Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]([CH3:8])([CH3:7])CC(O)=O.[CH:9]1[CH:14]=[N:13][C:12]2N(O)N=N[C:11]=2C=1.[CH3:19]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:9][CH2:14][N:13]([CH:2]([CH3:7])[CH3:8])[CH:12]([CH3:11])[CH3:19]
Reactant: On1nnc2cccnc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(O)CC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCN(C(C)C)C(C)C
Yield: 400 %

Procedure:
Treatment of 21 (0.71 g, 0.61 mmol), 1,3-propanedithiol (1.26 mL, 12.55 mmol) in pyridine (43 mL) and H2O (6.1 mL) with TEA (1.28 mL, 9.15 mmol) according to the general procedure for azide reduction and introduction of C-4″ moiety gave free amine (0.69 g, 99%). Treatment of the free amine (0.47 g, 0.41 mmol) in DMF (20 mL) with β-hydroxyisovaleric acid (88 μL, 0.82 mmol) which was activated with HOAt (0.23 g, 1.64 mmol) and HATU (0.62 g, 1.64 mmol) in DMF (10 mL) for 1 h, and then added DIPEA (5.71 mL, 3.28 mmol) gave compound 22 as colorless oil (0.32 g, 63%) and its α-isomer (76 mg, 15%). Rf=0.26 (Hexane/EtOAc, 1:1, v:v). [α]27D=+9.4 (CHCl3, c=2.8 mg/mL). 1H NMR (500 MHz, CDCl3): δ 0.73 (d, 3H, J5,6=5.5 Hz, H-6c), 1.09 (s, 3H, (CH3)2C(OH)CH2C(O)NH), 1.12 (d, 3H, J5,6=6.0 Hz, H-6b), 1.18 (s, 3H, (CH′3)2C(OH)CH2C(O)NH), 1.24 (d, 3H, J5,6=5.5 Hz, H-6a), 1.74 (m, 2H, OCH2CH2CH2NHZ), 1.99 (d, 1H, J=15.0 Hz, (CH3)2C(OH)CH2C(O)NH), 2.09 (d, 1H, J=15.0 Hz, (CH3)2C(OH)CH′2C(O)NH), 2.91 (m, 1H, H-5c), 2.98 (t, 1H, J1,2=8.0, J2,3=8.5 Hz, H-2c), 3.15 (t, 1H, J2,3=8.5, J3,4=9.0 Hz, H-3c), 3.22 (m, 2H, OCH2CH2CH2NHZ), 3.38 (s, 3H, OCH3), 3.39 (m, 2H, OCH2CH2CH2NHZ, H-4c), 3.52 (t, 1H, J3,4=9.0, J4,5=9.5 Hz, H-4b), 3.54 (t, 1H, J3,4=9.0, J4,5=9.5 Hz, H-4a), 3.67 (m, 2H, OCH′2CH2CH2NHZ, H-5a), 3.76 (m, 1H, H-5b), 4.12 (dd, 1H, J2,3=3.5, J3,4=9.0 Hz, H-3b), 4.21 (dd, 1H, J2,3=3.0, J3,4=9.0 Hz, H-3a), 4.34 (d, 1H, J1,2=8.0 Hz, H-1c), 4.48 (d, 1H, J=11.0 Hz, PhCH2), 4.54 (d, 1H, J=11.0 Hz, PhCH′2), 4.60 (d, 1H, J=10.5 Hz, PhCH2), 4.71 (d, 1H, J=12.5 Hz, PhCH′″2), 4.77 (s, 1H, H-1a), 4.83 (d, 1H, J=11.5 Hz, PhCH″″2), 4.85 (broad, 1H, NH), 4.95 (d, 1H, J=11.0 Hz, PhCH′″″2), 5.00 (s, 2H, PhCH2OC(O)), 5.15 (s, 1H, H-1b), 5.30 (d, 1H, J2,3=3.0 Hz, H-2a), 5.39 (d, 1H, J2,3=3.5 Hz, H-2b), 7.14-8.00 (m, 30H, Harom); 13C NMR (75 MHz, CDCl3): δ 17.7 (C-6c), 17.8 (C-6b), 18.1 (C-6a), 29.2 (OCH2CH2CH2NHZ), [29.3, 29.7 ((CH3)2C(OH)CH2C(O)NH)], 38.5 (OCH2CH2CH2NHZ), 47.7 ((CH3)2C(OH)CH2C(O)NH), 55.7 (C-4c), 60.3 (OCH3), 65.6 (OCH2CH2CH2NHZ), 66.6 (PhCH2OC(O)), 67.9 (C-5a), 68.6 (C-5b), 69.4 ((CH3)2C(OH)CH2C(O)NH), 70.6 (C-5c), 72.8 (C-2a), 73.1 (C-2b), [73.5, 74.1, 75.5 (PhCH2)], 76.1 (C-3b), 78.1 (C-3a), 79.8 (C-3c), 80.0 (C-4a), 80.5 (C-4b), 84.4 (C-2c), 97.1 (C-1a), 99.2 (C-1b), 103.0 (C-1c), [127.5, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 129.7, 129.8, 129.9, 130.2, 133.0, 133.3, 137.9, 138.3, 138.5 (Carom)], 156.4 (PhCH2OC(O)), [165.6, 165.9 (PhC(O)O)], 172.2 ((CH3)2C(OH)CH2C(O)NH); MALDI-TOF/MS: m/z: found [M+Na]+ 1261.4, MALDI-FTICR/MS: m/z: found [M+Na]+ 1261.5427. C70H82N2O18 calcd for [M+Na]+ 1261.5460.
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1([CH2:24][N:25]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])C2C=CC=CC=2N=N1.O>C1COCC1.[Zn]>[CH2:33]([N:25]([CH2:24][C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CCOC(=O)CCN(Cc1ccccc1)Cn1nnc2ccccc21
