Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:21][CH2:22][C@@:23]([CH3:28])([CH:25]1[CH2:27][CH2:26]1)[OH:24]>>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:21][CH2:22][C@@:23]([CH:25]1[CH2:27][CH2:26]1)([OH:24])[CH3:28])=[O:9]
Reactant: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Reactant: C[C@](O)(CN)C1CC1
Product: C[C@](O)(CNC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1c, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid and (R)-α-(aminomethyl)-α-methyl-cyclopropanemethanol as starting materials, MS (ISP) 462.9, 464.9 (M−H).
Reaction SMILES: [OH-].[Na+].O.[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([OH:19])[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.Cl.Cl[CH2:22][C:23]1[N:24]=[C:25]([CH3:28])[S:26][CH:27]=1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O1CCCC1>[ClH:4].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([O:19][CH2:22][C:23]1[N:24]=[C:25]([CH3:28])[S:26][CH:27]=1)[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([O:19][CH2:22][C:23]1[N:24]=[C:25]([CH3:28])[S:26][CH:27]=1)[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: Cc1nc(CCl)cs1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)cs1
Reaction time: 2 h

Procedure:
In a three-necked flask, fitted with stirrer, reflux condenser and gas inlet tube, 44 g of sodium hydroxide (1.1 mol) and 50 ml of water are introduced. While passing nitrogen through the flask, the solution is cooled to 45° and then 11.6 g of (1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (0.045 mol) [prepared by the method of J. Med. Chem. 12, 784, (1969)], 0.75 g of benzyltrimethylammonium chloride and 150 ml of tetrahydrofuran are added. To the mixture, which is warmed to 50°, 8.3 g of 4-chloromethyl-2-methylthiazole, hydrochloride (0.045 mol) are added and the mixture is stirred vigorously for two hours at 60°. The filtered biphasic solution is transferred into a separating funnel, the lower aqueous sodium hydroxide is extracted with 10 ml of tetrahydrofuran. The combined tetrahydrofuran layers are treated with charcoal and after drying with sodium sulphate, the solvent is evaporated in vacuo. The resulting oily product, dissolved in 250 ml of ether, is allowed to stand overnight in a refrigerator, by which operation unreacted 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol is separated. Filtering off and addition of ethereal hydrochloric acid to the clear ethereal solution yields the hydrochloride of 4-[[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethoxy]methyl]-2-methylthiazole. Yield: 12.8 g (71%). Recrystallization from acetonitrile gives a hydrochloride with the m.p. of 194°-196° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12]C)=[O:11])[C:3]=1[CH:14]=[CH2:15].[OH-].[Na+]>CO.CC(C)=O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([OH:12])=[O:11])[C:3]=1[CH:14]=[CH2:15]
Reactant: C=Cc1c(C(=O)OC)nc(Cl)c(F)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: C=Cc1c(C(=O)O)nc(Cl)c(F)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a solution of methyl 4-amino-6-chloro-5-fluoro-3-vinylpicolinate (0.150 g, 0.650 mmol) in methanol (3.25 mL) and acetone (3.25 mL) was added sodium hydroxide (0.078 g, 1.951 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated, diluted with ethyl acetate, and washed with 1N HCl. The organic phase was dried over Na2SO4, filtered, concentrated, and dried under high vacuum to afford the title compound (89 mg, 0.411 mmol, 63.2% yield) as a white solid: mp 164-166° C.; 1H NMR (400 MHz, DMSO) δ 13.34 (s, 1H), 6.67 (s, 2H), 6.67 (dd, J=17.7, 11.5 Hz, 3H), 5.53 (dd, J=10.4, 1.2 Hz, 1H), 5.49 (dd, J=16.7, 1.1 Hz, 1H); 19F NMR (376 MHz, DMSO) δ −142.00 (s); ESIMS m/z 215 ([M−H)−].
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.[O:58]1[CH:62]=[CH:61][CH:60]=[C:59]1[S:63](Cl)(=[O:65])=[O:64]>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:63]([C:59]3[O:58][CH:62]=[CH:61][CH:60]=3)(=[O:65])=[O:64])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: O=S(=O)(Cl)c1ccco1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.291 mmol) and furan-2-sulfonyl chloride (72 mg, 0.437 mmol), the title compound was obtained as a white solid (87 mg, 63% yield). MS (ESI): 474 [M+H]+.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][S:5](=[O:9])(=[O:8])[NH:4]1)[CH3:2].Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[C:13]([F:33])[CH:12]=1>>[CH3:31][C:30]1[C:25]([N:22]2[CH2:23][CH2:24][N:19]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([N:4]4[C@H:3]([CH2:1][CH3:2])[CH2:7][CH2:6][S:5]4(=[O:9])=[O:8])=[CH:12][C:13]=3[F:33])=[O:18])[CH2:20][CH2:21]2)=[N:26][CH:27]=[C:28]([CH3:32])[CH:29]=1
Reactant: CC[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: CC[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(F)c1
Yield: 13 %

