Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][N:20]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:16]=[C:15]([CH2:33][N:34]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:14]=2)C(=O)C2=CC=CC=C12.[OH-].[Na+].Cl.S(Cl)(Cl)=O>O1CCOCC1.C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH2:33][N:34]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[N:16]=[C:17]([CH2:19][N:20]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=1
Reactant: CCOC(=O)CN(CC(=O)OCC)Cc1cc(CCCCCCCN2C(=O)c3ccccc3C2=O)cc(CN(CC(=O)OCC)CC(=O)OCC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)CN(CC(=O)OCC)Cc1cc(CCCCCCCN)cc(CN(CC(=O)OCC)CC(=O)OCC)n1

Procedure:
Compound (23) (400 mg, 0.55 mmol) was dissolved in dioxane (5 ml) and sodium hydroxide (2 M, 5 ml) was added. A mixture was stirred neutralized with conc. hydrochloric acid and evaporated almost to dryness. The residue was treated with hydrazine hydrate (2.0 ml) dissolved in ethanol (10 ml) and refluxed for 6 h. Volatile matter was evaporated and coevaporated with dry acetonitrile. The residue obtained was suspended in dry ethanol (50 ml) previously treated with thionyl chloride (4 ml). The mixture was refluxed for 2 h, filtered, evaporated and partitioned between saturated sodium hydrogen carbonate and chloroform. Combined chloroform extracts were dried over sodium sulphate, concentrated and finally purified using short column chromatography.
Reaction SMILES: [H-].[Na+].CCCCCC.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl>C(OCC)(=O)C.O>[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:18][C:15]1[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: COCCOCOc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.2 %

Procedure:
To 200 mg (0.5 mmol) of sodium hydride (60% dispersion in oil) was added 10 mL of hexane. After settling, the hexane was decanted. To the residue was added 10 mL of freshly distilled tetrahydrofuran and the slurry mixture was cooled at 0° C. To this was added slowly 200 mg (1.43 mmole) of 4-nitrophenol (20) as a solid portionwise. The reaction mixture was stirred at 0° C. for 5 minutes and 197 μL (1.71 mmol) of 2-methoxyethoxy methyl chloride was added. The mixture was stirred at room temperature for 18 hours. To the reaction mixture 25 mL of water was slowly added and the reaction mixture was diluted with 50 mL of ethyl acetate. The organic part was separated and the aqueous layer was extracted with 2×50 mL of ethyl acetate. The organic layers were combined and washed with 7×100 mL of saturated sodium carbonate solution, followed by 100 mL of water. The ethyl acetate layer was dried over MgSO4 and concentrated to yield 225 mg (0.99 mmol, 69%) of 1-[(2-methoxyethoxy)methoxy]-4-nitrobenzene (21) as a pale yellow oil. NMR, IR and MS data confirmed compound identity.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23](C(OC(C)(C)C)=O)[CH:22]=[CH:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].O1CCOCC1.Cl.Cl.O1CCOCC1>CCOC(C)=O>[NH:23]1[C:24]2[C:20](=[CH:19][C:18]([C:15]3[N:14]=[C:13]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:17][N:16]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(ccn4C(=O)OC(C)(C)C)c3)no2)cc1C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a flask containing tert-butyl 5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole-1-carboxylate INT-67 (75 mg, 0.17 mmol) was added dioxane (2 mL) followed by 4N HCl in dioxane (0.5 mL, 2 mmol). The reaction mixture was stirred overnight at room temperature then heated at 50° C. overnight. Additional 4N HCl/dioxane (0.5 mL, 2 mmol) was added and the mixture was heated at 50° C. for an additional 2 h to complete the deprotection. The reaction mixture was diluted with EtOAc and washed with NaHCO3. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The material was purified by chromatography (EtOAc/hexanes) to provide 17 mg (30%) of 5-(3-(1H-indol-5-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 68 as a white solid. LCMS-ESI (m/z) calculated for C20H16N4O2: 344.5; found 345.1 [M+H]+, tR=2.34 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.51-8.47 (m, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.38 (d, J=7.2 Hz, 1H), 8.35 (dd, J=8.9, 2.2 Hz, 1H), 7.99 (dd, J=8.5, 1.6 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.33-7.28 (m, 1H), 7.11 (d, J=9.0 Hz, 1H), 6.72-6.64 (m, 1H), 4.79 (dt, J=12.2, 6.1 Hz, 1H), 1.47 (t, J=5.8 Hz, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[NH2:16][C:17]1[S:18][CH:19]=[C:20]([CH3:25])[C:21]=1[C:22]([NH2:24])=[O:23]>>[CH3:25][C:20]1[C:21]([C:22]([NH2:24])=[O:23])=[C:17]([NH:16][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:18][CH:19]=1
Reactant: Cc1csc(N)c1C(N)=O
Reactant: O=C(O)CN1C(=O)CCc2ccccc21
Product: Cc1csc(NC(=O)CN2C(=O)CCc3ccccc32)c1C(N)=O

