Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH2:7][CH2:6][CH:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)[CH2:4][CH:3]=1.[CH2:16]([CH:19]([CH2:22]O)[CH2:20][OH:21])[CH2:17][CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH2:7][CH2:6][CH:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[O:21][CH2:20][C@H:19]([CH2:16][CH2:17][CH3:18])[CH2:22][O:15]3)[CH2:10][CH2:9]2)[CH2:4][CH:3]=1
Reactant: O=C[C@H]1CC[C@H](C2CC=C(F)CC2)CC1
Reactant: CCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[C@H]1CO[C@H]([C@H]2CC[C@H](C3CC=C(F)CC3)CC2)OC1

Procedure:
500 mg of trans-4-(4-fluoro-cyclohex-3-enyl)cyclohexanecarbaldehyde, 310 mg of 2-propyl-propane-l,3-diol and 50 mg of p-toluenesulphonic acid in 8 ml of toluene were boiled at reflux for 1 hour in an apparatus which was gassed with nitrogen and which was fitted with a water separator. After cooling the reaction solution was partitioned in water/ether. The organic phase was washed twice with water. The aqueous phases were extracted twice with ether. The organic phases were combined, dried over magnesium sulphate, filtered and the filtrate was evaporated. The crude product was recrystallized several times from ethanol/1% ethyl acetate and gave 350 mg of trans-2-[trans-4-(4-fluoro-cyclohex-3-enyl)cyclohexyl]-5-propyl-[1,3]-dioxane, m.p. (C-N)<room temperature; S-N 104° C., c1.p. (N-I) 118.3° C.;
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[N:12]=[N+:13]([O-:24])[C:14]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][CH2:21]3)=[CH:17][C:15]=2[N:16]=1>COCCOC>[N:1]1([CH2:7][CH2:8][NH:9][C:11]2[N:12]=[N+:13]([O-:24])[C:14]3[CH:23]=[C:22]4[C:18]([CH2:19][CH2:20][CH2:21]4)=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NCCN1CCOCC1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: COCCOC
Product: [O-][n+]1nc(NCCN2CCOCC2)nc2cc3c(cc21)CCC3
Yield: 97.7 %

Procedure:
2-(4-Morpholinyl)ethylamine (3.93 mL, 30.0 mmol) was added to a stirred solution of chloride 21 (2.21 g, 10.0 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue stirred with water (150 mL) at room temperature for 30 min. The solid was filtered, washed with water (3×10 mL) and dried to give 1-oxide 44 (3.08 g, 98%) as an orange solid: mp (water) 178-179° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.79 (br s, 1H, NH), 3.72 (br t, J=4.6 Hz, 4H, CH2O), 3.59 (q, J=5.6 Hz, 2H, CH2N), 2.97-3.05 (m, 4H, H-6, H-8), 2.63 (t, J=5.9 Hz, 2H, CH2N), 2.51 (br t, J=4.6 Hz, 4H, CH2N), 2.10-2.19 (m, 2H, H-7); 13C NMR δ 158.6, 154.6, 148.7, 143.3, 129.8, 120.5, 114.6, 66.9 (2), 56.8, 53.3 (2), 37.5, 33.1, 32.3, 25.7. Anal. calcd for C16H21N5O2: C, 60.9; H, 6.7; N, 22.2. Found: C, 61.0; H, 6.8; N, 22.3%.
Reaction SMILES: [CH2:1]([CH:4]1[C:8]2[CH:9]=[N:10][C:11]([CH2:21]Cl)=[C:12]([O:13]CC3C=CC=CC=3)[C:7]=2[CH2:6][O:5]1)[CH2:2][CH3:3].[CH3:23][NH2:24]>C1C=CC=CC=1>[CH2:1]([CH:4]1[C:8]2[CH:9]=[N:10][C:11]([CH2:21][NH:24][CH3:23])=[C:12]([OH:13])[C:7]=2[CH2:6][O:5]1)[CH2:2][CH3:3]
Reactant: CCCC1OCc2c1cnc(CCl)c2OCc1ccccc1
Reactant: CN
Solvent: c1ccccc1
Product: CCCC1OCc2c1cnc(CNC)c2O
Yield: 66 %

