Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:25][CH3:26].[C:27]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>COCCOC>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:37]5[CH:38]=[CH:39][C:34]([C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:33])=[CH:35][CH:36]=5)[C:3]([CH2:25][CH3:26])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: CC(C)(C)OC(=O)c1ccc(B(O)O)cc1
Reactant: CCc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 120 °C

Procedure:
N-(6-Chloro-5-ethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (38 mg; 0.10 mmol) was dissolved in 1 mL of 1,2-dimethoxyethane (DME) in a microwave reactor tube. 4-(tert-butoxycarbonyl)phenyl-boronic acid (29 mg, 0.13 mmol), 0.1 mL of an aqueous 2 M potassium carbonate solution, and tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4, 5.6 mg, 0.0048 mmol) were added and the reaction mixture was heated at 120° C. in a microwave reactor for 20 minutes. The resulting material was cooled to room temperature, filtered, and the layers were separated. The organic layer was concentrated in vacuo to yield tert-butyl 4-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-ethylpyridin-2-yl)benzoate which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([F:10])[CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=2[F:10])([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Fc1cc(Cl)ccc1CBr
Product: OC1(Cc2ccc(Cl)cc2F)CCN(Cc2ccccc2)CC1

Procedure:
A sample of 4-chloro-2-fluorobenzyl bromide is converted to its Grignard reagent which is reacted with N-benzyl-4-piperidone to provide 1-benzyl-4-(4-chloro-2-fluorobenzyl)-4-piperidinol in the manner described in Example 4A. This product is distilled at 175°-180° C., 0.18 mm, to provide an orange oil which is converted in ether to its hydrogen chloride salt. The salt is recrystallized four times from an ethyl alcohol-ether mixture to provide the purified salt, mp 211.5°-213° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:28][C:7]1[CH:6]=[CH:5][C:4]([C:8]2[O:12][C:11]([P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)=[CH:3][C:2]=1[NH2:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOP(=O)(OCC)c1ccc(-c2cccc(N)c2)o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)c1ccc(-c2ccc(Br)c(N)c2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of diethyl 5-(3-aminophenyl)-2-furanphosphonate (1 mmol), NBS (0.9 mmol) and AIBN (0.1 mmol) in 30 mL of CCl4 was stirred at rt for 2 h. Extraction and chromatography provided diethyl 5-(4-bromo-3-aminophenyl)-2-furanphosphonate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=O)[CH2:13][S:14][CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:23].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([NH2:23])[CH2:13][S:14][CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CSCC(=O)C1(c2ccc(Cl)cc2)CCC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CSCC(N)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 456 h

Procedure:
Crude 1-[1-(4-chlorophenyl)cyclobutyl]-2-methylthioethan-1-one (8.3 g prepared as described above), ammonium acetate (25 g) and sodium cyanoborohydride (2.6 g) were dissolved in methanol (120 ml). The solution was kept at room temperature for 19 days and then poured into water (300 ml) and basified to pH 8. The mixture was extracted with ether and the ethereal solution extracted with 2N hydrochloric acid. The acid solution was basified and extracted with ether. The extracts were dried and evaporated to give an oil which was purified by flash chromatography using ethyl acetate as eluant to give 1-[1-(4-chlorophenyl)cyclobutyl]-2-methylthioethylamine the boiling point of which was not determined.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:27]([OH:29])=O.[CH2:36]([NH:41][CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:37][CH:38]([CH3:40])[CH3:39]>C(Cl)(Cl)Cl.C1COCC1>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:27]([N:41]([CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:36][CH2:37][CH:38]([CH3:39])[CH3:40])=[O:29]
Reactant: CC(C)CCNCCC(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (4.4 g, 1.1 eq) in solution in chloroform (25 ml) and 1-hydroxybenzotriazole (HOBt) (3.05 g, 1.1 eq) in solution in THF (40 ml) are successively added to 3-fluoro-4-nitrobenzoic acid (3.8 g, 1 eq) in solution in anhydrous THF (30 ml). The mixture is stirred for 1 hour at a temperature of approximately 20° C. then diisoamylamine (3.6 g, 1.1 eq) in solution in THF (30 ml) is added. After stirring for 16 hours at a temperature of approximately 20° C., the reaction mixture is concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (200 ml) and water (70 ml). After decantation and extraction, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the compound by flash chromatography on silica gel (eluent: heptane/ethyl acetate 9:1) produces the expected compound in the form of a yellow oil (4.3 g; 65% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:37](=[O:38])[C:31]3[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=3)[C:40]2=[O:39])=[CH:7][CH:6]=1
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3ccc4c(c3)OCO4)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccc4c(c3)OCO4)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(3,4-methylenedioxyphenyl)benzoxazole (50 mg, 0.14 mmol) and 1,2,4-benzenetricarboxylic anhydride (27 mg, 0.14 mmol) the title compound was obtained (72 mg, 92%). 1H NMR (DMSO) δ 13.85(s, 1H), 8.44(dd, 1H), 8.33(s, 1H), 8.21(d, 1H), 8.11(d, 1H), 8.02(d, 1H), 7.83(d, 1H), 7.71(dd, 1H), 7.66(dd, 1H), 7.47(d, 1H), 7.35(d, 1H), 7.22(dd, 1H), 7.03(d, 1H), 6.08(s, 2H), 4.03(s, 3H). MS 535.1 m/z (M+H)+.
Reaction SMILES: CC(C)=O.[Br:5][C:6]1[N:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(#N)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:10][N:11]=1
Reactant: ClCCN1CCCC1
Reactant: Oc1ccc(Br)nc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CC#N
Product: Brc1ccc(OCCN2CCCC2)cn1

