Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Br.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]>CCOCC>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:3]1[CH:2]=[C:1]([CH3:9])[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccccc1[Mg]Br
Reactant: Fc1ccccc1Br
Solvent: CCOCC
Product: Cc1cccc(-c2ccccc2F)c1
Temperature: 25 °C

Procedure:
A 1.46M solution (45 ml) of toluylmagnesium bromide in ether was added to a mixture of 10 g 2-bromofluorobenzene and 250 mg bis(diphenylphosphinoethane)-nickel dichloride in 70 ml dry diethyl ether. The mixture was then heated at reflux for 18 hours. The mixture was cooled to room temperature and quenched with 10% aqueous ammonium chloride, followed by 1M hydrochloric acid, and then partitioned between ether and water. The aqueous phase was extracted once more with ether and the combined organic extracts were dried and evaporated yielding the crude product as an oil which was purified by elution from silica gel with hexanes. The product was a colorless oil (7.0 g, 66% yield) which was used without further purification. NMR (CDCl3, 60MHz): 7.4-6.9 (m, 8H), 2.4 (s, 3H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][C@H:29]([CH3:32])[CH2:30][OH:31]>>[OH:31][CH2:30][C@H:29]([NH:28][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[N:20][CH:21]=1)=[O:25])[CH3:32]
Reactant: C[C@@H](N)CO
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N[C@H](C)CO)cn2)CC1
Yield: 80 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazine-4-yl-carbonyl]nicotinic acid and using (R)-(−)-2-amino-1-propanol. Then, the product was recrystallized with ethanol and hexane to give a desired compound.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([NH:10][N:11]=[C:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1.[CH3:25]I>CN(C=O)C>[Br:3][C:4]1[N:9]=[C:8]([N:10]([CH3:25])[N:11]=[C:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(=NNc2cccc(Br)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(N=C1CCN(C(=O)OC(C)(C)C)CC1)c1cccc(Br)n1
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.72 g, 18 mmol) was added to a solution of tert-butyl 4-(2-(6-bromopyridin-2-yl)hydrazono)piperidine-1-carboxylate (5.5 g, 15 mmol) in DMF (50 mL) at room temperature under N2, and the resulting solution was stirred for 20 min. Methyl iodide (1.0 mL, 17 mmol) was added to the solution, and the resulting solution was stirred for 2 h at ambient temperature. The mixture was quenched with H2O (100 mL) and extracted with EtOAc (4×50 mL). The combined organic extracts were concentrated to an orange oil under reduced pressure. The oil was diluted with EtOAc (100 mL) and washed with brine (7×50 mL). The organics were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure to provide the title compound (5.7 g, 99%) as an orange oil: 1H NMR (300 MHz, DMSO-d6) δ 7.45 (dd, J=8.1, 7.5 Hz, 1H), 6.91 (d, J=7.5 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 3.56 (t, J=6.0 Hz, 2H), 3.44 (t, J=6.0 Hz, 2H), 3.09 (s, 3H), 2.53-2.46 (m, 4H, overlap with solvent), 1.42 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.Cl>ClCCl.C(OCC)(=O)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:7][CH:8]=1
Reactant: C1=COCCC1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: FC(F)(F)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.7 %

Procedure:
a solution of 4-(trifluoromethyl)phenol (2.44 g, 15 mmol) in dichloromethane (5 ml) was added to a solution of 3,4-dihydro-2H-pyran (4.10 ml, 45 mmol) and a 3.6 M solution of hydrogen chloride in ethyl acetate (0.015 ml, 0.05 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 16 h. It was diluted with ethyl acetate (100 m) and washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml). The aqueous phase was extracted with ethyl acetate (2×30 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crud product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane 1:10 as eluent to give 3.09 g of 2-(4-(trifluoromethyl)phenoxy)tetrahydropyran.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][C@H:5]1[CH2:10][O:9][CH2:8][C@@H:7]([C:11]([OH:13])=[O:12])[CH2:6]1>C(OCC)C.CO>[OH:4][C@H:5]1[CH2:10][O:9][CH2:8][C@@H:7]([C:11]([O:13][CH3:3])=[O:12])[CH2:6]1
Reactant: O=C(O)[C@@H]1COC[C@H](O)C1