Procedure:
The method of example 1 was repeated, but starting with 1,3-dihydro-3-propyl-6-chloromethyl-7-benzoxy-furo-(3,4-c)-pyridine and gaseous methylamine dissolved in benzene. Yield 66% of an oily product, elemental analysis of which showed good correspondence with the formula C12H18N2O2.HCl.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](N)=[N:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].N([O-])=[O:16].[Na+]>C(O)(=O)C.O>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:16])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cnc2nc(N)[nH]c(=O)c21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Temperature: 50 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of 7-allyl-2-amino-1H-purin-6(7H)-one (20 g, 104.7 mmol) in acetic acid (500 mL) and water (70 mL) was added a solution of sodium nitrite (30 g, 434.8 mmol) in water (70 mL) dropwise at 50° C. The reaction was stirred at 50° C. for 1 h. The reaction was concentrated and poured into ice-water. The solids that formed were filtered and the filter cake was washed with water and ethanol, then dried under vacuum to give 7-allyl-1H-purine-2,6(3H,7H)-dione (15 g, 74.4% yield) as yellow solid. LCMS retention time 0.555 min; LCMS MH+ 193.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](Cl)=[O:8].[CH2:13]([NH2:15])[CH3:14]>C1C=CC=CC=1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([NH:15][CH2:13][CH3:14])=[O:8]
Reactant: O=C(Cl)/C=C/c1cccc(Cl)c1
Reactant: CCN
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCNC(=O)/C=C/c1cccc(Cl)c1

Procedure:
Trans 3-chlorocinnamoyl chloride (4.4 g) in dry benzene (75 ml) was allowed to react with an excess of ethylamine in dry ether (75 ml) according to the procedure of Example 2. Trans 3-chloro-N-ethylcinnamamide, m.p. 87°-88° C., was obtained which had NMR, IR, and elemental analysis consistent with this structure.
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]([CH:29]=1)=[N:25][C:26](=[O:28])[N:27]=2.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[C:24]([CH:29]=3)=[N:25][C:26](=[O:28])[N:27]=4)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=C1N=c2ccc(CCBr)cc2=N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1N=c2ccc(CCN3CCN(c4cccc5ccccc45)CC3)cc2=N1
Yield: 14 %

Procedure:
To a 100 ml round-bottomed flask equipped with magnetic stirrer, condenser, and nitrogen inlet were added 2.64 grams (12.4 mmol) of N-(1-naphthyl)-piperazine, 3.0 grams (12.4 mmol) of 6-(2-bromoethyl)-benzimidazolone, 1.31 grams (12.4 mmol) sodium carbonate, 50 ml methylisobutylketone, and a catalytic amount of sodium iodide. The reaction was refluxed for 3 days, cooled, and evaporated to a brown gum. The gum was partitioned between 50 ml water and 75 ml ethyl acetate, and the ethyl acetate layer washed with brine, dried over sodium sulfate, and evaporated, then chromatographed on silica gel. Fractions containing the product were combined and evaporated, the residue taken up in tetrahydrofuran, treated with hydrochloric acid gas, and the resulting hydrochloride salt of the product filtered off to give a white solid, m.p. 260-262° C., 716 mg (14% yield).
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:22][O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([OH:19])=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:30][C:31]([NH2:33])=[S:32].C([O-])(=O)C.[Na+].Cl>O>[NH2:33][C:31]1[S:32][CH:2]=[C:3]([C:4](=[N:22][O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:5]([NH:7][CH:8]2[C:20](=[O:21])[N:10]3[C:11]([C:17]([OH:19])=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]23)=[O:6])[N:30]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)C(=O)CCl)[C@H]2SC1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)c3csc(N)n3)[C@H]2SC1
Yield: 90.6 %

Procedure:
To a suspension of 7-(4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyramido)-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g) in water (20 ml) were added thiourea (0.683 g) and sodium acetate (1.84 g) at 40° C. with stirring. The reaction mixture was stirred at the same temperature for 1.5 hours. The resultant solution was adjusted to pH 2.8 with 10% hydrochloric acid and stirred under ice-cooling for 20 minutes. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.9 g).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6](Br)[CH:5]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[CH3:11][O:10][C:7]1[C:6]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:15]([F:26])([F:25])[F:14])[CH:21]=2)=[CH:5][C:4]([C:3]([OH:2])=[O:13])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OC)c(Br)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: COc1ccc(C(=O)O)cc1-c1cccc(C(F)(F)F)c1