Procedure:
Using (R)-3-ethylisothiazolidine 1,1-dioxide (150 mg) described in Preparation Example 3 and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (439 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 1, the title compound (60 mg) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].[O:10]1[CH2:33][CH:11]1[CH2:12][O:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[N:17]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:16]([CH3:32])([CH3:31])[CH2:15]1>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:33][CH:11]([OH:10])[CH2:12][O:13][CH:14]2[CH2:15][C:16]([CH3:31])([CH3:32])[N:17]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:18]([CH3:20])([CH3:21])[CH2:19]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(O)cc1
Reactant: CCCCCCCCON1C(C)(C)CC(OCC2CO2)CC1(C)C
Product: C=Cc1ccc(OCC(O)COC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)cc1

Procedure:
4-Vinylphenol is reacted with 4-(2,3-epoxypropoxy)-1-octyloxy-2,2,6,6-tetra-methylpiperidine (=epoxide A3) analogously to Example B6) to form the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[O:11][CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:16])[C:12](=[O:14])[O:11][CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2CCO1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)OCCc2cc([N+](=O)[O-])ccc21

Procedure:
A mixture of 2-nitro-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (0.7 g, 3.36 mmol), potassium carbonate (1.4 g, 10.1 mmol, 3 eq.), and iodomethane (0.42 mL, 6.7 mmol, 2 eq.) was stirred for 16 hours in DMF (10 mL). The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried (sodium sulfate) and concentrated to provide 2-nitro-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one: 1H NMR (300 MHz, CDCl3) δ 8.19 (dd, 1H), 8.13 (d, 1H), 7.28 (d, 1H), 4.55 (t, 2H), 3.43 (s, 3H), 3.10 (t, 2H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1[C:19]([C:20]2[C:21](=[O:36])[NH:22][C:23](=[O:35])[C:24]=2[C:25]2[C:33]3[C:28](=[C:29]([CH3:34])[CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[C:8]2[CH:9]=[C:10]([CH2:13]OS(C)(=O)=O)[CH:11]=[CH:12][N:7]2[N:6]=1>>[CH3:1][N:2]([CH2:13][C:10]1[CH:11]=[CH:12][N:7]2[N:6]=[C:5]([CH3:4])[C:19]([C:20]3[C:21](=[O:36])[NH:22][C:23](=[O:35])[C:24]=3[C:25]3[C:33]4[C:28](=[C:29]([CH3:34])[CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)=[C:8]2[CH:9]=1)[CH3:3]
Reactant: CNC
Reactant: Cc1nn2ccc(COS(C)(=O)=O)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Product: Cc1nn2ccc(CN(C)C)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.6 %

Procedure:
Dimethylamine (approx. 50% solution in DMF, 0.04 ml, 0.27 mmol, 2.0 equiv) is added at room temperature under an atmosphere of argon to a solution of methanesulfonic acid 2-methyl-3-[4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-pyrazolo[1,5-a]pyridin-5-ylmethyl ester (80 mg, 0.17 mmol). The reaction mixture is stirred at room temperature for 20 minutes. After dilution with water, the mixture is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (CH2Cl2/MeOH 95:5) affords the title compound (44 mg, 62%). 1H NMR (400 MHz, d6-DMSO): δ=11.77 (s, 1H), 10.93 (s, 1H), 8.48 (d, J=6.9 Hz, 1H), 7.94 (d, J=3.0 Hz, 1H), 6.79 (br s, 1H), 6.74 (d, J=7.1 Hz, 1H), 6.65 (dd, J=7.1/1.7 Hz, 1H), 6.45 (t, J=7.1 Hz, 1H), 6.11 (d, J=8.1 Hz, 1H), 4.10 (q, J=5.4 Hz, 2H), 3.18 (s, 3H), 3.17 (s, 3H), 2.39 (s, 3H), 2.20 (s, 3H). MS (ES+): 414 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N+:19]([O-])=[CH:18][CH:17]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:30].O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18](=[O:30])[CH:17]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc(-c2nn3c(c2-c2cc[n+]([O-])c4ccccc24)CCC3)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nn3c(c2-c2cc(=O)[nH]c4ccccc24)CCC3)n1
Reaction time: 40 h