Procedure:
4-Methyl-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxamide was prepared from 2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (0.49 g, 2.38 mmol) and 2-amino-4-methylthiophene-3-carboxamide (0.37 g, 2.38 mmol) according to protocol B Retention time (min)=3.405, method [1], MS (ESI) 344.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(O)cc(C)c1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(OC(=O)C(C)(C)C)cc(C)c1O
Yield: 61 %

Procedure:
By using 6.90 g of 2,6-dimethylbenzene-1,4-diol, 6.63 g of pivaloyl chloride, 11.85 g of pyridine and 60 ml of dichloromethane, reaction and purification were carried out in a similar manner to that described in Reference Example 9, whereby 6.77 g of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[O:9][CH3:10].[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOCC.CCOC(C)=O>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=2[O:9][CH3:10])[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COc1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1c(Cl)cccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 7.5 %

Procedure:
An intermediate compound 1-(3-Chloro-2-methoxy-phenyl)-piperazine, was produced as follows. A solution of 2,6-dichloroanisole (1.55 mL, 11.30 mmol) in dry toluene (40 mL) was degassed for 10 min by blowing nitrogen into the solution. This solution was then added via cannula to a flask containing Boc-piperazine 3.16 g, 16.90 mmol), Cs2CO3 (5.15 g, 15.80 mmol), Pd2(dba)3 (414 mg, 0.452 mmol, 4 mol %) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (356 mg, 0.904 mmol, 8 mol %) under nitrogen. The reaction mixture was heated at 100° C. overnight (16 h). MS showed a small product peak and a large Boc-piperazine peak. TLC (10% EtOAc/Hex) showed a product spot. The reaction was allowed to cool to room temperature and Et2O was added. The mixture was filtered through Celite washing with Et2O. The filtrate was washed 3 times with 0.5 M citric acid (to remove excess Boc-piperazine) and once with brine, dried over MgSO4 and concentrated to give a brown oil. Purification by SiO2 chromatography (10% EtOAC/Hexanes) gave 4-(3-chloro-2-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a pale yellow solid (278 mg, 8%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[S:15][CH2:14][CH2:13][CH2:12]2.C(N(CC)C(C)C)(C)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>C(#N)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[S:15][CH2:14][CH2:13][CH2:12]3)[CH2:36][CH2:35]1
Reactant: BrCCCCOc1cccc2c1SCCC2
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCCOc2cccc3c2SCCC3)CC1

Procedure:
1.5 g (4.98 mmol) of the compound obtained in Step A are dissolved in 15 cm3 of acetonitrile, under argon. 0.94 g (7.47 mmol) of N,N-diisopropylethylamine diluted in 11 cm3 of acetonitrile is added, followed by 1.44 g (0.747 mmol) of 1-(2-methoxyphenyl)piperazine dissolved in 11 cm3 of acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:16](O)(=O)[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18]>C1(C)C(C)=CC=CC=1>[OH:18][CH:17]([C:16]1[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][C:2]=2[N:1]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Reactant: O=C(O)C(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(C)c1ccc2oc(C(O)c3ccccc3)nc2c1
Reaction time: 24 h

Procedure:
A mixture of ethyl 2-(3-amino-4-hydroxyphenyl)propionate (1.2 g.), mandelic acid (1 g.) and xylene (50 ml.) was heated using a Dean and Stark apparatus. After 24 hours, the solution was evaporated to dryness and the residue was taken up in chloroform. This solution was washed first with sodium hydroxide solution, then with hydrochloric acid and finally dried over sodium carbonate. The solution was evaporated to dryness to give ethyl 2-[2-(α-hydroxybenzyl)-5-benzoxazolyl]propionate, the structure of which was confirmed by n.m.r. spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.Cl>O1CCOCC1>[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[NH:23][C:7](=[O:9])[C:6]3[CH:5]=[C:4]([CH3:12])[S:3][C:2]=3[N:1]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: CCOC(=O)c1cc(C)sc1N
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2nc3sc(C)cc3c(=O)[nH]2)cc1
Yield: 119.2 %