Procedure:
The product is obtained analogously to Example 3.1 e (1:1 mixture of acetone:acetonitrile instead of DMF) from 3.90 g (22.4 mmol) 6-bromo-pyridin-3-ol and 4.25 g (25.0 mmol) N-(2-chloroethyl)-pyrrolidine hydrochloride.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][N:15]3[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:11]([NH2:24])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:25]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[Br:25][C:14]1[N:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:16]2[C:12]([N:13]=1)=[C:11]([NH2:24])[N:10]=[C:9]([O:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[N:17]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(OCC2CCCCC2)nc2c1ncn2C1CCCCO1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc(OCC2CCCCC2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 2 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
2-[(Cyclohexylmethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.0364 g) was dissolved in chloroform (20 mL) and cooled to 0° C. before N-bromosuccinimide (0.5852 g) was added gradually (the reaction temperature not exceeding 1.9° C. during the addition of N-bromosuccinimide). The reaction mixture was stirred at ˜2° C. for 15 minutes before being warmed to room temperature at which it was stirred for 6 hours (under nitrogen). Water (100 mL) was added to the reaction mixture and stirred rapidly before the organic layer was separated using a hydrophobic frit. The organic phase was evaporated under reduced pressure to give dark brown oil. This material was purified by silica chromatography eluting with 0-50% ethyl acetate; cyclohexane to give the title compound as a pale yellow solid (0.8200 g).
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:10])[C:5](=[CH:8]O)[C:6]#[N:7].P(Cl)(Cl)(Cl)(Cl)[Cl:12].O>ClCCl>[CH3:2][O:3][C:4](=[O:10])[C:5](=[CH:8][Cl:12])[C:6]#[N:7]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)C(C#N)=CO
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(C#N)=CCl
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To a suspension of the sodium salt of methylhydroxymethylene-cyanoacetate (19.0 g, 127 mmol) in 200 mL of dichloromethane was added phosphorous pentachloride (26.5 g, 127 mmol) in one portion. The reaction mixture was allowed to exotherm to reflux temperature and then maintained at reflux with stirring for 4 hours. The resulting light yellow suspension was allowed to cool to 23° C. and then poured into 400 mL of cold water. The mixture stirred for 15 minutes and the phases were separated. The aqueous layer was extracted with 100 mL of dichloromethane and the combined organic layers were washed twice with water, dried over magnesium sulfate, and concentrated to 16.8 g of the title compound which was of sufficient purity for use in Example 1. 1H NMR (300 MHz, CDCl3) δ 3.88 (s, 3H), 7.58 (s, 0.35H), 8.04 (s, 0.65H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:10]1[C:11]2[C:6](=[CH:5][C:4]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[CH:3][C:2]=2[F:1])[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: COc1ccc(-c2cc(F)c3cc(O)ccc3c2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2)cc1
Yield: 83.9 %

