Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.Cl>C(OCC)C>[F:1][C:2]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH2:21][CH2:20]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1CCN(C(=O)OC(C)(C)C)c2ccccc21
Agent: Cl
Solvent: CCOCC
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1CCNc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
229 mg of rac-tert-butyl 4-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-carbonyl)amino]-3,4-dihydroquinoline-1(2H)-carboxylate (Example 105A, 0.41 mmol) were dissolved in 10 ml of diethyl ether, 2.05 ml of a 2 M solution of hydrochloric acid (4.09 mmol) were added and the mixture was stirred at RT overnight. Another 1.02 ml of a 2 M solution of hydrochloric acid in diethyl ether were then added, and the mixture was stirred at RT overnight. A little diethyl ether was added to the reaction mixture and the solid obtained was filtered off and washed with diethyl ether. The solid was dissolved in dichloromethane containing a little methanol and washed with saturated aqueous sodium bicarbonate solution. The organic phase was concentrated. The crude product was purified by preparative HPLC (RP18 column, mobile phase: methanol/water gradient with addition of 0.1% TFA). The product fractions were concentrated, taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate, filtered and concentrated. This gave 140 mg of the title compound (75% of theory).
Reaction SMILES: [C:1]1([C:7]2([CH2:16][CH2:17][CH2:18][N:19](C)[CH3:20])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30].O>C(Cl)Cl>[C:1]1([C:7]2([CH2:16][CH2:17][CH2:18][N:19]([C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30])[CH3:20])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN(C)CCCC1(c2ccccc2)COc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(CCCC1(c2ccccc2)COc2ccccc21)C(=O)OCC(Cl)(Cl)Cl
Yield: 30.4 %

Procedure:
A mixture of 3-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylpropylamine (7.40 g, 26 mmol), anhydrous K2CO3 (14.3 g, 104 mmol), and CH2Cl2 (125 ml) was stirred at 5°. A solution of 2,2,2-trichloroethyl chloroformate (4.3 ml, 32 mmol) in CH2Cl2 (5 ml) was added dropwise over 15 minutes. The reaction mixture was stirred at room temperature for 4 hours. Water was then added to dissolve the inorganic salts and the phases were separated. The organic phase was washed with saturated NaHCO3 and saturated NaCl, dried over Na2SO4, filtered, and evaporated in vacuo to give 7.6 g of a crude oil. This residue was chromatographed by HPLC using CH2Cl2 /hexane (2:1, by volume) as an eluent to yield 3.5 g (30%) of an oil.
Reaction SMILES: [CH3:1][C@H:2]([NH2:11])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+]>C(O)C>[CH3:1][C@@H:2]([NH2:11])[C@@H:3]([OH:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](N)[C@@H](O)c1ccccc1

Procedure:
As shown in the scheme above, (1R, 2S)-(−)-norephedrine is reacted with an optionally substituted benzaldehyde by refluxing in ethanol, and reducing the product of that reaction with sodium borohydride at ambient temperature to produce the desired norephedrine derivative compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][C:8]1([CH2:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C>[C:28]([O:27][C:26](=[O:32])[CH2:25][C:8]1([CH2:7][C:6](=[O:33])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[CH2:20][CH2:21][C:22]([O:24][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:23])[CH2:9]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(O)ccc2CCC(=O)O)=NO1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(O)ccc2CCC(=O)OCc2ccccc2)=NO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)propanoic acid (413 mg), (bromomethyl)benzene (0.117 mL), N,N-diisopropylethylamine (0.342 mL), and DMF (4 mL) was stirred overnight at room temperature. To the reaction mixture, 0.1 M hydrochloric acid was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (227 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[N:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][C:29]=1[CH3:43]>>[CH3:43][C:29]1[N:28]=[CH:33][C:32]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:31][CH:30]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Cc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-((4-methanesulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2-picoline-5-boronic acid pinacol ester in General Procedure A. Purification on silica and ether trituration gave 194. NMR (CDCl3): 2.63 (3H, s), 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H, m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 7.23 (1H, d, J=8.1), 7.35 (1H, s), 8.55 (1H, dd, J=8.1, 2.1), 9.50 (1 h, d, J=2.1). MS (ESI+): MH+ 489.24 (95%)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16]C)=[CH:5][CH:4]=1)[CH3:2].B(Br)(Br)Br.O>ClCCl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Cc2ccccc2OC)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCc1ccc(Cc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.83 g of (4-ethylphenyl)(2-methoxyphenyl)methane 55 is dissolved in dichloromethane. 11.0 ml of boron tribromide (1 M in CH2Cl2) are added dropwise to the mixture. The mixture is stirred at room temperature for 5 hours and, after addition of water, the dichloromethane phase is separated off. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water and NaCl solution, dried over sodium sulfate and concentrated. 0.77 g is obtained as crude product which can be purified by chromatography. C15H16O (212.29) MS (ESI): 235.20 (M+Na+)
Reaction SMILES: [CH:1]1[C:10]2[N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[C:7]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[O:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[F:26][C:27]([F:42])([F:41])[S+]1C2C=CC=CC=2C2C=CC=CC1=2.O>CN(C=O)C>[F:26][C:27]([F:42])([F:41])[C:11]1[N:9]2[C:10]3[CH:1]=[CH:2][CH:3]=[N:4][C:5]=3[O:6][C:7]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:8]2=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1cccc12
Reactant: FC(F)(F)[s+]1c2ccccc2c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1c(C(F)(F)F)ccc12
Yield: 51.6 %