Procedure:
3-bromo-4-methoxybenzoic acid methyl ester was coupled to 3-trifluoromethyl-phenylboronic acid in analogy to step 3 of example 92, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield 6-methoxy-3′-trifluoromethyl-biphenyl-3-carboxylic acid. This intermediate was coupled to the compound of step 1 of example 361 in analogy to step 1 of example 3, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[N:21]=[C:20]([CH:22]4[CH2:27][CH2:26][N:25](S(CC5C=CC=CC=5)(=O)=O)[CH2:24][CH2:23]4)[NH:19][C:18]=3[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:16][C:11]=2[O:10][CH2:9]1.C(N(C(C)C)CC)(C)C>C1COCC1>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[N:21]=[C:20]([CH:22]4[CH2:27][CH2:26][N:25]([C:1](=[O:3])[CH3:2])[CH2:24][CH2:23]4)[NH:19][C:18]=3[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: O=S(=O)(Cc1ccccc1)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.6 %

Procedure:
Acetic anhydride (0.011 mL, 0.12 mmol) was added to a solution of 2-(5-benzo[1,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-pyridine (0.035 g, 0.10 mmol; prepared as described in Example 11) and diisopropylethylamine (0.021 mL, 0.12 mmol) in anhydrous THF (3 mL). The mixture was stirred at room temperature for 18 hours and was partitioned between ethyl acetate and water. The organic solution was washed with brine, dried over sodium sulfate, filtered, and concentrated. HPLC purification eluting with acetonitrile:water gave 0.010 g (26%) of the title compound as a yellow solid. MS (ESP+) m/z 391.2 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 8.59 (m, 1H), 7.73 (m, 1H), 7.34 (m, 2H), 6.94 (m, 3H), 5.98 (s, 2H), 4.83 (s, 3H), 4.60 (m, 2H), 4.01 (m, 2H), 3.28 (m, 3H), 2.69 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[C:23]([CH3:28])[CH:22]=[CH:21][N:20]=1.C(N(CC)CC)C>C(O)C>[CH3:28][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])[C:24]=1[N+:25]([O-:27])=[O:26]
Reactant: Cc1ccnc(Cl)c1[N+](=O)[O-]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccnc(Nc2ccc3[nH]cc(CC4CCCN4C)c3c2)c1[N+](=O)[O-]
Yield: 34 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 2-chloro-4-methyl-3-nitropyridine were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was heated at reflux for 24 hours. Column chromatography afforded the title compound (34%) as a red amorphous solid: 1H NMR (CDCl3) δ9.26 (brs, NH),8.79 (brs, NH),8.10 (d,J=4.8 Hz, 1H), 7.64(d,J=1.7 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.17 (dd, J=8.5 and 1.9 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.56 (d, J=4.8 Hz, 1H), 3.25-3.16 (m, 2H), 2.67 (dd, J=13.2 and 9.4 Hz, 1H), 2.64-2.56 (m, 1H), 2.56 (s, 3H), 2.46 (s, 3H), 2.30 (dd, J=17.7 and 9.4 Hz, 1H), 1.90-1.60 (m, 4H); 13C NMR (CDCl3) δ152.2, 151.5, 146.6, 134.3, 131.0, 130.0, 127.9, 123.4, 119.4, 117.1, 114.0, 113.3, 111.6, 67.0, 57.4, 40.7, 31.4, 29.5, 21.8, 21.7; FAB HRMS calculated for [C20H23N5O2.H]366.1932, found 366.1957.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[C:19]([O:21]C)=[O:20])[CH:14]=[CH:13][C:12]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:40])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:31])[CH:24]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.CO>[CH2:3]([O:10][C:11]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH:14]=[CH:13][C:12]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:40])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:31])[CH:24]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)O)cc2OCc2ccccc2)c1
Yield: 64 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 200 mg (5.0 mmol, 12.8 eq) of sodium hydroxide and 200 mg (0.39 mmol, 1 eq) of methyl (E)-3-[2-benzyloxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate in 6 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 125 mg of (E)-3-[2-benzyloxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylic acid are obtained in the form of a white powder (m.p.=115-116° C.). Yield=64%
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([OH:10])[CH2:8][NH:7][C@@H:6]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=O)C.N.CO>>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][C@@H:6]2[C@H:5]([OH:4])[C@@H:9]([OH:10])[CH2:8][NH:7]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(C[C@H]2NC[C@H](O)[C@H]2OC(C)=O)cc1
Agent: N
Solvent: CO
Product: COc1ccc(C[C@H]2NC[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a 500 mL round bottom flask containing solid (2R,3S,4S)-4-hydroxy-2-(4-methoxybenzyl)pyrrolidin-3-yl acetate (513.3 mg, 1.935 mmol) and a magnetic stir bar is added 2M NH3/MeOH (200 mL, 400 mmol). The resulting light tan solution is capped and stirred at room temp for 5 days. The solvent is removed in vacuo to give the title compound that is used directly “as is” in the next step. LC/MS (Condition A): ret. T=1.42 min, (M+H)+ 224.11.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]4([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]4)=[CH:5][CH:4]=3)[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: COC(=O)C1(c2ccc(CCl)cc2)CC1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: COC(=O)C1(c2ccc(CN3CCN(c4ccc(F)cc4)CC3)cc2)CC1