Procedure:
To a solution of 4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-1-oxide (103 mg, 0.30 mmol) in N,N-dimethylformamide (3 mL) is added trifluoroacetic anhydride (425 μL, 3.0 mmol). The mixture is stirred for 40 h, poured into water, and the pH adjusted to 8 with saturated aqueous sodium bicarbonate solution. The mixture is extracted three times with ethyl acetate, the combined organic extracts washed three times with water and once with brine, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue is triturated with 10% acetone/90% dichloromethane and filtered. The solid is dried under vacuum to yield the title compound, 11.6 mg (10%), as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2=[CH:9][CH:10]=[C:11]3[C:20]([N:19]=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[C:17]4[C:21]([OH:23])=O)=[N:12]3)=[C:7]2[CH:6]=[CH:5][N:4]=1.[NH2:24][C@@H:25]([CH2:28][N:29]([CH3:31])[CH3:30])[CH2:26][OH:27]>>[CH3:30][N:29]([CH3:31])[CH2:28][C@H:25]([NH:24][C:21]([C:17]1[C:18]2[C:13](=[N:12][C:11]3[C:20]([N:19]=2)=[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]2=[CH:9][CH:10]=3)[CH:14]=[CH:15][CH:16]=1)=[O:23])[CH2:26][OH:27]
Reactant: CN(C)C[C@H](N)CO
Reactant: COc1nccc2c1ccc1nc3cccc(C(=O)O)c3nc12
Product: COc1nccc2c1ccc1nc3cccc(C(=O)N[C@H](CO)CN(C)C)c3nc12

Procedure:
4-Methoxypyrido [4,3-α]phenazine-11-carboxylic acid (2-dimethylamino-1-(S)-hydroxymethyl-ethyl)-amide was prepared from 4-methoxypyrido[4,3-α]phenazine-11-carboxylic acid (II.4) and (S)-2-Amino-3-dimethylamino-propan-1-ol
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[CH:19]=[C:20]([C@@H:24]([NH2:26])[CH3:25])[CH:21]=[CH:22][CH:23]=1>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:26][C@H:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:14]2[S:13][CH:17]=[CH:16][N:15]=2)[CH:19]=1)[CH3:25])=[O:8]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: C[C@H](N)c1cccc(-c2nccs2)c1
Product: C[C@H](NC(=O)C=Cc1ccccc1F)c1cccc(-c2nccs2)c1

Procedure:
The title compound was prepared from 2-fluorocinnamic acid and (S)-1-(3-thiazol-2-yl-phenyl)-ethylamine following the general procedures as described for Example 1.
Reaction SMILES: [NH4+].[Cl-].[N+:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)([O-])=O>CO.O.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:21][CH:20]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Oc2ccccc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
Fe (2.9 g, 52.4 mmol, 4.0 eq) and NH4Cl was added to a solution of 6-nitro-4-((4-phenoxyphenyl)amino)quinoline-3-carbonitrile (5.0 g, 13.1 mmol, 1.0 eq) in methanol/water (50/50 mL). The mixture was heated to reflux for 8 hours, cool to room temperature and extracted with ethyl acetate (100×3 mL). The organic layers were combined, dried over anhydrous sodium sulfate. The crude product was purified by flash column chromatography on silica gel to give 6-amino-4-((4-phenoxyphenyl)amino)quinoline-3-carbonitrile (Compound 19) as a solid 3.5 g.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:9]1([CH:16]=[CH:15][C:13]([OH:14])=[CH:12][CH:11]=1)[OH:10].[CH3:17][C:18](O)(CCCC(C)CCCC(C)CCCC(C)C)[CH:19]=C>[Cl-].[Cl-].[Zn+2]>[O:10]1[C:9]2[C:16](=[CH:15][C:13]([OH:14])=[CH:12][CH:11]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: Oc1ccc(O)cc1
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Product: Oc1ccc2c(c1)CCCO2

Procedure:
2,6-dimethylquinone 111 is reduced with sodium dithionite to the hydroquinone 112, which is then reacted with 3,7,11,15-tetramethyl-3-hydroxy-1-hexadecene 113 and ZnCl2 to form the 6-chromanol 114. Conversion to the protected intermediate 115 is followed by bromination with Br2 and silver trifluoroacetate to form the bromide 116. Finally, 116 can be deprotected and oxidized with ceric ammonium nitrate (CAN) to yield 117.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH2:14][CH2:15][NH:16][C:17](=O)[CH3:18])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>O.C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]3[CH2:14][CH2:15][N:16]=[C:17]([CH3:18])[C:11]3=[CH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)NCCn1cccc1-c1ccc(Cl)c(Cl)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: CC1=NCCn2c1ccc2-c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 65 %