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCN(Cc1ccccc1)CC(F)(F)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To a solution of 1H-benzotriazole (2.38 g) in methanol (20 mL) were added ethyl N-benzyl-β-alaninate (4.14 g) and aqueous formaldehyde solution (37%, 2 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give ethyl N-(1H-benzotriazol-1-ylmethyl)-N-benzyl-β-alaninate (5.60 g). To a mixture of zinc powder (1.74 g) in anhydrous THF (16 mL) was added chlorotrimethylsilane (1.58 g) under nitrogen atmosphere, and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added ethyl bromodifluoroacetate (2.97 g) at room temperature, and then a solution of ethyl N-(1H-benzotriazol-1-ylmethyl)-N-benzyl-β-alaninate (4.50 g) in THF (8 mL) was added thereto at room temperature. The reaction mixture was stirred at room temperature for 18 hr, and added to water. The insoluble substance was removed by the filtration, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (3.23 g).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([C:26]2[O:27][C:28]([CH2:31]Cl)=[N:29][N:30]=2)[CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([C:26]2[O:27][C:28]([CH2:31][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH:1]3[CH2:2][CH2:3]3)=[N:29][N:30]=2)[CH:23]=[N:22][CH:21]=1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Reactant: ClCc1nnc(-c2cncc(Br)c2)o1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2nnc(-c3cncc(Br)c3)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-bromo-5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridine: 1H NMR (400 MHz, CDCl3) δ 9.05 (d, J=1.7 Hz, 1H), 8.82 (d, J=1.9 Hz, 1H), 8.39 (m, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 6.52 (s, 1H), 5.80 (s, 2H), 2.06 (m, 1H), 1.19 (m, 2H), 0.92 (m, 2H); MS (ES) m/z 488 (M+1, isotope for Br) and 490 (M+1, isotope for Br).
Reaction SMILES: Br[C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:28]2[C@H:30]([C:31]([O:33]CC)=[O:32])[C:29]2([CH3:37])[CH3:36])=[CH:4][CH:3]=1.[F:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1>>[F:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[C@@H:28]3[C@H:30]([C:31]([OH:33])=[O:32])[C:29]3([CH3:37])[CH3:36])=[CH:38][CH:39]=2)=[CH:43][CH:42]=1
Reactant: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)C1(C)C
Reactant: OB(O)c1ccc(F)cc1
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3ccc(F)cc3)cc2)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 110 using racemic cis-ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropanecarboxylate and 4-fluorophenyl boronic acid in Step A. MS (ESI): mass calcd. for C36H30FN3O3, 571.23; m/z found, 572.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=8.5, 1H), 8.11 (d, J=8.6, 1H), 7.85 (d, J=8.0, 1H), 7.79-7.73 (m, 1H), 7.70 (d, J=8.5, 1H), 7.60-7.55 (m, 1H), 7.54-7.47 (m, 4H), 7.34-7.32 (m, 1H), 7.28-7.26 (m, 1H), 7.16-7.09 (m, 5H), 5.49-5.34 (m, 4H), 2.31 (d, J=8.1, 1H), 2.12 (d, J=8.2, 1H), 1.21 (s, 3H), 1.02 (s, 3H).
Reaction SMILES: C(OC=C)(=[O:3])C.[CH2:7]([SiH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH3:8].[CH:14]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH2:15]>C1(C)C=CC=CC=1>[CH2:14]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:15].[CH2:7]([Si:9]([CH2:12][CH3:13])([CH2:10][CH3:11])[OH:3])[CH3:8]
Reactant: C=C[Si](CC)(CC)CC
Reactant: CC[SiH](CC)CC
Reactant: C=COC(C)=O
Solvent: Cc1ccccc1
Product: CC[Si](CC)(CC)CC
Product: CC[Si](O)(CC)CC
Reaction time: 1 h

