Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([NH:17][C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].NC(C(C)C)C(=O)[CH2:28][CH2:29][N:30]([C:36]1[CH:41]=[CH:40][N:39]=[C:38]([C:42]2[O:46][N:45]=[C:44]([C:47]3[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:54])[CH:43]=2)[CH:37]=1)[C:31](=[O:35])[CH:32]([Cl:34])[Cl:33]>C(Cl)Cl>[Cl:34][CH:32]([Cl:33])[C:31]([N:30]([CH2:29][CH2:28][C:22](=[O:24])[CH:18]([NH:17][C:10](=[O:11])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH:19]([CH3:20])[CH3:21])[C:36]1[CH:41]=[CH:40][N:39]=[C:38]([C:42]2[O:46][N:45]=[C:44]([C:47]3[C:48]([Cl:54])=[CH:49][CH:50]=[CH:51][C:52]=3[Cl:53])[CH:43]=2)[CH:37]=1)=[O:35]
Reactant: CC(C)C(N)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Pybop (164 mg, 0.32 mmol), diisopropylethylamine (50 mg, 0.39 mmol) and N-boc-L-valine (69 mg, 0.32 mmol) were added to a solution of N-(4-amino-5-methyl-3-oxohexyl)-2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamide (Cpd. No. 3, lot 2, 75 mg, 0.11 mmol) in methylene chloride (5 mL) at 0° C. The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was then diluted with methylene chloride (15 mL) and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-scale reverse phase high performance liquid chromatography to provide tert-butyl 6-(2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamido)-2-methyl-4-oxohexan-3-ylcarbamate (Cpd. No. 49,100 mg) as a white solid. 1H NMR (CDCl3): 8.86 (d, 1H), 7.98 (s, 1H), 7.45-7.33 (m, 5H), 5.98 (s, 1H), 5.66 (br s, 1H), 4.98 (br s, 1H), 4.55-4.51 (m, 2H), 4.11-4.02 (m, 3H), 3.00-2.93 (m, 2H), 2.20 (m, 1H), 1.48 (s, 9H), 1.09 (d, 3H), 0.90 ppm (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O)([O-:11])=[O:10]>C(OC(=O)CC)(=O)CC>[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[CH:1][C:2]1[N:3]=[N:4][C:5]([CH:8]=[CH:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=1)([O-:11])=[O:10]
Reactant: Cc1ccc(C)nn1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: CCC(=O)OC(=O)CC
Product: O=[N+]([O-])c1ccccc1C=Cc1ccc(C=Cc2ccccc2[N+](=O)[O-])nn1
Yield: 39.8 %