Procedure:
2-Amino-5-methyl-3-ethoxycarbonyl-thiophene (5 g) and 4-cyanobenzoic acid methylester (2.7 g) are dissolved in dioxane (40 ml). Gaseous HCl is conducted through the solution for 5 hours. The usual workup yields 4-(3,4-dihydro-4-oxo-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester (6 g)
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH3:6][CH:7]([O:9][C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)[CH3:8]>CO>[CH3:6][CH:7]([O:9][C:10]1[N:11]=[N:12][C:13]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:14][CH:15]=1)[CH3:8]
Reactant: C=CCS
Reactant: CC(C)Oc1ccc(Cl)nn1
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OC(C)C)nn1

Procedure:
2.30 g(0.1 mol) of metallic sodium was dissolved in 150 ml of absolute methanol and then mixed with 9.28 ml(0.1 mol) of allylmercaptan. To this mixture was added 17.26 g(0.1 mol) of 3-(2-propoxy)-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale yellow oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:21]2[C:16]([C:17]([NH2:22])=[N:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:23]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[Br:23][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[N:21]2[C:16]=1[C:17]([NH2:22])=[N:18][CH:19]=[N:20]2
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1ccc2c(N)ncnn12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCc1cc(Br)c2c(N)ncnn12
Temperature: -20 °C
Reaction time: 2 h
Yield: 180.2 %

Procedure:
To a cooled (−20° C.) solution of 7-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (5.60 g, 17.5 mmol) in tetrahydrofuran (85 mL) was added 1,3-dibromo -5,5-dimethylhydantoin (2.50 g, 8.74 mmol) in four portions over 15 min. The mixture was allowed to stir (−20° C.) for 2 h. The reaction was quenched with the addition saturated aqueous Na2SO3 solution and was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×75 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated to dryness. The crude material was purified by MPLC chromatography using a gradient of 50% to 75% ethyl acetate in hexanes to afford 6.29 g (90%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.80 (s, 1 H), 6.58 (s, 1 H), 3.56 (t, 2 H), 2.81 (t, 2 H), 1.72-1.61 (m, 2 H), 1.51-1.42 (m, 2 H), 0.83 (s, 9 H), 0.00 (s, 6 H); ES-MS m/z 399.2 [M+H]+, HPLC RT (min) 3.72.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](I)[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC(C4C=CC=CC=4)=C(C)C=3)=CN=2)CC1)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[C:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]([CH3:26])=[CH:24][CH:25]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Reactant: OB(O)c1ccccc1
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4ccccc4)c(C)c3)cn2)CC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(-c4ccccc4)c3)cn2)CC1

Procedure:
5′-(6-methyl-biphenyl-3-yl-carbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester and phenylboronic acid following a method similar to the one described in the synthesis of 5′-(2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester above. The product was isolated after silica gel column purification with 20-50% EtOAc in hexanes gradient. HRMS m/z calcd for C27H29N3O3 [M+H]+: 444.2282. Found: 444.2282
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])C1C=CC=CC=1.CN(C)C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(Cl)Cl>[F:21][C:16]([F:22])([C:17]([F:18])([F:19])[F:20])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: FC(F)(F)C(F)(F)CCCCCCCOCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: OCCCCCCCC(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 74.4 %

Procedure:
16 g of 1-benzyloxy-8,8,9,9,9-pentafluorononane are dissolved in 700 ml of abs. methylene chloride, treated at 0° C. with 18.4 ml of N,N-dimethylaniline and stirred for 5 minutes. 26.4 g of aluminium trichloride are then added in portions and the reaction mixture is warmed to 50° C. for 45 minutes. For work-up, the mixture is allowed to come to room temperature, stirred into 2N hydrochloric acid, extracted 3 times with methylene chloride, dried over magnesium sulphate and concentrated in vacuo. The crude product is chromato-graphed on silica gel using a hexane-ethyl acetate gradient. 8.6 g of 8,8,9,9,9-pentafluorononan-1-ol are obtained as an oil.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH3:28])=[O:10])([CH3:5])[CH3:4])#[N:2].[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:16]2[CH:15]=[CH:14][C:13]([CH3:28])=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:29]=[CH:30][CH:31]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(Oc2ccc(N)cc2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 80 °C
Yield: 93.7 %