Procedure:
In a reactor were placed di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [IrCl(cod)]2 (0.05 mmol), vinyl acetate (20 mmol), and toluene (3 ml). The mixture was raised in temperature to 40° C. in a nitrogen atmosphere, triethylsilane (Et3SiH) (5 mmol) was added thereto over one hour, and a reaction was carried out at 40° C. for one hour. After the reaction, the reaction mixture was analyzed by gas chromatography to find that vinyltriethylsilane was produced in a yield of 36% and tetraethylsilane and acetic ester of triethylsilanol were by-produced in yields of 7% and 12%, respectively.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:15][CH2:16]C(O)=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-:23])(=[O:22])[CH3:21].[Na+]>C(O)(=O)C.[Pt]>[C:20]([O:23][CH2:16][NH:15][C:13](=[O:14])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])(=[O:22])[CH3:21]
Reactant: O=C(O)CNC(=O)CNC(=O)OCc1ccccc1
Reactant: CC(=O)[O-]
Agent: [Pt]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCNC(=O)CNC(=O)OCc1ccccc1
Yield: 60 %

Procedure:
Benzyloxycarbonylglycylglycine (3.99 g, 15 mmole) was suspended in a solution of anhydrous sodium acetate (0.9 g, 11 mmole) in glacial acetic acid (75 ml). The mixture was stirred and ice-cooled while being electrolysed (two 5 sq. cm. platinum foil electrodes placed 2 mm apart) using a current of 200-250 mA for 5 hours. The acetic acid was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (150 ml). The solution was washed with saturated sodium bicarbonate solution (5) ml portions, until the wash remained alkaline) and then with water (50 ml). The solution was dried (magnesium sulphate) and the solvent was evaporated under reduced pressure to yield the title compound as colourless crystals (1.85 g, 6.6 mmole).
Reaction SMILES: ClCC([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:25])=[CH:19][CH:18]=2)[C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]1=2)=O.[CH2:39]([OH:41])[CH3:40].C([O:44][CH2:45][CH3:46])C>>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][NH:26][C:24](=[O:25])[NH:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][N:8]3[C:9](=[O:15])[C@H:10]4[CH2:14][CH2:13][CH2:12][C@H:11]4[N:5]([C:45](=[O:44])[CH2:46][N:8]4[C:39](=[O:41])[C:40]5=[CH:14][CH:13]=[CH:12][CH:11]=[C:10]5[C:9]4=[O:15])[C:6]4[CH:38]=[CH:37][CH:36]=[CH:35][C:7]3=4)=[CH:22][CH:21]=2)=[CH:33][CH:32]=1
Reactant: CCOCC
Reactant: CCO
Reactant: O=C(NCc1ccc(F)cc1)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CCl)c3ccccc32)cc1
Product: O=C(NCc1ccc(F)cc1)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Yield: 35 %