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@@H]1COC[C@H](O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of diazomethane in diethyl ether (approx. 0.4 M) is added in excess to a solution of 23 mmol of (cis)-5-hydroxytetrahydropyran-3-carboxylic acid in 300 ml of methanol at 0° C. The mixture is stirred at 0° C. for 2 hours and then quenched with magnesium sulphate, filtered and evaporated. The crude title compound is identified by means of the Rf.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[F:21].[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:16]([F:20])[C:15]=1[F:21]
Reactant: Fc1cccc(Br)c1F
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(Br)c(F)c1F
Temperature: -75 °C
Yield: 21.8 %

Procedure:
Diisopropylamine (7.86 grams (g), 78 mmol) was dissolved in tetrahydrofuran (THF; 104 mL) and cooled to −75° C. utilizing a dry ice/acetone bath. A solution of n-BuLi (2.5 M in hexanes; 22.80 mL, 57.0 mmol) was added dropwise, and the solution was again cooled to −75° C. 1-Bromo-2,3-difluorobenzene (10 g, 51.8 mmol) was dissolved in THF (25.9 mL), and the solution was added dropwise keeping the temperature below −60° C. The reaction mixture was then allowed to warm to −15° C. before cooling again to −75° C. TMSCl (7.29 mL, 57.0 mmol) was then added dropwise, and the reaction mixture was allowed to warm to 25° C. and then concentrated under vacuum. The residue was partitioned between ethyl acetate (EtOAc) and H2O. The organic phase was washed twice more with H2O and concentrated. Kugelrohr distillation at 88° C. provided the product in greater purity but an impurity was distilling at that temperature. Kugelrohr distillation of that purified distillate at 75° C. led to purer product but some product was left in the pot. This process yielded the title compound as a clear oil (3.0 g, 21.83%, 90% purity): 1H NMR (300 MHz, CDCl3) δ 7.28 (ddd, J=7.8, 5.2, 1.3 Hz, 1H), 6.98 (ddd, J=8.0, 4.8, 1.9 Hz, 1H), 0.32 (s, 9H); EIMS m/z 264, 266.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[Br:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:39][C:38]1[CH:42]=[CH:43][C:35]([Br:34])=[CH:36][CH:37]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Br)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc(Br)cc3)c3c(Br)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The titled compound was prepared from 4-bromo-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 22-(1) and 4-bromobenzoyl chloride in a manner similar to Example 3 as a colorless powder. APCI-Mass m/Z 526/528/530 (M+H). 1H-NMR (DMSO-d6) δ 3.20-3.48 (m, 4H), 3.66 (m, 2H), 4.27 (s, 2H), 4.54 (t, J=5.4 Hz, 1H), 5.10 (d, J=5.3 Hz, 1H), 5.17 (d, J=5.0 Hz, 1H), 5.23 (d, J=5.8 Hz, 1H), 5.41 (d, J=9.0 Hz, 1H), 7.04 (t, J=7.9 Hz, 1H), 7.16 (d, J=8.3 Hz, 2H), 7.21 (d, J=7.5 Hz, 1H), 7.33 (s, 1H), 7.45 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([CH3:50])[CH2:46][CH2:45]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]1[CH2:49][CH2:48][CH:47]([CH3:50])[CH2:46][CH2:45]1)[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: CC1CCN(C(=O)CCl)CC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCC(C)CC3)c(F)c2)C(C)C)c1
Yield: 16 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.2 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(N(C(C)C)C(C)C)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)cn2)CC1
Yield: 63 %

Procedure:
A mixture of 6-chloro-nicotinonitrile (2.1 g, 15.16 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.86 g, 24.25 mmol, 1.6 equiv; commercially available) in N-ethyl diisopropylamine (5 mL) and anhydrous DMF (10 mL) was stirred at 60° C. for 3 d. To the reaction mixture was added a sat. solution of Na2CO3 (100 mL) and the crude extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography eluting with toluene/ethyl acetate (4:1) to provide 2.90 g (63%) of the title compound. 1H NMR (300 MHz, DMSO): δ1.24-1.42 (m, 2H), 1.41 (s, 9H), 1.84-1.89 (m, 2H), 2.85-2.94 (m, 2H), 3.87-3.91 (m, 2H), 3.98 (br s, 1H), 6.54 (d, J=8.9 Hz, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.66 (dd, J=8.9 Hz, J=2.1 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H). 13C NMR (75 MHz, DMSO): δ28.04, 31.19, 42.25, 47.12, 78.58, 94.49, 108.62, 118.91, 138.53, 153.00, 153.89, 159.17. MS (ISP): 303.1 [M+H]+.