Procedure:
First, 24 g of 3,6-dimethylpyridazine and 67 g of o-nitrobenzaldehyde were dissolved in 600 ml of propionic anhydride, then heated under reflux so as to obtain 33 g of 3,6-di(o-nitrostyryl)pyridazine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[O:14][C:13]([CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C(C)C.[C:27]1([CH:33]([O:40][C:41]([C:43]2[N:48]3[C:49](=[O:52])[C@@H:50]([NH2:51])[C@H:47]3[S:46][CH2:45][C:44]=2[CH2:53][O:54][C:55](=[O:57])[CH3:56])=[O:42])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.P([O-])([O-])(O)=O.[K+].[K+]>C(Cl)Cl.CN1CCOCC1.O>[C:27]1([CH:33]([O:40][C:41]([C:43]2[N:48]3[C:49](=[O:52])[C@@H:50]([NH:51][C:16](=[O:18])[CH2:15][C:13]4[O:14][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:11][CH:12]=4)[C@H:47]3[S:46][CH2:45][C:44]=2[CH2:53][O:54][C:55](=[O:57])[CH3:56])=[O:42])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)o1
Agent: CC(C)COC(=O)Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccc(CNC(=O)OC(C)(C)C)o3)[C@H]2SC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
1.87 g of 2-(5-tert.-butoxycarbonylaminomethyl-2-furyl)-acetic acid are dissolved in 200 ml of methylene chloride (distilled over phosphorus pentoxide) and 0.80 ml of 4-methylmorpholine, the solution, from which moisture is kept excluded, is cooled to -20° C. and 1.0 ml of chloroformic acid isobutyl ester is added dropwise whilst keeping the temperature at between -15° C. and -20° C. After 30 minutes, a solution of 2.31 g of 3-acetoxymethyl-7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester is added, after which the mixture is stirred for a further 2 hours at -10° C. and for 8 hours at room temperature. It is then poured out into icecold water, the pH is adjusted to 8.0 with dipotassium hydrogen phosphate and the mixture is repeatedly extracted with methylene chloride. The organic extracts are washed with a saturated aqueous sodium chloride solution and dried over magnesium sulphate, after which the solvent is removed under reduced pressure. 3-Acetoxymethyl-7β-[2-(5-tert.-butoxycarbonylaminomethyl-2-furyl)-acetylamino]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained as a colourless foam which is directly converted further; thin layer chromatogram (silica gel): Rf=0.84 (system: hexane/ethyl acetate/methanol, 20:40:40).
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=2)[C:19]#[N:20])=[N:12][C:11]2[C:10](=[O:23])[N:9]([CH2:24][CH3:25])[C:8]3=[N:26][C@H:27]([CH:29]([CH3:31])[CH3:30])[CH2:28][N:7]3[C:6]1=2.CO.[NH4+]=[S:40].O>CCOC(C)=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=2)[C:19](=[S:40])[NH2:20])=[N:12][C:11]2[C:10](=[O:23])[N:9]([CH2:24][CH3:25])[C:8]3=[N:26][C@H:27]([CH:29]([CH3:31])[CH3:30])[CH2:28][N:7]3[C:6]1=2
Reactant: CCN1C(=O)c2nc(-c3ccc(F)c(C#N)c3)n(Cc3ccc(F)cc3F)c2N2C[C@@H](C(C)C)N=C12
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1C(=O)c2nc(-c3ccc(F)c(C(N)=S)c3)n(Cc3ccc(F)cc3F)c2N2C[C@@H](C(C)C)N=C12
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
A 10 mL microwave vial was charged with (R)-5-(1-(2,4-difluorobenzyl)-5-ethyl-7-isopropyl-4-oxo-4,5,7,8-tetrahydro-1H-imidazo[2,1-b]purin-2-yl)-2-fluorobenzonitrile (50) (275 mg, 0.558 mmol), MeOH (5 mL), and ammonium sulfide solution in water (20 wt %, 600 μL, 1.67 mmol). The reaction mixture was stirred in a microwave at 85° C. for 15 minutes, cooled to room temperature and concentrated in vacuo. The residue obtained was diluted with EtOAc (200 mL) and brine (250 mL) and the layers separated. The aqueous phase was extracted with EtOAc (200 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified using CombiFlash chromatography (silica gel, 96:4, CH2Cl2/MeOH) to provide (R)-5-(1-(2,4-difluorobenzyl)-5-ethyl-7-isopropyl-4-oxo-4,5,7,8-tetrahydro-1H-imidazo[2,1-b]purin-2-yl)-2-fluorobenzothioamide (118 mg, 40%) as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:25]([C:27]4[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=4)[C:33]#[N:34])[CH2:24][C:23](=[O:35])[NH:22][C:9]=3[CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c3cccc(C#N)c3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)c1

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-3′-methoxy-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K21) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow powder (118 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:29]=[C:30]([S:34][C:35]2[CH:36]=[CH:37][C:38]3[N:39]([CH:41]=[C:42]([NH:44][C:45]([CH:47]4[CH2:49][CH2:48]4)=[O:46])[N:43]=3)[N:40]=2)[CH:31]=[CH:32][CH:33]=1>CN(C)C(=O)C.O1CCCC1>[CH:47]1([C:45]([NH:44][C:42]2[N:43]=[C:38]3[CH:37]=[CH:36][C:35]([S:34][C:30]4[CH:29]=[C:28]([NH:27][C:7]([C:5]5[N:4]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=6)[N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])[CH:33]=[CH:32][CH:31]=4)=[N:40][N:39]3[CH:41]=2)=[O:46])[CH2:48][CH2:49]1
Reactant: Cc1cc(C(=O)O)n(-c2ccccc2)n1
Reactant: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cccc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(-c2ccccc2)n1
Yield: 65.3 %

Procedure:
Using 3-methyl-1-phenyl-1H-pyrazole-5-carboxylic acid (186 mg, 0.92 mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (80 μL, 0.92 mmol), N-{6-[(3-aminophenyl)thio]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (200 mg, 0.61 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 255, the title compound (203 mg, 65%) was obtained as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=1)C.C(OC(=O)C1C=CC(NC2N=C(C3C=NC=CC=3)C=CN=2)=CC=1)C>>[N:19]1([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=3[CH3:11])[C:4]([OH:24])=[O:3])[N:18]=2)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: CCOC(=O)c1ccc(C)c(Nc2nccc(-n3ccnc3)n2)c1
Agent: CCOC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Product: Cc1ccc(C(=O)O)cc1Nc1nccc(-n2ccnc2)n1

