:36][C:37]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=2)=[O:38])[CH:19]=[C:18]([C:15]([CH3:14])([CH3:16])[CH3:17])[CH:23]=1)([CH3:25])[CH3:26]
Reactant: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2SCC(=O)NCCNc2ccc([N+](=O)[O-])cn2)cc(C(C)(C)C)c1

Procedure:
Substituting 2-(2-aminoethylamino)-5-nitropyridine for the 2-(2-methylaminoethyl)pyridine of Example 16, and following the procedure described therein, gives trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-[[(5-nitropyridin-2-yl)amino]ethyl]acetamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[CH:11]=2)=[CH:4][CH:3]=1.[CH3:24][Mg]I.CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:19]([NH2:20])[CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH:11]=2)=[CH:6][CH:7]=1
Reactant: Cn1nc(-c2cccc(C#N)c2)cc1CCc1ccc(F)cc1
Reactant: C[Mg]I
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(N)c1cccc(-c2cc(CCc3ccc(F)cc3)n(C)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the nitrile from Step 1 (50 mg, 0.16 mmol) in THF (5 mL) was treated with MeMgI in Et2O (3.0 M, 0.32 mL, 0.96 mmol). A milky solution formed, which was stirred at RT for 30 mins, then further MeMgI was added (1.0 mL, 3 mmol) and stirred for 1 hour. A solution of LiAlH4 in THE (1.0 M, 2.5 mL, 2.5 mmol) was added and stirred at RT for 1 hour. The reaction was quenched by addition of H2O and the solvent evaporated under reduced pressure. The residue was partitioned between CH2Cl2 and H2O, the CH2Cl2 layer was separated and the aqueous layer re-extracted with CH2Cl2. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to give crude 1-(3-{5-[2-(4-fluorophenyl)-ethyl]-1-methyl-1H-pyrazol-3-yl}-phenyl)-ethylamine as a yellow gum (50 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]1([CH2:41]O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:41]([O:15][C:14](=[O:16])[C@@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
(S)-6-tert-Butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid (5.00 g, 10.67 mmol) and phenyl-methanol (2.305 g, 21.34 mmol) were dissolved in 25 mL of CH2Cl2 and treated successively with N-hydroxybenzotriazole (1.933 g, 11.74 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 2.250 g, 11.74 mmol), and ethyl-diisopropyl-amine (2.137 ml, 12.49 mmol). After stirring for 90 min, the volatiles were removed i.V. at ambient temperature, the residue taken up in ethyl acetate, washed with water, NH4Cl-solution and brine, dried over Na2SO4, and evaporated. The crude mixture was then dissolved in 20 mL of ethanol, and the product precipitated by adding 10 mL of water. Filtration and drying yielded 5.669 g of the title compound which was recrystallized from ethanol/hexane to give 4.27 g of pure benzyl ester. MS (ISP): 559.2 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: BrCCCCCCBr
Reactant: CC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(OCCCCCCBr)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-4-(4-hydroxyphenyl)piperazine (5.00 g) in N,N-dimethylformamide (50 ml) was treated with 1,6-dibromohexane (10.5 ml) and potassium carbonate (4.71 g), and the mixture was stirred for 18 hours at ambient temperature. To the reaction mixture was added water (200 ml), and the resulting precipitate was collected by filtration, washed with water and n-hexane successively and dried under reduced pressure to give crude 1-acetyl-4-[4-(6-bromohexyloxy)phenyl]piperazine (10.52 g), that was used in the next reaction directly.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CO>[H][H]>[OH:4][CH:3]([CH3:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: [H][H]
Solvent: CO
Product: CCOC(=O)CC(C)O
Yield: 26 %

Procedure:
To 3.90 g of ethyl acetoacetate were added 7.4 mg of rhodium 1,5-cyclooctadiene chloride complex compound, 22.1 mg of BCPM and 10 ml of methanol, and the mixture was charged into an autoclave. The mixture was stirred in the autoclave for 45 hours at 50° C. in hydrogen atmosphere at an initial pressure of 50 atm. It was confirmed by gas chromatography that 100% of the starting material had been converted. After distilling off the solvent, ethyl β-hydroxybutyrate was obtained almost theoretically by distillation under reduced pressure. [α]D23 =-2.67° (neat) (optical yield: 26%).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[O:19][C:15]=2[C:14](F)=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[CH3:32])#[N:10].C(N(CC)CC)C>CS(C)=O>[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[O:19][C:15]=2[C:14]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[CH3:32])#[N:10]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(=O)N(C)C)nc2c1C#N
Reaction time: 0.83 h

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (2 ml) solution (3S)-3-(dimethylamino)pyrrolidine (75 μl, 594 μmol) was added at 150° C. to a dimethyl sulfoxide (8 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (160 mg, 495 μmol) and triethylamine (90 μl, 644 μmol), followed by stirring at the same temperature for 50 minutes.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[CH2:7][C:8]([C:18]1([Cl:21])[CH2:20][CH2:19]1)([OH:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1>CN(C)C=O>[F:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8]([C:18]2([Cl:21])[CH2:19][CH2:20]2)([OH:17])[CH2:7][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:15][CH:14]=1
Reactant: c1nc[nH]n1
Reactant: OC(CCl)(Cc1ccc(F)cc1)C1(Cl)CC1
Solvent: CN(C)C=O
Product: OC(Cc1ccc(F)cc1)(Cn1cncn1)C1(Cl)CC1
Temperature: 80 °C
Yield: 36.7 %

Procedure:
65 g (0.94 mol) of 1,2,4-triazole and 71 g (0.63 mol) of potassium tert.-butylate are taken in 160 ml of absolute dimethylformamide under a nitrogen atmosphere and are heated to 80° C. A solution of 70.6 g (0.26 mol) of 1-chloro-2-(1-chlorocyclopropyl)-3-(4-fluorophenyl)-propan-2-ol in 90 ml of absolute dimethylformamide is added dropwise at this temperature, with stirring. The mixture is subsequently stirred at 100° C. for 6 hours and is then concentrated by stripping off the diluent under reduced pressure. The residue is taken up in ethyl acetate, the mixture is washed with water and, after drying over sodium sulphate, the solvent is stripped off under reduced pressure. The product which remains is chromatographed over a silica gel column with chloroform as the mobile phase. 28.2 g (39% of theory) of 1-(4-fluorophenyl)-2-(1-chloro-cyclopropyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol are obtained in this manner in the form of a solid substance of melting point 111° C. Preparation of precursors ##STR32##