Reaction SMILES: C1(S([NH2:10])(=O)=O)C=CC=CC=1.[OH-].[Na+].[CH:13]1([N:19]=[C:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CC(C)=O>[CH:13]1([NH:19][C:20](=[O:21])[NH2:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)NC1CCCCC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
6.0 g of 4-(β-<1-ethyl-1,2-dihydro-2-oxo-nicotinamido>-ethyl)-benzenesulfonamide (melting point 215 - 216° C, prepared from 4-(β-aminoethyl)-benzenesulfonamide and 1-ethyl-1,2-dihydro-2-oxo-nicotinic acid chloride) were suspended in 60 ml acetone. After the addition of 8.55 ml 2N sodium hydroxide solution, the reaction mixture was cooled to 0° C, 2.35 g of cyclohexyl isocyanate in 5 ml acetone were added dropwise while stirring and stirring was continued for 1 hour at 0° C and for 4 hours at room temperature. The volume of the reaction mixture was then doubled by adding water, the mixture was filtered and the filtrate acidified with 2N hydrochloric acid. The precipitate was dissolved in dilute ammonia solution and precipitated again with dilute hydrochloric acid, stirred with sodium bicarbonate solution and recrystallized from methanol. The N-[4-(β-<1-ethyl-1,2-dihydro-2-oxo-nicotinamido>-ethyl)-benzenesulfonyl]-N'-cyclohexyl urea obtained in this manner melted at 189 - 190° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:50])[CH2:30][CH2:31][N:32]([S:40]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>>[CH3:28][N:29]([CH3:50])[CH2:30][CH2:31][N:32]([C:33]1[CH:34]=[CH:35][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:38]=1)[S:40]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:41])=[O:42]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C)CCN(c1ccc(N)cc1)S(=O)(=O)Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)S(=O)(=O)Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-benzylsulphonyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C34H34N4O5S
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1>O.CC(C)=O>[Cl:13][C:14]1[N:15]=[CH:16][N:17]=[C:18]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH:19]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Clc1cc(Oc2ccc3[nH]ccc3c2)ncn1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
5-Hydroxyindole (91.8 g, 0.69 mol) is added in portions to a stirred solution of NaOH (27.9 g, 0.69 mol) in water (560 m L) at 10° C., to give a solution which is then cooled to −10° C. A solution of 4,6-dichloropyrimidine (95.3 g, 0.63 mol) in acetone (560 mL) is then added over a period of 65 min. The mixture is stirred at 0° C. for 30 min and then the acetone is evaporated off under reduced pressure, to give a mixture which is extracted with CH2Cl2. The combined extracts are washed with cold aqueous NaOH (0.5 M), dried (Na2SO4) and the solvent is evaporated off under reduced pressure to afford the product to afford the crude product which is purified by chromatography (silica gel; eluent 10% EtOAc in CH2Cl2) and recrystallised from CH2Cl2—hexane to give the title compound as a colourless crystalline solid, m.p. 149-150° C. Utilising a similar procedure, but employing 2,4-dichloropyrimidine in lieu of 4,6-dichloropyrimidine afforded 5-[(2-chloro-4-pyrimidinyl)oxy]-1H-indole, as cream crystalline solid, m.p. 169-176° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[F:9][C:10]1[CH:11]=[C:12]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH:13]=[CH:14][C:15](O)=[O:16].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:9][C:10]1[CH:11]=[C:12](/[CH:13]=[CH:14]/[C:15]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)=[O:16])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: OCC1CCNCC1