Procedure:
3-(4-imidazol-1-yl-pyrimidin-2-ylamino)-4-methylbenzoic acid ethyl ester prepared in Preparation 17 was used instead of 4-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester according to the similar procedure to Preparation 19 to give the titled compound as yellow solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:40])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:17][CH:18]=2)[C:13]1=[O:41])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:40])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:17][CH:18]=2)[C:13]1=[O:41]
Reactant: COC(=O)CCCCC(=O)Nc1ccc2c3c(n(CCCNC(=O)OC(C)(C)C)c(=O)c2c1)-c1ccccc1C3=O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCCCC(=O)Nc1ccc2c3c(n(CCCN)c(=O)c2c1)-c1ccccc1C3=O

Procedure:
Compound 21 (0.030 g, 0.053 mmol) was treated with trifluoroacetic acid (0.25 mL) in chloroform (3 mL) for 2 h at room temperature. The solvent was removed on a rotary evaporator and the residue was then basified with 2 N NH3 in methanol to get the free amine, which was purified by silica gel column chromatography, eluting with chloroform-methanol, 9.2:0.8, to yield the product 26 (0.015 g, 55%) as a red solid: mp 153-155° C. IR (KBr) 2947, 1739, 1705, 1693, 1661, 1570, 1530, 1431, 1197, 760, 665 cm−1; 1H NMR (CD3OD, 300 MHz) δ 8.51 (d, J=2.4 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 7.70 (dd, J=2.4, J=9.0 Hz, 1H), 7.60 (t, J=9.0 Hz, 1H), 7.51 (m, 2H), 7.31 (m, 1H), 4.55 (t, J=4.5 Hz, 2H), 3.67 (s, 3H), 3.13 (m, 2H), 2.39 (m, 4H), 2.26 (m, 2H), 1.70 (m, 2H); 13C NMR (DMSO-d6, 125 MHz) δ 190.0, 173.3, 171.3, 162.3, 154.4, 138.3, 136.6, 134.2, 133.9, 130.9, 127.0, 125.6, 123.5, 123.4, 123.3, 122.5, 116.5, 107.2, 51.2, 42.1, 38.2, 36.0, 33.0, 30.9, 24.4, 24.0; ESIMS (m/z, relative intensity) 462 (MH+, 100); HRESIMS calcd for C26H27N3O5 462.2023 (MH+). found 462.2031 (MH+); HPLC purity: 98.5% (1% TFA in MeOH—H2O, 70:30).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C[O-].[Na+].ClC1C=CC=CC=1.Cl[CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40]>CO>[CH2:37]([N:38]([CH2:41][CH3:42])[CH2:39][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH:9]2[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:4][CH:3]=1)[CH3:36]
Reactant: Oc1ccc(N2c3ccccc3CCC2c2ccc(Cl)cc2)cc1
Reactant: CCN(CC)CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Clc1ccccc1
Product: CCN(CC)CCOc1ccc(N2c3ccccc3CCC2c2ccc(Cl)cc2)cc1

Procedure:
A procedure was followed similar to that described in Example 1 but using 18 g. 1-(4-hydroxyphenyl)-2-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline, 3.8 g. sodium methoxide, 160 ml. chlorobenzene, 15 ml. dry methanol and 8.8 g. N-(2-chloroethyl) diethylamine. The crude material was chromatographed on 700 g. activated magnesium silicate (60-100 mesh) using benzene, benzene containing increasing amounts of ether, and ether as eluants and there was thus eluted with 7 - 50% ether in benzene and with ether 15 g. 1-{4-[2-(diethylamino)ethoxy]phenyl}-2-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline which was converted to the cyclohexanesulfamate salt; m.p. 161°-163°C. (isopropyl alcohol).
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N:10]=O)=[C:5]([NH2:12])[N:4]=1.[C:13]([O:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][C:22]#[N:23])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].O>C(OCCO)C>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]2[C:5](=[N:12][C:22]([NH2:23])=[C:21]([C:20]3[CH:19]=[CH:18][C:17]([O:16][C:13](=[O:15])[CH3:14])=[CH:25][CH:24]=3)[N:10]=2)[N:4]=1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Reactant: CC(=O)Oc1ccc(CC#N)cc1
Agent: [Na]
Solvent: CCOCCO
Solvent: O
Product: CC(=O)Oc1ccc(-c2nc3c(N)nc(N)nc3nc2N)cc1
Reaction time: 2 h