Procedure:
Using (3aR*,10aS*)-4-(chloroacetyl)-9-[4-[3-(4-fluorobenzyl)ureido]benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one, the title compound was synthesized in otherwise the same manner as Example 30. Yield 35%, m.p. 154°-156° C. (ethanol-diethyl ether).
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.CS([Cl:24])(=O)=O>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:24][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH3:9]
Reactant: CCC(O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.7 %

Procedure:
Under ice cooling, to a solution of 1-phenyl-1-propanol (1.0 g, 7.34 mmol) and N-ethyldiisopropylamine (1.42 g, 11.01 mmol) in dichloromethane (10 ml) was added methanesulfonyl chloride (690 μl, 8.81 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent:ethyl acetate/hexane:5/1) to give 1-chloro-1-phenylpropane (610 mg, 54%) as pale yellow liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Li]CCCC.[C:18](=[O:20])=[O:19]>C1COCC1.CCCCCC>[CH3:12][O:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:18]([OH:20])=[O:19])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: COc1cc(Br)c2[nH]ccc2c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)c2[nH]ccc2c1

Procedure:
A solution of 7-Bromo-5-methoxy-1H-indole (described in WO 2002028861) in THF was treated with 2 eq. of a solution of n-BuLi in n-hexane (1.6M) at 5° and after 30 min at this temperature was cooled to −75°. Dry ice (excess) was added and after 15 mins the mixture was quenched with H2O and washed with EtOAc. After acidification of the aqueous layer and extraction into CH2Cl2, evaporation gave the desired product.
Reaction SMILES: [K].[N+:2]([C:5]1[CH:6]=C(O)C(OC)=[CH:9][CH:10]=1)([O-:4])=[O:3].[C:14]([O:17][C:18](=[O:20])[CH3:19])(=O)[CH3:15].CN([CH:24]=[O:25])C>>[C:18]([O:17][C:14]1[CH:9]=[CH:10][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][C:15]=1[O:25][CH3:24])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CN(C)C=O
Agent: [K]
Product: COc1cc([N+](=O)[O-])ccc1OC(C)=O
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A mixture of the potassium salt of 4-nitroguaiacol (10.15 g, 49 mmol), acetic anhydride (80 ml) DMAP (250 mg) and DMF (5 ml) was heated at 80° C. After stirring for 10 minutes, acetic arhydride was removed by evaporation and water was added to give a cream solid. The solid was collected by filtration, washed with water followed by ether and isohexanes to give 4-acetoxy-3-methoxynitrobenzene (9.84 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)\[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.Cl>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Agent: Cl
Solvent: ClCCCl
Product: CC(C)(C)C(O)C(=Cc1ccc(Cl)cc1)n1cncn1
Yield: 61.7 %

Procedure:
88 Milligrams (0.53 mmole) of the present compound obtained in Example 1 was dissolved in 2 ml of 1,2-dichloroethane, and 2 ml of a 1,2-dichloroethane solution containing 290 mg (1.0 mmole) of (E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=95.8/4.2) was added dropwise thereto. After reaction at room temperature for 24 hours, 2% hydrochloric acid was added to separate the reaction solution into an aqueous and organic layers. After concentrating the organic layer, the residue was purified by column chromatography on silica gel to obtain 180 mg of 1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3ol. The ratio of E-form alcohol to Z-form alcohol was 95.6 to 4.4, and the enantiomer ratio of the E-form alcohol was: (+)-isomer: (-)-isomer=19:81.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.C([NH2:16])(=O)C.C([O-])([O-])=O.[K+].[K+]>>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:16])[CH:11]=[CH:10]2
Reactant: CC(N)=O
Reactant: Clc1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ccc2cc(Cl)ccc2n1
Temperature: 200 °C
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
A mixture of 2,6-dichloroquinoline (500 mg, 2.5 mmol), acetamide (3 g, 50.8 mmol) and K2CO3 (1.75 g, 12.7 mmol) in a round bottom flask was stirred at 200° C. for 1.5 hours until TLC indicated that 2,6-dichloroquinoline was consumed. The resulting mixture was cooled to room temperature, and was partitioned between dichloromethane and H2O, the organic layer was dried over anhydrous Na2SO4, concentrated, and the residue was purified by a standard method to give 440 mg of the title compound. LCMS (m/z): 179.7 (M+1)+
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.O.CS(O)(=O)=O>[Rh].C(O)(C)C>[CH2:4]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([OH:11])[CH2:9][CH2:10]1)[CH2:3][CH:2]([CH3:12])[CH3:1].[CH2:4]([C@H:5]1[CH2:6][CH2:7][C@H:8]([OH:11])[CH2:9][CH2:10]1)[CH2:3][CH:2]([CH3:12])[CH3:1]
Reactant: CC(C)=CCc1ccc(O)cc1
Agent: [Rh]
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CC(C)CC[C@H]1CC[C@@H](O)CC1
Product: CC(C)CC[C@H]1CC[C@H](O)CC1
Reaction time: 5 h