Procedure:
A solution of 8-fluoro-6-(4-methoxyphenyl)-2-naphthol (0.17 g, 0.63 mmol) and NCS (0.10 g, 0.76 mmol) in THF (20 mL) were stirred under nitrogen at room temperature overnight according to Method C. The solution was concentrated onto Florosil and purified on a silica column (20% ethyl acetate—hexanes) to yield 0.16 g (84%) of the title compound as a yellow solid. An analytical sample was further prepared by preparative reverse phase HPLC to yield a light yellow solid: mp 120-124° C.; 1H NMR (DMSO-d6): δ 3.82 (3H, s), 7.06 (2H, d, J=8.80 Hz), 7.34 (1H, d, J=8.91 Hz), 7.67 (1H, dd, J=1.69 Hz, J=15.48 Hz), 7.78 (2H, d, J=8.78 Hz), 8.01 (1H, d, J=1.54 Hz), 10.62 (1H, s); MS (ESI) m/z 301/303 (M−H)−.
Reaction SMILES: C([Sn](CCCC)(CCCC)/[CH:6]=[CH:7]/[CH2:8][CH:9]([O:14][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])CCC.[I:30]I>CCOCC>[I:30]/[CH:6]=[CH:7]/[CH2:8][CH:9]([O:14][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](CC)(CC)CC
Reactant: II
Solvent: CCOCC
Product: CCCCC(C/C=C/I)O[Si](CC)(CC)CC

Procedure:
To a solution of E-1-tri-n-butystannyl-4-triethylsilyloxy-1-octene (11 g) in 200 ml ether is added 0.9 equivalents of iodine in one portion. After 25 minutes the color of the iodine has disappeared. An additional 0.1 equivalents of iodine is added in portions until the iodine color persists. The ether is removed in vacuo to provide (E)-1-iodo-4-triethylsilyloxy-1-octene. This residue is placed on a silica-gel column (240 g SilicAR CC-7) packed in hexane. A liter fraction of hexane contains 7.5 g of mostly tri-n-butylidostannane. A 500 ml elution of benzene gives only a small amount of material. An elution with 600 ml of ether provides 7.0 g of 1-iodo-4-hydroxy-1-octene as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[C:4]([C:15]2(O)[CH2:20][CH2:19][N:18]([CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)[CH:3]=1.O>OS(O)(=O)=O.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:15]2[CH2:20][CH2:19][N:18]([CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[CH2:17][CH:16]=2)[CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C1(O)CCN(C/C=C/c2ccc(Cl)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Cl)cc1C1=CCN(C/C=C/c2ccc(Cl)cc2)CC1

Procedure:
A suspension of N-(4-chloro-2-{1-[(E)-3-(4-chloro-phenyl)-allyl]-4-hydroxy-piperidin-4-yl}-phenyl)-2,2-dimethyl-propionamide (1.00 g) in 3N H2SO4 (7.5 ml) and DMSO (3 ml) was heated to reflux temperature for 48 hours. Then, water was added and the mixture extracted three times with CH2Cl2, the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (CH2Cl2:MeOH 95:5) to afford 4-chloro-2-{1-[(E)-3-(4-chloro-phenyl)-allyl]-1,2,3,6-tetrahydro-pyridin-4-yl}-phenylamine (0.205 g; viscous oil; Retention Time HPLC 2.15 min; MS (ES+) 359 (M+H+) and 4-(2-amino-5-chloro-phenyl)-1-[(E)-3-(4-chloro-phenyl)-allyl]-piperidin-4-ol (0.182 g; M.p. 168-170° C.; Retention Time HPLC 1.95 min; MS (ES+) 377 (M+H+).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][CH2:8]1>>[Br:1][C:2]1[S:3][C:4]([C:7](=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: Brc1cccs1
Reactant: O=C1CCC(=O)O1
Product: O=C(O)CCC(=O)c1ccc(Br)s1
Yield: 51 %