Reactant: O=C(O)C=Cc1cc(F)cc(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(/C=C/c1cc(F)cc(F)c1)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
4-Piperidinemethanol (17.7 g, 1.0 eq.), 3,5-difluorocinnamic acid (28.3 g, 1.0 eq.) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 78.2 g, 1.15 eq.) were dissolved in dichloromethane (DCM, 700 mL). Triethylamine (TEA, 46.6 g, 3.0 eq.) was added and the resulting solution was stirred at room temperature overnight. LCMS showed 100% conversion. The reaction mixture was concentrated and purified via silica gel column eluting with 0-75% ethyl acetate in hexanes to afford the product as a white solid (35 g, 81%). MS (ES) m/e 282 [M+H]+.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([C:18]1[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([CH:27]=1)[C:23](OC)=[O:24])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:7][CH2:6]1.Cl.OC(C1C=CC(OC)=C(C=1)C(OC)=O)[CH2:33][N:34]1CCN(C2C=CC=CC=2OC)CC1>>[ClH:1].[OH:2][CH:3]([C:18]1[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([CH:27]=1)[C:23]([NH:34][CH3:33])=[O:24])[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:9][CH2:10]1
Reactant: COC(=O)c1cc(C(O)CN2CCN(c3ccccc3OC)CC2)ccc1OC
Reactant: COC(=O)c1cc(C(O)CN2CCN(c3ccccc3C)CC2)ccc1OC
Agent: Cl
Product: CNC(=O)c1cc(C(O)CN2CCN(c3ccccc3C)CC2)ccc1OC

Procedure:
Following essentially the same procedure but substituting methyl 5-[1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]ethyl]-2-methoxybenzoate hydrochloride for the methyl 5-[1-hydroxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-methoxybenzoate hydrochloride above results in the preparation of 5-[1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]ethyl]-2-methoxy-N-methylbenzamide hydrochloride, having a m.pt. of 226°-7° C. (dec.).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([O:7][CH3:8])=[O:6])[CH3:4].Br[CH:10]([CH3:14])[C:11]([OH:13])=[O:12].[OH-].[Na+]>O1CCOCC1.O>[C:5]([CH:3]([NH:2][C@H:10]([C:11]([OH:13])=[O:12])[CH3:14])[CH3:4])([O:7][CH3:8])=[O:6]
Reactant: CC(Br)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C(C)N[C@@H](C)C(=O)O
Reaction time: 0.5 h

Procedure:
Neutralize a solution of 1.4 g of methyl L-alaninate HCl and 3.1 g of α-bromopropionic acid in a dioxane-water mixture to pH 9 with sodium hydroxide. Warm to 70° and hold for 30 minutes, keeping the pH at 8 to 9 by addition of sodium hydroxide as necessary. Cool, apply to a column of Dowex 50 (H+) ion exchange resin, wash with water, and elute with 2% pyridine in water. Combine the product fractions and freeze dry. Purify this crude by chromatography on an ion-exchange column of Dowex 50 (Na+) in 0.5 M sodium citrate buffer pH 3.3. Collect the product fractions, concentrate to a small volume in vacuo, and repeat the Dowex 50 (H+) chromatography. Freeze dry the product fractions to obtain the pure N-(1-carbomethoxyethyl)-alanine.