Procedure:
410 mg of metallic sodium are dissolved with stirring in 100 ml of 2-ethoxy-ethanol. 1100 mg of 2,4,6-triaminonitroso-pyrimidine and 1140 mg of p-acetoxybenzyl-cyanide are added with stirring one after the other and the mixture is heated to the boiling point with stirring. The color of the mixture changes from violet to brown. After two hours' boiling under reflux, heating is discontinued and the reaction mixture is left to cool. Subsequently, 70 to 80 percent of the 2-ethoxy-ethanol are drawn off using the vacuum from a water aspirator and the residue is combined with 500 ml of water. After extraction four times with ether, the extract is adjusted to pH 5 with 2 N hydrochloric acid. The precipitate is filtered off, washed with a little ice-cold acetone and recrystallized from 10 percent acetic acid. Further purification can follow using a silica gel column. The compound mentioned in the title is obtained, which compound decomposes (with charring) at 319°-321° C.
Reaction SMILES: [ClH:1].[N+:2]1([O-])[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[NH4+]>P(Cl)(Cl)(Cl)=O>[Cl:1][C:5]1[CH:4]=[C:3]([CH3:9])[N:2]=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1cccc(C)[n+]1[O-]
Reactant: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)cc(C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.7 %

Procedure:
A mixture of 2,6-lutidine-N-oxide hydrochloride (48 g) and phosphorus oxychloride (110 ml) is heated 6.5 hours at reflux. After cooling the reaction mixture is carefully poured into crushed ice (1 kg). While the temperature is maintained below 15° C., concentrated ammonium hydroxide is added up to reach pH 8. The product that separates is extracted with ethyl ether (2×500 ml) which is dried and distilled off. The residue is dissolved in ethanol (400 ml) and boiled 3 hours with triethylamine (20 ml). After cooling, the solution is evaporated to dryness, treated with water (200 ml) and extracted with ethyl ether (4×150 ml). The combined extracts are dried and the solvent evaporated. The residue after distillation gives 4-chloro-2,6-dimethylpyridine (25 g), b.p. (15 mm)=67°-69° C. To a mixture of sodium (10 g, 30% dispersion in toluene) in anhydrous dimethyoxyethane (40 ml) cooled in an ice-bath and kept under argon, trimethyltin chloride (12.1 g) in dimethoxymethane (6 ml) is added over a one hour period while keeping the temperature at 0° C. The mixture is stirred 2.5 hours at 0° C.; then 4-chloro-2,6-dimethylpyridine (7 g) in dimethoxyethane is slowly dropped into. Stirring is continued for an additional hour then the reaction mixture is allowed to stand overnight at room temperature. The reaction mixture is diluted with ethyl ether (100 ml) and filtered. The solvent is evaporated, the residue dissolved in ethyl ether (100 ml) and filtered again. After evaporation of the solvent the residue is distilled giving 2,6-dimethyl-4-(trimethyl-stannyl)pyridine (8.8 g), b.p. (15 m)=130°-140° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[CH3:11][C:12]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:24][CH3:25])([CH3:15])[C:13]#N.CC[O:28]CC>>[CH3:15][C:12]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:24][CH3:25])([C:13](=[O:28])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11]
Reactant: BrCCc1ccccc1
Reactant: CCOCC
Reactant: COc1ccc(OC)c(C(C)(C)C#N)c1
Agent: [Mg]
Product: COc1ccc(OC)c(C(C)(C)C(=O)CCc2ccccc2)c1

Procedure:
To a solution of the Grignard reagent prepared from 2-phenylbromoethane (5.5 g.), magnesium (0.8 g.) and dry ether (60 ml.) is added a solution of 2-methyl-2-(2,5-dimethoxyphenyl)propionitrile (2.75 g.) in dry ether (20 ml.). The ether is distilled off and replaced by dry benzene (50 ml.) and the mixture refluxed for 48 hours. It is then decomposed by careful treatment with dilute sulfuric acid and heated on a steam bath for one hour. The mixture is then extracted with ether, the extract dried (MgSO4) and concentrated to an oil. Distillation of the oil in vacuo affords 2-methyl-2-(2,5-dimethoxyphenyl)-5-phenyl-3-pentanone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.CCOCC.C([Li])(C)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>CCCCCCC.O>[CH2:35]([O:34][C:32]([C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1)=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Agent: [Li]C(C)(C)C
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)OCc3ccccc3)cnc21
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 50.9 %