Procedure:
As described for Example 1, 0.3 mole of 2-bromothiophene is reacted with succinic anhydride to give 4-(5-bromo-2-thienyl)-4-ketobutyric acid (51%), m.p. 141°-143° C. The preceding compound is coupled to L-proline to give 1-[3-(5-bromo-2-thenoyl)propionyl]-L-proline (56%) as crystals, m.p. 166°-168° C. The preceding compound (0.008 mole) is reacted with bromine in acetic acid to yield 1-[3-bromo-3-(5-bromo-2-thenoyl)propionyl]-L-proline as a glass (97%). As for Example 1, reaction of the preceding compound with sodium thioacetate gives the product of the Example (88%) as a yellow glass.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:13]([Mg]Br)=[CH2:14]>O1CCCC1.[Cu]I>[CH2:1]([O:8][CH2:9][C@H:10]([OH:11])[CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: C=C[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CC[C@@H](O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of (2R)-2-[(benzyloxy)methyl]oxirane (167 g, 1.02 mol) in tetrahydrofuran (2 L) was added copper(I) iodide (11.62 g, 61.02 mmol) at room temperature. The mixture was stirred for 5 minutes, then cooled to −78° C. A solution of vinylmagnesium bromide (1 M in tetrahydrofuran, 1.12 L, 1.12 mol) was added drop-wise over 1 hour while the reaction temperature was maintained below −70° C. Upon completion of the addition, the cooling bath was removed and the reaction mixture was left to stir at room temperature for 1 hour, then quenched by slow addition of aqueous ammonium chloride solution (200 mL). After dilution with aqueous ammonium chloride solution (1.5 L) and ethyl acetate (1.5 L), the aqueous layer was extracted with ethyl acetate (1 L) and the combined organic layers were washed with aqueous ammonium chloride solution (1.5 L), dried over magnesium sulfate, filtered, and concentrated in vacuo. Three batches of this reaction were carried out and combined to give the product as an orange oil. Yield: 600 g, 3.1 mol, quantitative. 1H NMR (400 MHz, CDCl3) δ 7.28-7.40 (m, 5H), 5.78-5.90 (m, 1H), 5.08-5.17 (m, 2H), 4.57 (s, 2H), 3.86-3.94 (m, 1H), 3.53 (dd, J=9.6, 3.3 Hz, 1H), 3.39 (dd, J=9.6, 7.4 Hz, 1H), 2.26-2.34 (m, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)C.[NH3:13]>>[NH2:13][C:4]([CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: CCOC(=O)Cc1cccnc1
Reactant: N
Product: NC(=O)Cc1cccnc1