Procedure:
N-[2-[2-(3,4-Dichlorophenyl)-pyrrol-1-yl]ethyl]-acetamide (4.6 g) was treated with 25 ml of phosphorus oxychloride under argon and boiled for 1 hour while stirring. The reaction mixture was hydrolyzed at 0° C. with 70 ml of 2N sodium hydroxide solution and 120 ml of 28% sodium hydroxide solution, diluted with 1400 ml of water and extracted with methylene chloride (1×500 ml, 2×250 ml). The organic extracts were combined, dried with MgSO4 and freed from solvent. 2.0 g of a total of 3.8 g of crude product were dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 2.1 g (65%) of 6-(3,4-dichlorophenyl)-3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 193°-195° C. (dec.).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:31](=[O:34])[CH2:32][CH3:33])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (4.60 g, 15.8 mmol) and N,N-diisopropylethylamine (1.40 mL, 15.8 mmol) in 25 mL of dry methylene chloride was added propionyl chloride (1.40 mL, 15.8 mmol) dropwise at 0° C. After being stirred at room temperature overnight, the reaction mixture was quenched with 30 mL of H2O and extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with aqueous HCl (5%, 20 mL), NaHCO3 (sat., 2×30 mL), brine (50 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by a flash column chromatography (silica gel, hexane:ethyl acetate) to afford N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 as a colorless oil (4.50 g, 82%). IR (film, cm−1) 2975, 2934, 2854, 1690, 1663, 1591, 1496, 1422, 1402, 1365, 1265, 1242, 1176, 1149, 1038, 962,775, 702; 1H NMR (CDCl3, ppm) 7.44-7.22 (m, 5H), 4.09-3.22 (m, 4H), 2.80-2.09 (m, 2H), 2.06 (q, 2H, J=7.5 Hz), 1.75-1.19 (m, 5H), 1.48(s, overlap, 9H), 1.06 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(O)c(C(=O)OC)c1
Yield: 69.9 %

Procedure:
A mixture of 2.0 g (11.9 mmol) of 2,5-dihydroxybenzoic acid methyl ester, 4.55 g (13.1 mmol) of 1-bromooctadecane and 1.9 g (13.7 mmol) of potassium carbonate in 50 ml of acetone was stirred at reflux for 24 hours. The solvent was removed at reduced pressure and the residue was treated with water. The product was extracted with ethyl acetate and the dried extract was concentrated to a solid which was recrystallized from ethyl acetate-hexane to give 3.5 g (70% yield, mp 53°-54°) of 2-hydroxy-5-(octadecyloxy)benzoic acid methyl ester.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH3:16])[C:10]([OH:12])=O)[N:8]=1)=[O:2].C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:37][CH:38]1[C:59](=[O:60])[N:40]2[C:41]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=3)=[O:47])=[C:42]([OH:45])[CH2:43][S:44][C@H:39]12.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH3:16])[C:10]([NH:37][CH:38]2[C:59](=[O:60])[N:40]3[C:41]([C:46]([O:48][CH2:49][C:50]4[CH:51]=[CH:52][C:53]([N+:56]([O-:58])=[O:57])=[CH:54][CH:55]=4)=[O:47])=[C:42]([OH:45])[CH2:43][S:44][C@H:39]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: CCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12)c1csc(NC=O)n1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
N,N-Dimethylformamide (0.114 g.), phosphoryl chloride (0.240 g.) and ethyl acetate (0.5 ml.) were reacted in a conventional manner to give a Vilsmeier reagent. Ethyl acetate (5 ml.) and 2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer, 0.35 g.) were added at the same temperature for 30 minutes to give the activated acid solution. On the other hand, trimethylsilylacetamide (1.31 g.) and bis(trimethylsilyl)acetamide (1.14 g.) were added to a suspension of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate (0.50 g.) in ethyl acetate (7.5 ml.) and stirred at room temperature for an hour. To the solution was added the activated acid solution obtained above all at once at -10° C., and stirred at the same temperature for 30 minutes. Water (15 ml.) and ethyl acetate (15 ml.) were added to the resultant solution. The organic layer was separatwashed with a saturated aqueous solution of sodium bicarbonate (15 ml.) and water (10 ml.), dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether and the precipitates were collected by filtration to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 0.634 g.).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: Nc1ccccc1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)Nc2ccccc2)cn1
Yield: 70 %

Procedure:
As described for example 15, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using aniline instead of 3-methoxypropylamine, to the title compound (87 mg, 70%) which was obtained as an off white solid. MS: m/e=386.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([OH:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.ClCCCCCCOC1C(OC)=CC=C2C=1NC(=O)C=C2NC1C(Cl)=CN=CC=1Cl>>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11](=[O:22])[CH:10]=[C:9]2[NH:8][C:7]1[C:6]([Cl:23])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: BrCCCCCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Agent: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCBr

Procedure:
8-(6-Bromohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one was prepared from 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (Intermediate 3) and 1,6-dibromohexane following the procedure outlined for Intermediate 4 (modifications: 1.3 equiv NaH and 2.5 equiv of dibromide used; reaction run at room temperature). MS (ESI): 514.0.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[NH2:8][C@H:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[CH3:27][CH:26]([CH3:28])[C:25]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C@@H:9]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:8][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[CH2:17][CH2:16]2)[CH:19]=1)=[O:29]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using 1-propanesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 486.2 (M+H)+.