Reaction SMILES: [C:1](Cl)(=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]1([C:18]2[NH:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C(C)=CC=CC=1C>O1CCCC1>[CH2:3]([O:2][C:1]([N:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)n1c(-c2ccccc2)nc2ccccc21
Temperature: 50 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
In a nitrogen atmosphere, 107 g of benzyl chlorocarbonate was added dropwise to a solution of 97 g of 2-phenylbenzimidazole and 107 g of 2,6-lutidine in 700 g of tetrahydrofuran, which was heated and stirred at 50° C. for 20 hours. After ordinary aqueous work-up, the insoluble was filtered off. The filtrate was concentrated, washed with hexane, and dried, obtaining 118 g of 1-benzyloxycarbonyl-2-phenylbenzimidazole (yield 72%).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[F:5][C:6]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:7]=1[CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13]Br>O1CCCC1>[CH:1]([NH:4][CH2:13][C:12]#[C:11][CH2:10][O:9][CH2:8][C:7]1[CH:15]=[C:16]([Br:19])[CH:17]=[CH:18][C:6]=1[F:5])([CH3:3])[CH3:2]
Reactant: Fc1ccc(Br)cc1COCC#CCBr
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NCC#CCOCc1cc(Br)ccc1F
Yield: 85.6 %

Procedure:
A solution of isopropylamine (0.25 ml, 2.9 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl bromide (97 mg, 0.29 mmol) in tetrahydrofuran (1.4 ml). The cloudy reaction mixture was stirred for about twenty hours, at which time no starting material remained, as determined by thin layer chromatography. The solvents were removed in vacuo. The residue was taken up in methylene chloride and washed with 1 M potassium carbonate. The aqueous phase was back extracted with methylene chloride (2×5 ml). The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The resulting oil was further purified by flash chromatography, affording 78 milligrams (86%) of the title intermediate.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([O:18]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:13][CH:12]([C:28]([O:30][CH3:31])=[O:29])[CH2:11]2)=[CH:6][CH:5]=1.[NH:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[N:34]1([C:16]([N:14]2[CH2:15][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][C:2]([F:32])([F:33])[F:1])=[CH:5][CH:6]=3)[CH2:11][CH:12]([C:28]([O:30][CH3:31])=[O:29])[CH2:13]2)=[O:18])[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1
Reactant: C1CSCCN1
Reactant: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Temperature: 150 °C

Procedure:
A solution of 10.3 g (17.9 mmol, purity 81%) of the compound from Example 54A in 1-methyl-2-pyrrolidone (65 ml) was admixed with 12.6 ml (13.7 g, 132 mmol) of thiomorpholine and 11.5 ml (8.56 g, 66.2 mmol) of N,N-diisopropylethylamine and then heated in 5 portions in a single-mode microwave (Emrys Optimizer) at 150° C. for 1 h. For workup, the reaction solutions were combined and purified directly by means of preparative HPLC. Yield: 5.63 g (71% of theory)
Reaction SMILES: [OH:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:4][CH2:3]1.[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH2:21]([N:8]([CH:5]1[CH2:6][CH2:7][C:2]([OH:1])([CH3:20])[CH2:3][CH2:4]1)[C:9]1[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[CH3:22]
Reactant: COC(=O)c1cccc(NC2CCC(C)(O)CC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cccc(C(=O)OC)c1C)C1CCC(C)(O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
To a stirred solution of methyl 3-((4-hydroxy-4-methylcyclohexyl)amino)-2-methylbenzoate (1.4 g, 5.05 mmol) and acetaldehyde (0.7 ml, 13 mmol) in 20 ml of dichloroethane was added acetic acid (1.7 mL, 30 mmol) and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (3.2 g, 15 mmol) was added and the mixture was stirred at room temperature for overnight. The reaction mixture was neutralized with sat. NaHCO3 and extracted with DCM. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and the residue purified by silica gel column chromatography to afford the title compound (1.42 g, 94%).