Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([C@H:13]([OH:15])[CH3:14])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][N:17]1[C:21](S(C)(=O)=O)=[N:20][N:19]=[C:18]1[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]([O:15][C:21]3[N:17]([CH3:16])[C:18]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[N:19][N:20]=3)[CH3:14])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](O)c1nc(-c2cccc(Cl)c2)no1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CC(Oc1nnc(-c2ccncc2)n1C)c1nc(-c2cccc(Cl)c2)no1
Yield: 83.3 %

Procedure:
0.57 g (2.54 mmol) (+)-(1R)-1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethanol, 0.64 g (2.68 mmol) 4-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine and 0.90 g (2.76 mmol) cesium carbonate were stirred at 65° C. for 6 h, followed by dilution with water. Extraction with EA, washing with aq. citric acid, drying over Na2SO4, followed by purification via chromatotron 2 mm (Hep/EA/MeOH=10/10/1) gave 0.81 g (83%) racemic 4-(5-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine. Prep. chiral separation on Chiralpak AD using 100% 2-propanol yielded 0.25 g of the title compound as the second eluting enantiomer. 1H NMR: 8.76 (d, 2 H), 8.07 (t, 1 H), 7.92-7.99 (m, 1 H), 7.60-7.68 (m, 2 H), 7.45-7.51 (m, 1 H), 7.41 (t, 1 H), 6.45 (q, 1 H), 3.66 (s, 3 H), 1.99 (d, 3 H)
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:62])(=O)=O)=CC=1>C(O)(=O)C.C1COCC1>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@:9]([F:62])([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reaction time: 2 h
Yield: 18.2 %

Procedure:
Erythromycin A (5 g, 6.813 mmole) was dissolved in glacial acetic acid (20 mL) at room temperature and stirred for 2 hours. N-fluorobenzenesulfonimide (2.2 g, 6.813 mmole) dissolved in THF (4 mL) was added and stirring continued for an additional 18 hours at 22° C. The reaction was worked up in the same manner as Example 1 to afford only 0.93 g (7% yield) of crude flurithromycin.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:29](=[O:32])[NH:30][CH3:31])[CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH2:13][CH:12]1[CH2:33][CH3:34])=[O:10])(C)(C)C.ClCCCl>Cl.O1CCOCC1>[ClH:42].[NH2:7][CH:8]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[C:29]([NH:30][CH3:31])=[O:32])[CH2:13][CH:12]1[CH2:33][CH3:34])=[O:10]
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)NC)CCN1C(=O)C(Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCCl
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)NC)CCN1C(=O)C(N)Cc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
{1-(4-Chlorobenzyl)-2-[2-ethyl-4-(1-methylcarbamo yl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl]-carbamic acid tert-butyl ester, 44, (1.0 g, 1.6 mmol) is dissolved in 4M HCl in dioxane (20 mL). The reaction mixture is stirred for 60 minutes then 1,2-dichloroethane (20 mL) is added. Solvent is removed in vacuo to afford 1 g (quantitative yield) of the desired product.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]2[CH:16]=[C:17]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[C:18]3[N:19]([C:21]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[O:25])=[CH:22][N:23]=3)[N:20]=2)[CH2:9]1)C1C=CC=CC=1>CO>[NH:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]2[CH:16]=[C:17]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[C:18]3[N:19]([C:21]([C:24]([NH:26][C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)=[O:25])=[CH:22][N:23]=3)[N:20]=2)[CH2:9]1
Reactant: O=C(Nc1ccncc1)c1cnc2c(Nc3ccccn3)cc(N[C@H]3CCCN(Cc4ccccc4)C3)nn12
Solvent: CO
Product: O=C(Nc1ccncc1)c1cnc2c(Nc3ccccn3)cc(N[C@H]3CCCNC3)nn12
Reaction time: 8 h
Yield: 20.8 %

Procedure:
A Parr bottle was charged with (S)-6-(1-benzylpiperidin-3-ylamino)-8-(pyridin-2-ylamino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 37B (0.055 g, 0.106 mmol), and dissolved in 30 mL of methanol with heating. The solution was purged with nitrogen and 200 mgs of 10% Pd/C was added. The resulting mixture was hydrogenated overnight on a Parr apparatus at 50 psi hydrogen. The mixture was filtered through celite and concentrated in vacuo. The resulting residue was dissolved in 2 mL methanol and 2 mL Solvent B (90% MeOH, 10% water, 0.1% TFA). One drop of TFA was added to the solution and the sample was split into 3 equal volumes and purified by reverse phase preparative HPLC on a Phenx Luna Axia Column 5u (21.2×100 mm) Solvent A (10% MeOH, 90% water, 0.1% TFA), Solvent B (90% MeOH, 10% water, 0.1% TFA) 20-100% solvent B gradient, 20 mL/min, 220 nM UV detection to provide (S)-6-(piperidin-3-ylamino)-8-(pyridin-2-ylamino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (0.0169 g, 0.022 mmol, 20.69% yield). 1H NMR (500 MHz, CD3OD) δ ppm 8.58 (2 H, m), 8.26 (1H, m), 8.19 (2H, m), 8.13 (1H, s), 8.02 (1H, s), 7.66 (1H, m), 7.08 (1H, m), 6.93 (1H, m), 4.18 (1H, m), 3.433 (1H, m), 3.27 (1H, m), 3.06 (2H, m), 2.14 (1H, m), 2.04 (1H, m), 1.86 (2H, m). LC/MS: HPLC Retention time: 2.15 min, MS: 430 (M+1) (Shimidazu LC, Waters Sunfire C-18 column (4.65×50 mm, 5 um, 0-100% Solvent B, 4 min gradient, 4 mL/min, 220 UV detection. Solvent A: 10% MeOH/90% Water/0.1% TFA, Solvent B 90% MeOH/10% Water/0.1% TFA.)
Reaction SMILES: [CH2:1]([NH:3][S:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)(=[O:6])=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]=O>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][S:4]([NH:3][CH2:1][CH3:2])(=[O:6])=[O:5])=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: CCNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=[Pd]
Solvent: CCO
Product: CCNS(=O)(=O)Cc1ccc(N)cc1
Yield: 52.4 %