Procedure:
85 g 4-(3-methyl-but-2-enyl)-phenol, 3 wt % rhodium-on-active charcoal (Rh content, based on the weight of the dry catalyst: 5%; water content about 50%) are initially introduced into 500 ml isopropanol and 9.6 g methanesulfonic acid in a stirred autoclave with a gassing stirrer. Hydrogenation is carried out for 5 hours at 80° C. under a hydrogen pressure of 10 bar. After filtration, 85 g 4-isoamylcyclohexanol are obtained as a crude product. After distillation, 80 g 4-isoamylcyclohexanol, which has the following composition: 67.6% cis-4-isoamylcyclohexanol and 31.8% trans-4-isoamylcyclohexanol, are obtained.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=O)C(O)=O.[CH2:19]([NH:21][NH2:22])[CH3:20]>C(O)(=O)C>[CH2:19]([N:21]1[C:9]([CH2:10][CH3:11])=[CH:8][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:22]1)[CH3:20]
Reactant: CCNN
Reactant: CCOC(=O)C(=O)CC(=O)CC
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)n(CC)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.3 %

Procedure:
A solution of ethyl 2,4-dioxohexanoate (˜0.345 mol), prepared as described in Part A of Example 10, in glacial acetic acid (350 mL) was cooled to 0° C. Ethylhydrazine oxalate (41.43 g, 0.276 mol) was added over a period of 20 minutes. The reaction was allowed to warm to ambient temperature, stirred for 20 hours, and concentrated under reduced pressure. The residue was adjusted to pH 10 with the addition of 2 M aqueous sodium carbonate, and chloroform was added. The mixture was filtered to remove a solid. The aqueous filtrate was extracted with chloroform (3×), and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 29.4 g of ethyl 1,5-diethyl-1H-pyrazole-3-carboxylate as an orange oil, which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH3:15])[NH:12]C(=O)N[C:9]1=[O:14].[OH-].[Na+].NC(C1C=CC=CC=1F)(C)[C:20](O)=[O:21].S(Cl)(Cl)=O>CO>[CH3:20][O:21][C:9](=[O:14])[C:8]([NH2:12])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:15]
Reactant: CC1(c2ccccc2F)NC(=O)NC1=O
Reactant: CC(N)(C(=O)O)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)C(C)(N)c1ccccc1F

Procedure:
The hydrolysis of the (RS)-5-(2-fluoro-phenyl)-5-methyl-imidazolidine-2,4-dione with 3 N sodium hydroxide solution and esterification of the resulting (RS)-2-amino-2-(2-fluoro-phenyl)-propionic acid with methanol and thionylchloride yielded the (RS)-2-amino-2-(2-fluoro-phenyl)-propionic acid methylester as a light yellow liquid. The purity of the product allowed using it in the next step without further purification. MS (ISP): m/z=198.2 [M+H]+.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.C[N:10]1[CH2:15][CH2:14][C@@H:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C@H:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:11]1.C(=O)([O-])[O-].[K+].[K+].C1C=CC=CC=1.Cl[C:45]([O:47][CH2:48][CH3:49])=[O:46]>CCOCC.O>[CH2:48]([O:47][C:45]([N:10]1[CH2:15][CH2:14][C@@H:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)[C@H:12]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:11]1)=[O:46])[CH3:49]
Reactant: CN1CC[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](c2ccccc2)C1
Reactant: CCOC(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)N1CC[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](c2ccccc2)C1