Procedure:
A solution of tert-butyl spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (134 mg, 0.393 mmol) and 5-(trifluoromethyl)dibenzothiophen-5-ium (99.4 mg, 0.393 mmol) in DMF (2 mL) was stirred at 80° C. for 1.5 hours. The mixture was poured into water and was extracted with EtOAc (3×). The organics were combined, washed with water and brine, dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography (1-30% EtOAc/hexanes) to give tert-butyl 9′-(trifluoromethyl)spiro-[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (83 mg, 56%). ESI-MS m/z calc. 409.2. found 410.5 (M+1)+; Retention time: 1.92 minutes (3 min run).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:11][CH:10]=1)(=O)=O.[Na].[NH:41]1[CH:45]=[N:44][CH:43]=[N:42]1>CN(C)C=O>[CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:38]=[CH:39][C:30]=1[CH2:29][O:28][CH:16]1[CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:41]3[CH:45]=[N:44][CH:43]=[N:42]3)=[CH:10][CH:11]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOS(C)(=O)=O)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCn3cncn3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 100 °C
Yield: 85.1 %

Procedure:
A solution of 110 mg (0.2 mmol) of crude tert-butyl (3RS,4RS)-4-[4-(2-methylsulphonyloxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 5 ml of dimethylformamide was treated with 70 mg (1.0 mmol) of 1,2,4-triazole sodium salt and the reaction mixture was heated to 100° C. for 6 hours. Subsequently, the mixture was cooled to room temperature and the dimethylformamide was distilled off in an oil pump vacuum. The residue was taken up in 10 ml of methylene chloride, washed with 2 ml of water, the organic phase was dried over sodium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica gel using a 95:5:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There were obtained 90 mg (85% of theory) of tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-[4-(2-[1,2,4]triazol-1-yl-ethoxy)-phenyl]-piperidine-1-carboxylate as a colourless oil; MS: 529 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]1[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1)[N:20]=[CH:19]2.[ClH:40].C(Cl)[Cl:42]>CO.CCOCC>[ClH:42].[ClH:40].[CH2:8]([C:6]1[CH:5]=[CH:4][N:3]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:20]=[CH:19]3)[C:2](=[O:1])[CH:7]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2ncc3cc(-n4ccc(CCc5ccccc5)cc4=O)ccc32)CC1
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=c1cc(CCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of tert-butyl 4-(2-(5-(2-oxo-4-phenethylpyridin-1(2H)-yl)-1H-indazol-1-yl)ethyl)piperazine-1-carboxylate (247 mg, 0.468 mmol) in MeOH (2 mL) was treated with 2N HCl in ether (7 mL) under a nitrogen atmosphere. The solution was stirred at room temperature for 2 h and then treated with CH2Cl2 (20 mL) to precipitate product. The liquid was decanted off, and the solids were triturated with ether (3×100 mL) and concentrated to yield the title compound (161.7 mg, 69%) as yellow solid: mp 280-290° C.; 1H NMR (500 MHz, CD3OD) δ 8.23 (s, 1H), 7.83 (s, 2H), 7.62 (d, J=6.95 Hz, 1H), 7.46 (d, J=1.4 Hz, 1H), 7.30-7.17 (m, 5H), 6.51 (dd, J=7.0, 1.1 Hz, 1H), 6.48 (s, 1H), 4.95 (t, J=5.85, 2H), 3.57 (m, 2H), 3.61-3.56 (m, 8H), 3.01-2.98 (m, 2H), 2.94-2.91 (m, 2H); ESI MS m/z 428 [M+H]+. HPLC (Method D) 95.4% (AUC), tR=12.9 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][SH:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:14]([SH:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:14]([S:23][S:13][CH2:12][CH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCS
Reactant: SCCCc1ccc2c(c1)OCO2
Product: CCCCCCCCCSSCCCc1ccc2c(c1)OCO2
Yield: 56.1 %