Procedure:
A suspension of 3-(1-cyano-1-methylethyl)-N-[2-methyl-5-(4-nitrophenoxy)phenyl]benzamide (3.50 g, 8.0 mmol), calcium chloride (2.36 g, 21.2 mmol) and reduced iron (4.75 g, 85 mmol) in ethanol (180 mL)/water (20 mL) was stirred with heating at 80° C. for 10 hr. The reaction mixture was cooled to room temperature, passed through a pad filled with celite to separate insoluble material, and the insoluble material was washed with ethanol. The filtrate and the washing were combined and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL), washed with 5% aqueous ammonium chloride solution (200 mL), water (200 mL), 5% aqueous sodium hydrogencarbonate solution (200 mL) and saturated brine (200 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (2.89 g, 94%) as a colorless amorphous substance.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[NH:24][N:25]=[C:26]([CH:28]2[CH2:30][CH2:29]2)[CH:27]=1)=[O:4].[OH-].[Li+]>>[CH:28]1([C:26]2[CH:27]=[C:23]([N:6]3[CH2:7][C@H:8]([S:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:20])[F:21])(=[O:12])=[O:11])[CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])[NH:24][N:25]=2)[CH2:29][CH2:30]1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CC2)n[nH]1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CC2)n[nH]1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-(5-cyclopropyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as brown solid which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1([OH:18])[CH2:17][NH:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:16]2[CH2:17][C:14]([OH:18])([CH3:13])[CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(O)CNC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC1(O)CN(C2CN(C(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.21 g, 1.23 mmol), 3-methylazetidin-3-ol (0.13 g, 1.48 mmol) and 4 Å molecular sieves (1.2 g) in DCE (5 mL). The reaction mixture was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.52 g, 2.47 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the solution was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, 0:100 to 100:0) to give 3-Hydroxy-3-methyl-[1,3′]biazetidinyl-1′-carboxylic acid tert-butyl ester as a colourless oil (0.09 g, 30%). 1H NMR (300 MHz, CDCl3): δ 3.93 (dd, J=9.2, 7.2 Hz, 2 H), 3.82-3.70 (m, 2 H), 3.50-3.40 (m, 1 H), 3.32 (d, J=8.1 Hz, 2 H), 3.21 (d, J=8.1 Hz, 2 H), 1.51 (s, 3 H), 1.43 (s, 9 H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]Cl)[N:9]=1)(=[O:3])[CH3:2].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:21][C:18]2[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCl)cs1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CSc2ccc([N+](=O)[O-])cc2)cs1
Temperature: 100 °C
Yield: 95.7 %

Procedure:
A mixture of 2-acetylamino-4-chloromethylthiazole (1.9 g), 4-nitrothiophenol (1.6 g) and potassium carbonate (2.0 g) in a N,N-dimethylformamide (50 ml) was heated at 100° C. for 3 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-4-(4-nitrophenylthiomethyl)thiazole (2.95 g, yield: 95.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=C[O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=1)=[O:4].[ClH:22]>CO>[ClH:22].[NH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[C:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=1)=[O:8]
Reactant: COC(=O)COc1ccc(-c2ocnc2C(=O)OC)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)COc1ccc(C(=O)C(N)C(=O)OC)cc1

Procedure:
A mixture of 4-methoxycarbonyl-5-[4-(methoxycarbonylmethoxy)phenyl]oxazole (2.34g.) and a saturated solution of hydrogen chloride in methanol (20ml.) was heated under reflux for 2 hours. The reaction mixture was then evaporated in vacuo and the yellow residue obtained was triturated with ether (100ml.) (dried over sodium wire) to give methyl 4-(α-amino-α-methoxycarbonylacetyl)phenoxyacetate hydrochloride as an off-white amorphous solid (1.9g.), m.p. 120°-125° C., having a satisfactory analysis; found: C, 48.9%; H, 5.1%; N, 4.2%; required: C, 49.2%; H, 5.05%; N, 4.42%.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-])=O>O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1nccn1Cc1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)c1nccn1Cc1ccccc1N
Yield: 85.4 %

Procedure:
49.6 g (0.18 mol) of ethyl 1-(2-nitrobenzyl)-imidazole-2-carboxylate were hydrogenated in 500 ml of tetrahydrofuran at room temperature under a pressure of 5 bar in the presence of Raney nickel. After the theoretical quantity of hydrogen had been absorbed, the catalyst was suction-filtered off, and the filtrate was evaporated. 37.7 g (85.4% of theory) of ethyl 1-(2-aminobenzyl)-imidazol-2-carboxylate, m.p. 104°-106° C. (m.p. from toluene 105°-107° C.) were obtained.