Procedure:
A mixture of 3.63 g of the free base of Example 3, 1.6 g of anhydrous potassium carbonate and 25 ml of anhydrous benzene is treated with 1.22 ml of ethyl chloroformate, and the mixture is allowed to reflux 18 hours under nitrogen. Then another 0.44 ml of ethyl chloroformate is added and the mixture is refluxed 18 hours, then poured into a mixture of 100 ml of water and 100 ml of ether. The aqueous phase is extracted with ether. The combined ether extracts are washed with water and saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated in vacuo to a gum. This material is chromatographed on silica gel, using chloroform as solvent. A fraction of pure material and two fractions of slightly less pure material are obtained. The product of trans-1-ethoxycarbonyl-4-(4-nitrophenoxy)-3-phenylpiperidine is obtained as a glass.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C:31]([CH3:35])([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:20][O:21][C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C:31]([CH3:35])([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)c(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Product: CN1c2cc(OCc3cc(F)c(Oc4ccc(C(F)(F)F)nc4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and 7-chlo-ro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[C:8]([C:19]([O:21]C)=[O:20])[C:7]=2[C:6]([CH3:23])=[N:5]1)([CH3:3])[CH3:2].BrC1C=C(C(OC)=O)C2C(C=O)=NNC=2C=1.O[Li].O>C1COCC1.O>[CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[C:8]([C:19]([OH:21])=[O:20])[C:7]=2[C:6]([CH3:23])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2cccnc2)cc2c1c(C)nn2C(C)C
Agent: COC(=O)c1cc(Br)cc2[nH]nc(C=O)c12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(C(C)C)c2cc(-c3cccnc3)cc(C(=O)O)c12
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 1-isopropyl-3-methyl-6-(pyridin-3-yl)-1H-indazole-4-carboxylate, 1 (0.5 g, 1.618 mmol) in a mixture of THF and H2O (30 mL) was added LiOH.H2O (0.2 g, 4.85 mmol) and the mixture was refluxed at 80° C. for 8 h. THF was distilled off and the aqueous layer was adjusted to pH˜5 with 10% HCl at 0° C. and the precipitated solid was collected by filtration and dried to afford 1-isopropyl-3-methyl-6-(pyridin-3-yl)-1H-indazole-4-carboxylic acid as an off-white solid (0.51 g). LCMS (ES+) m/z: 296.7.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[C:10]([Cl:16])[N:9]=1)=[O:7].[Br:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>CC(C)=O>[Br-:18].[NH2:14][C:13]1[C:8]([C:6]([NH:5][CH2:4][CH2:3][N+:2]([CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)([CH3:17])[CH3:1])=[O:7])=[N:9][C:10]([Cl:16])=[C:11]([NH2:15])[N:12]=1
Reactant: COc1ccc(CCCBr)cc1
Reactant: CN(C)CCNC(=O)c1nc(Cl)c(N)nc1N
Solvent: CC(C)=O
Product: COc1ccc(CCC[N+](C)(C)CCNC(=O)c2nc(Cl)c(N)nc2N)cc1
Product: [Br-]
Temperature: 25 °C

Procedure:
A mixture comprising 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (2-dimethylamino-ethyl)-amide (Intermediate H) (1.8 g, 7.0 mmol) and 1-(3-bromo-propyl)-4-methoxy-benzene (3.2 g, 14.0 mmol) in acetone (50 mL) is heated at reflux for 72 h. After cooling to RT, the solvent is removed in vacuo and the resulting solid is recrystallised from ethanol to afford the title compound. M+ 407. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (1H, t), 7.76 (2H, br), 7.19 (2H, br), 7.17 (2H, d), 6.90 (2H, d), 3.79 (3H, s), 3.67 (2H, q), 3.49 (2H, t), 3.15 (6H, s), 2.55 (2H, t), 2.02 (2H, quintet).