Procedure:
6.2 g of the title compound was prepared from 10 g of 3-(1,3-benzodioxol-5-yl)propanethiol and 5 g of nonyl mercaptan as a colorless oil according to the same procedure as that described in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH3:11])=[O:9])=[N:6][CH:7]=1.[OH:26][CH2:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1)=[O:29]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([C@@H:12]2[CH2:17][CH2:16][N:15]([C:36]([CH:33]3[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][OH:26])[CH2:31][CH2:32]3)=[O:37])[CH2:14][C@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)C1CCN(C(=O)CO)CC1
Reactant: CN(C(=O)c1ccc(Br)cn1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)c1ccc(Br)cn1)[C@@H]1CCN(C(=O)C2CCN(C(=O)CO)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in step 1 and 1-(hydroxyacetyl)piperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 265, the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH:5]=[CH:6][CH:7]=1.[CH3:18][NH:19][NH2:20]>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:19]([CH3:18])[N:20]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNN
Reactant: O=C(C=Cc1cccc(O)c1)c1ccccc1
Solvent: CCO
Product: CN1N=C(c2ccccc2)CC1c1cccc(O)c1
Yield: 96.9 %

Procedure:
To a 100 ml round bottom flask equipped with a magnetic stirrer and reflux condensor was charged 1.0 g (0.0045 moles) of 3-hydroxychalcone, and 25 mls of absolute ethanol. To this solution was then added 0.21 g (0.0045 moles) of methyl hydrazine in one portion. The reaction was then heated to reflux for two hours, then cooled. The solvent was removed under reduced pressure to afford 1.1 g of 5-(3-hydroxyphenyl)-1-methyl-3-phenyl-2-pyrazoline as a thick brown oil. 97% yield.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:30])[CH2:18][CH2:17][C:16]([CH2:28][NH2:29])([C:19]2[CH:20]=[N:21][C:22]([CH:25]3[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:29][CH2:28][C:16]1([C:19]2[CH:20]=[N:21][C:22]([CH:25]3[CH2:26][CH2:27]3)=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:30])[CH2:14][CH2:15]1)=[O:6]
Reactant: NCC1(c2ccc(C3CC3)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC1(c2ccc(C3CC3)nc2)CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and C-[4,4-difluoro-1-(6-cyclopropyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=439.0, tR (minutes, Method E)=0.55
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.CCN(CC)CC.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:25][CH2:26][C:27]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:12]=1)=[O:28]
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 75.6 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (4.43 g, 20 mmol) and Et3N (3 mL, 22 mmol) in THF (100 mL), chloroacetyl chloride (1.6 mL, 20 mmol) was added dropwise with stirring. The solvent was evaporated in vacuo. The residue was slurred with water, filtered, and dried. The solid was dissolved in hot toluene (300 mL), treated with silica gel, filtered and left to recrystallize to afford 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (4.5 g, 76% yield). LCMS calculated for C16H12ClN3O (M+H): 298.75. found 298.06. 1H-NMR (400 MHz, DMSO-d6) δH: 10.6 (1H, br. s), 9.52 (1H, s), 8.54 (1H, m), 8.20-8.05 (3H, m), 7.90-7.70 (3H, m), 7.62-7.51 (1H, m), 4.31 (2H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[I:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:28]1[CH:29]=[CH:30][C:25]([I:24])=[CH:26][CH:27]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Ic1ccc(I)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 1,4-di-iodobenzene in analogy to Example 1a): MS (ISP): 506.1 (M+H)+ and MS (ISN): 503.9 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:8](=[CH:21][CH2:22][CH3:23])[CH2:9][C:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([CH:8]([CH2:21][CH2:22][CH3:23])[CH2:9][C:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC=C(CC(O)(C(=O)OCC)C(F)(F)F)c1cccc(F)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCC(CC(O)(C(=O)OCC)C(F)(F)F)c1cccc(F)c1OC
Yield: 100 %