Procedure:
16.8 g of ethyl-3-pyridylacetate and 1 l of methanolic ammonia solution are shaken in a pressure vessel at 100° C. for 40 hours. After cooling and concentration, the precipitate is triturated with ether and filtered off with suction. 12.7 g of the 3-(aminocarbonylmethyl)pyridine obtained in this way are hydrogenated with 250 ml of ethanol and 3 g of rhodium/platinum catalyst at 50° C. under a pressure of 3 bar of hydrogen for 2 hours. After cooling, filtration and concentration, the precipitate is triturated with ether and filtered off with suction.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[OH:14].I[CH3:16]>CN(C=O)C>[CH3:16][O:14][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][CH:13]=[C:4]2[NH2:3]
Reactant: CI
Reactant: Nc1cccc2c(O)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c(N)cccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a stirred suspension of NaH (7.5 g, 188.0 mmol) in DMF (500 mL) was added a solution of 5-amino-1-naphthol (25.0 g, 157 mmol) dropwise at 0° C. After the addition, mixture was stirred for 30 min at 0° C. and for 1 h at RT. Then a solution of iodomethane (9.82 mL, 157 mmol) in DMF (25 mL) was added dropwise to the mixture at 0° C. and the reaction mixture was allowed to RT and stirred overnight. It was slowly quenched with ice and extracted with EtOAc. The combined organic layers were washed with water, brine, and dried. The solvent was removed under reduced pressure and the residue was purified by column chromatography to afford the title compound (23.0 g, 85%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[N:24]([CH3:33])[CH:23]=1>CN(C=O)C.O>[NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=2[C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[N:24]([CH3:33])[CH:23]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2F)c2ccccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2O[C@H]2CC[C@@H](N)CC2)c2ccccc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To compound cis-4-aminocyclohexan-1-ol (275 mg, 1.81 mmol) in DMF (3 mL), was added NaH (127 mg, 3.17 mmol, 60% in mineral oil) in one portion at 0° C. The mixture was stirred at 0° C. for 30 min, 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (150.00 mg, 0.45 mmol) was added in one portion and the mixture stirred at 0° C. for 2 hrs. The reaction was diluted with water (20 mL) and extracted with EA (3×20 mL). The combined organic layers were washed with saturated brine (2×20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC to give the title compound as its hydrochloride salt (91.01 mg, 47.1%). 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, J=8.0 Hz, 1H), 8.00 (s, 3H), 7.95 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.56 (s, 1H), 7.51 (t, J=7.2 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 4.70 (s, 1H), 3.59 (s, 3H), 3.22 (s, 3H), 2.96-2.94 (m, 1H), 1.85-1.82 (m, 1H), 1.64-1.46 (m, 5H), 1.32-1.26 (m, 1H), 1.04-0.98 (m, 1H). LCMS (M+H)+ =427.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH:11]2[CH2:13][CH2:12]2)=[N:9]/[OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:17][C:18]1[C:19]([F:32])=[C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([F:25])=[CH:22][C:23]=1[F:24].CN(C)C=O>C1(C)C=CC=CC=1>[F:32][C:19]1[C:18]([CH2:17][O:10]/[N:9]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)\[CH:11]2[CH2:12][CH2:13]2)=[C:23]([F:24])[CH:22]=[C:21]([F:25])[C:20]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Fc1cc(F)c(-c2ccccc2)c(F)c1CCl
Reactant: O/N=C(/c1ccc(Cl)cc1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Fc1cc(F)c(-c2ccccc2)c(F)c1CO/N=C(/c1ccc(Cl)cc1)C1CC1
Yield: 40.1 %

Procedure:
In a manner similar to Example 6 of U.S. Pat. No. 4,079,149, the reaction of 0.59 g (0.003 mole) of (E)-(4-chlorophenyl)(cyclopropyl)methanone oxime with 0.072 g (0.003 mole) of sodium hydride and 0.77 g (0.003 mole) of 3-chloromethyl-2,4,6-trifluoro[1,1'-biphenyl] in 25 ml of a 20% solution of N,N-dimethylformamide in toluene produced 0.5 g of (E)-(4-chlorophenyl)(cyclopropyl)methanone O-[(2,4,6-trifluoro[1,1'-biphenyl]-3-yl)methyl]oxime as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][CH:18]=1>>[N:17]1([C:2]2[N:7]=[C:6]([NH:8][C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: C[C@@H](Nc1cncc(Cl)n1)c1ccccc1
Reactant: c1ccc2[nH]cnc2c1
Product: C[C@@H](Nc1cncc(-n2cnc3ccccc32)n1)c1ccccc1
Yield: 57.6 %

Procedure:
In a procedure analogous to example 12, reaction of 6-chloro-N-[(1R)-1-phenylethyl]pyrazin-2-amine (240 mg, 1.03 mmol) and benzimidazole (130 mg; 1.10 mmol) furnished the product (187 mg, 59%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].F[C:19]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1.ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:26]1[CH:27]=[C:28]([F:30])[CH:29]=[CH:19][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(F)cc1OCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)ethanol (4.34 g, 26.9 mmol) in THF (16 mL) at 0° C. under N2, was added potassium tert-butoxide (K+−OtBu, 26.9 mL, 26.9 mmol, 1.0 M in THF). The reaction mixture was stirred for 20 min at 0° C. during which time a thick slurry formed. The anion solution was then poured into a solution of ethyl 2,4-di-fluorobenzoate (5.00 g, 26.9 mmol) in THF (16 mL) which had been cooled to −65° C. The reaction mixture was allowed to slowly warm to room temperature and was stirred for 18 h. The mixture was diluted with dichloromethane and washed with water. The water layer was extracted with additional dichloromethane and the dichloromethane layers combined and washed with brine, dried, and concentrated in vacuo to give a yellow oil. Purification on silica gel, eluting with a gradient of 4:1 to 3:1 hexane:EtOAc, yielded 3.82 g (43.5%) of the ether as a colorless oil.