Procedure:
Into a Round bottom flask was added compound 20 (425.0 mg, 0.001203 mol) and Ether (8.0 mL, 0.076 mol) under an atmosphere of Nitrogen, −78 Celsius. Into the reaction mixture, was added 1.7 M of tert-Butyllithium in Heptane (1.5 mL) slowly. The reaction mixture was stirred at −78 Celsius for 90 minutes, followed by addition of benzyl chloroformate (0.20 mL, 0.0014 mol). 2 hours later at −78 Celsius, the reaction mixture was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage to give product 21 (250 mg).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][Cl:28])[CH:22]=1>CN(C)C=O>[Cl-:28].[C:14]1([P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClCc1cccnc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: [Cl-]
Product: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
13.1 g of triphenyphosphine are added to a solution of 8.2 g of 3-picolyl chloride hydrochloride in 120 ml of dimethylformamide. After stirring for 5 minutes, the mixture is heated at reflux for 30 minutes in a microwave apparatus and then cooled to 5° C. The crystals obtained are filtered off, rinsed with dimethylformamide and then with ether, and dried under reduced pressure, allowing the expected product to be isolated.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:17](Cl)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>O.ClCCl>[C:17]([C:10]1[C:6]([CH3:5])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8][C:9]=1[CH3:11])(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)c1c(C)[nH]c(C(=O)OCC)c1C

Procedure:
1.46 g (11 mmol) of AlCl3 were added to a solution of 1.67 g (10 mmol) of ethyl 3,5-dimethylpyrrole-2-carboxylate a 2.63 g (12 mmol) of dodecanoyl chloride in 30 ml of absol. Dichloromethane and then stirred for 24 h. Addition of water and dilute HCl is followed by extraction twice with CH2Cl2. The organic phases are washed with dilute NaOH, dried over Na2SO4 and concentrated. The product is recrystallized from isopropanol.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[O:18]1[CH2:19][CH2:20][N:15]([S:2]([C:5]2[CH:6]=[N:7][CH:8]=[C:9]([CH:14]=2)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3])[CH2:16][CH2:17]1
Reactant: COC(=O)c1cncc(S(=O)(=O)Cl)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cncc(S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.4 %

Procedure:
Methyl 5-(chlorosulfonyl)nicotinate (35 mg, 0.149 mmol) was added to the morpholine (25.9 mg, 0.297 mmol) in presence of Potassiumcarbonate (41.1 mg, 0.297 mmol) in THF (8 mL) at room temperature and the reaction mixture was stirred for 12 h at room temperature. The reaction was monitored by TLC, after completion of the reaction, Solvent was removed by vacuum and then compound was purified by column chromatography (2% Methanol/DCM) afforded the product methyl 5-(morpholinosulfonyl)nicotinate (26 mg, 0.090 mmol, 60.5% yield) as a solid. 1HNMR (400 MHz, CDCl3): δ 9.41 (s, 1H), 9.12 (s, 1H), 8.60 (d, 1H, J=2.0 Hz), 4.01 (s, 3H), 3.76 (m, 4H), 3.07 (m, 4H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][OH:16].[H-].[Na+].Br[CH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:22]=1[C:23]([O:25][CH3:26])=[O:24].O>CN1C(=O)N(C)CCC1.C1COCC1>[CH3:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][O:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: OCCCOCc1ccc2ccccc2n1
Reactant: COC(=O)c1c(C)cccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: COC(=O)c1c(C)cccc1COCCCOCc1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-(Quinolin-2-ylmethoxy)-propan-1-ol (4.6 g, 21.2 mmol, EXAMPLE 3a) is dissolved in 20% DMPU in THF (50 mL) and cooled to 0° C. Sodium hydride (60%, 920 mg, 23 mmol) is added portionwise, and the contents are allowed to stir for 15 min. at 0° C. Methyl 2-bromomethyl-6-methyl-benzoate (77%, 7.25 g, 23 mmol, EXAMPLE 2a) is added and the reaction is allowed to warm to r.t. and continue to stir overnight. The reaction is poured into water (600 mL) and extracted with ethyl acetate (3×200 mL). The organic fractions are pooled and washed with water (3×250 mL) and brine (2×300 mL), dried over MgSO4, filtered and reduced under vacuum to an oil. The crude material is purified by flash chromatography (silica, 2% methanol in dichloromethane) to give the title compound. MS (ESI) 380 (M+H)+.