Procedure:
By similar reaction and treatment to that in Example 1(5) using methyl 1-(4-chloromethylphenyl)cyclopropanecarboxylate obtained in Example 75(2) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(4-fluorophenyl)piperazine dihydrochloride instead of phenylpiperazine, the title compound was obtained as a pale-yellow oil.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[F:21][C:22]([F:27])([F:26])[C:23](O)=[O:24]>C(Cl)Cl>[ClH:1].[F:21][C:22]([F:27])([F:26])[C:23]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:24]
Reactant: O=C(O)C(F)(F)F
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)C(F)(F)F
Yield: 60.1 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.70 ml (4.96 mmol) of anhydrous trifluoroacetic acid under ice-cooling with stirring and the mixture was stirred for at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to, obtain the powder which was washed with hexane and dried to obtain 750 mg of the desired compound (free base) (68.4%, pale yellow prisms).
Reaction SMILES: Cl[CH:2]([C:11]1[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=1)[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[NH4+:17].[OH-]>C1COCC1.ClCCl>[NH2:17][CH:2]([C:11]1[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=1)[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: Cn1cncc1C(Cl)c1ccc(C#N)cc1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cncc1C(N)c1ccc(C#N)cc1
Reaction time: 2 h
Yield: 77 %

Procedure:
A suspension of Example 41E (200 mg, 0.746 mmol) in THF (5 mL) at room temperature was treated dropwise with concentrated NH4OH (2.0 mL), stirred for 2 hours, diluted with dichloromethane, washed with water, dried (MgSO4), filtered, and concentrated to provide 123 mg (77%) of the desired product. MS (ESI) m/z 213 (M+H)+; 1H NMR (CDCl3) δ 7.65 (m, 2H), 7.48 (m, 2H), 7.39 (s, 1H), 6.84 (s, 1H), 5.26 (s, 1H), 3.49 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3]1.C(N(CC)CC)C.[CH2:31]([O:38][CH2:39][C:40](Cl)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:31]([O:38][CH2:39][C:40]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3][C:2]3=[O:1])=[CH:8][CH:9]=2)[CH2:18][CH2:17]1)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)cc2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)COCc4ccccc4)CC3)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 17, 300 mg) and triethylamine (0.20 mL) in dry methylene chloride (19 mL) at 0° C. under N2 is treated with benzyloxyacetyl chloride (0.18 mL), and the resulting solution is stirred at 0° C. for one hour and at ambient temperature for one hour. The reaction mixture is then washed with water (2×10 mL), saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 45 g), eluting with a gradient of methanol/methylene chloride (1/99-2/98). Pooling and concentration of those fractions with an Rf =0.28 by TLC (methanol/chloroform, 5/95) gives the title compound, NMR (CDCl3, 400 MHz) 7.45, 7.35, 7.18, 6.26, 4.75, 4.63, 4.22, 4.04, 3.78, 3.70, 3.60, 3.09, 2.70, 2.02, 1.85, 1.60 δ.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(=O)[CH2:34][C:35](=[O:37])[CH3:36]>CS(C)=O.[Cu]I>[F:21][C:20]([F:23])([F:22])[O:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH:11]=[N:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH2:34][C:35](=[O:37])[CH3:36])=[CH:3][CH:4]=3)=[N:9]2)=[CH:14][CH:15]=1
Reactant: CC(=O)CC(C)=O
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(Br)cc3)n2)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 110 °C
Yield: 35.3 %