Procedure:
698 mg (2.56 mmol) of 1,1′-bi-2-naphthol are admixed with 2.56 ml (1.28 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred at room temperature for 2 hours. 4.26 g (21.9 mmol) of 2-fluoro-6-(1-methylenbutyl)anisole and 5.7 ml (44 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 18 hours. After cooling it is immediately purified by column chromatography on silica gel (hexane/ethyl acetate 0-15%) to give 5.82 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hept-4-enoate. 2.6 g (7.1 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hept-4-enoate are dissolved in 65 ml of methanol and the solution is admixed with 260 mg of palladium on carbon (10%). The suspension is shaken under a hydrogen atmosphere at atmospheric pressure for 4 hours until the hydrogen uptake is 155 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 2.6 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanoate. 2.6 g (7.1 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-heptanoate in 150 ml of diethyl ether are cooled to −10° C. and over 15 minutes 520 g (14.2 mmol) of solid lithium aluminum hydride are added in portions. The mixture is stirred at −15° C. for 1.5 hours, followed by dropwise addition in succession of ethyl acetate and water and by a further hour of stirring until a readily filterable precipitate is formed. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/diisopropyl ether 0-15%) yields 2.1 g of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanal as a mixture of the diastereomers.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NCCCOc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCOc1ccncc1)c1cccnc1
Yield: 88.7 %

Procedure:
To a solution of 700 mg (4.60 mmol) of 4-(3-aminopropyloxy)pyridine and 1.54 ml (11.0 mmol) of triethylamine in 30 ml of methylene chloride, 830 mg (4.66 mmol) of nicotinoyl chloride hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10 to 1:5) to obtain 1.05 g of the desired compound (yield: 85.8% , colorless crystals) .
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].[CH3:18]I>CN(C=O)C.O>[CH3:18][O:1][C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CI
Reactant: N#Cc1ccc(C2(O)CCOCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(c2ccc(C#N)cc2)CCOCC1

Procedure:
To a solution of 4-(4-hydroxytetrahydro-2H-pyran-4-yl)benzonitrile (Step 1 of Intermediate I, 300 mg, 1.48 mmol) in DMF (6.5 mL) was added sodium hydride (60% suspension in mineral oil, 65 mg, 1.62 mmol) at a temperature of ˜5° C. The reaction mixture was allowed to stirr for 1 h at this temperature, before methyl iodide (110 μL, 1.77 mmol) was added. Stirring was continued over night at rt. The mixture was diluted with water and extracted with diethyl ether. The organic extract was dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 20:1→4:1) to afford the title compound in pure form (238 mg, 74%): 1H NMR (500 MHz, CDCl3) δ 7.68 (d, 2H), 7.51 (d, 2H), 3.89-3.82 (m, 4H), 2.99 (s, 3H), 2.03-1.98 (m, 2H), 1.94-1.91 (m, 2H); DCI(NH3)-MS m/z 235 (M+NH4)+; HPLC RT (Method I) 3.99 min.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+](N[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[S:25][C:26]([CH2:29][N:30]([CH3:32])[CH3:31])=[CH:27][CH:28]=2)=[CH:18][N:17]=1)([O-])=O>C(O)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[S:25][C:26]([CH2:29][N:30]([CH3:31])[CH3:32])=[CH:27][CH:28]=2)=[CH:18][N:17]=1
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)s1
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccc(CN(C)C)s2)c(=O)[nH]1

Procedure:
A mixture of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.37 g) and 2-nitroamino-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone (2.32 g) in ethanol was heated under reflux for 48 hrs. The ethanol was evaporated at reduced pressure yielding 2-[2-(5-methyl-4-imidazolyl-methylthio)ethylamino]-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone as a glassy residue which was washed with hot water by decantation. The residue was dissolved in isopropanol and a solution of ethanolic hydrochloric acid (3 ml) was added. Excess of solvent was removed at reduced pressure and trihydrochloride crystallized as a light buff solid (3.11 g). The solid was recrystallized from methanol-ethanol (2.36 g) 185.5°-188.5° C.