Procedure:
3-(4-Bromophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C52) (11 g, 29 mmol), copper(I) iodide (0.55 g, 2.9 mmol), potassium phosphate (18 g, 86 mmol), and pentane-2,4-dione (8.9 mL, 86 mmol) were dissolved in dimethylsulfoxide (120 mL) in a 500 mL round bottomed flask. The reaction was heated at 110° C. for 19 hours. The solution was cooled to room temperature and then quenched with hydrogen chloride (2 N). The excess base was removed by gravity filtration and the filtrate was extracted with ethyl acetate. The organics were washed with water, extracted, dried, and concentrated. Purification by flash column chromatography using 0-30% ethyl acetate/hexanes afforded the title compound as a pure orange solid (3.7 g, 35%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.17 (d, J=8.2 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 7.39 (dt, J=8.1, 1.0 Hz, 2H), 7.33 (dd, J=8.1, 0.6 Hz, 2H), 3.76 (s, 2H), 2.19 (s, 3H); ESIMS m/z 361 ([M]+).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:17])[CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:11][C:6]=2[C:5]([CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.[OH:21][CH:22]([CH3:25])[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:21][CH:22]([CH3:25])[CH2:23][O:1][C:2]1[C:7]2[C:8](=[O:17])[CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:11][C:6]=2[C:5]([CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: CCCc1ccc(O)c2c(=O)cc(C(=O)OCC)oc12
Reactant: CC(O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1ccc(OCC(C)O)c2c(=O)cc(C(=O)OCC)oc12

Procedure:
A mixture of ethyl 5-hydroxy-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate (2.2 g), 2-hydroxy propyl bromide (5 g), anhydrous potassium carbonate (5 g) and acetone (200 ml) was heated at reflux for 3 days. After cooling, the reaction mixture was filtered and the acetone removed from the filtrate in vacuo. The oily residue was dissolved in chloroform (100 ml) and the chloroform solution washed with 1 N aqueous sodium hydroxide solution (50 ml) and water (50 ml) and then dried. Removal of the chloroform in vacuo gave a brown solid which on crystallisation from ethanol gave ethyl 5-(2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate identical in all respects with authentic material.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([O:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=1)(=O)C>O.CO>[OH:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=1
Reactant: CC(=O)OCCCc1ccnc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#Cc1cc(CCCO)ccn1
Reaction time: 0.42 h

Procedure:
A solution of K2CO3 (1.67 g, 12.1 mmol) in H2O (30 ml) was added to a stirred solution of 3-(2-cyanopyridin-4-yl)propyl acetate (4.94 g, 24.2 mmol) in MeOH (130 ml). After 25 min, the MeOH was removed under reduced pressure, then the aqueous phase was extracted three times with EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give a residue that was purified by column chromatography (IH-EtOAc, 1:3) to furnish 4-(3-hydroxypropyl)pyridine-2-carbonitrile: m/z (ES+)=163.1 [M+H]+. A solution of this alcohol (500 mg, 3.1 mmol) in DMF (20 ml) was treated with PDC (7 g, 18.6 mmol) and H2O (0.5 ml). The reaction was stirred for 16 h, before being partitioned between H2O and EtOAc. The aqueous phase was extracted twice with EtOAc, then the combined organic extracts were washed with brine, before being dried (MgSO4), filtered, and concentrated to give the title compound: m/z (ES−)=177.0 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[F:21][CH:22]([F:29])[C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1>>[F:21][CH:22]([F:29])[C:23]1[N:24]=[C:25]([NH:28][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[S:26][CH:27]=1
Reactant: Nc1nc(C(F)F)cs1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2nc(C(F)F)cs2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluorophenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 4-Difluoromethyl-thiazol-2-ylamine instead of 3-chloroaniline to yield the final compound as a white solid, MS (ISP): m/e=382 [M]+.