Procedure:
A solution of N-ethyl-4-nitrobenzenemethanesulphonamide (4.35 g) in warm ethanol (125 ml) was added to 10% palladium oxide on carbon (0.75 g, 50% aqueous paste) prereduced in ethanol (25 ml) and hydrogenated at atmospheric pressure. Hydrogen uptake (1400 ml) ceased after 20 minutes. The suspension was filtered and the catalyst was washed with methanol (100 ml) and ethanol (100 ml). Evaporation of the combined filtrate and washings produced a grey solid (2.0 g) which was crystallised from isoprpopanol (120 ml) to present the title compound as cream micro needles (1.48 g), m.p. 161°-164°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[C:22]([F:31])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:33][OH:34].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[C:22]([F:31])[CH:21]=1)[CH2:9]/[C:10](=[N:33]\[OH:34])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: CCNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2Cl)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCNC(=O)c1ccc(C(C/C(=N\O)c2ccc(=O)n(C)c2)c2ccccc2Cl)cc1F

Procedure:
In analogy to example 151, step 3, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N-ethyl-2-fluorobenzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 4% of the corresponding Z isomer as a colorless waxy solid, MS (ESI+): m/z=456.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+:15]([CH:18]=[C:19](SC)[S:20][CH3:21])([O-:17])=[O:16]>ClC=C(Cl)Cl>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]([S:20][CH3:21])=[CH:18][N+:15]([O-:17])=[O:16])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: ClC=C(Cl)Cl
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]-thio]ethylamine (21.4 g; 0.1 mol) dissolved in trichloroethylene (200 ml) was added to a solution of 1-nitro-2,2-bis(methylthio)ethene (16.5 g; 0.1 mol), during about 30 minutes, under boiling. Boiling was continued for a further 90 minutes, then solvent was evaporated off under reduced pressure and the residue was chromatographed on silica gel, eluting with petroleum ether/dichloromethane. The product was already pure enough for the subsequent step (26.5 g; 79.9% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[CH:10](Cl)([CH2:12][CH3:13])[CH3:11].[K]>C1(C)C=CC=CC=1>[CH3:11][CH:10]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:12][CH3:13]
Reactant: Cc1ccc(CCl)cc1
Reactant: CCC(C)Cl
Agent: [K]
Solvent: Cc1ccccc1
Product: CCC(C)Cc1ccc(C)cc1
Temperature: 50 °C

Procedure:
0.05 Mol of p-methyl benzyl chloride and 0.05 mol of sec.-butyl chloride were dissolved in 100 ml. of toluene. The solution obtained was added dropwise to a toluene solution containing 0.1 mol of potassium metal with thorough stirring while obtaining the temperature of the solution at 20° to 30°C. After the addition, the temperature of the solution was raised to 50°C. with thorough stirring to complete the reaction. After the reaction, the product became black violet, and a white powder was precipitated. The resultant product containing the unreacted matter and by-products was distilled to afford 3-methyl-4-(p-tolyl) butane. The resulting product was used in the following Examples.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:20][C:21]#[N:22]>C(O)C>[CH3:4][C:2]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:20][C:21]#[N:22])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCNCC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A solution of (3-aminopropyl)carbamic acid 1,1-dimethylethyl ester (6.00 g, 34 mmol), prepared by the method of Saari et al., J. Med. Chem., 33, 97 (1990), in absolute ethanol (90 mL) was treated with sodium carbonate (3.96 g, 37 mmol) followed by a solution of bromoacetonitrile (2.6 mL, 37 mmol) in ethanol (30 mL) over 45 min. After stirring at room temperature overnight, the contents of the flask were filtered, preadsorbed onto silica gel, and purified by flash chromatography (7 cm diameter, elution with 2.5% methanol in dichloromethane) to afford [3-(cyanomethylamino)propyl]carbamic acid 1,1-dimethylethyl ester as a yellow oil (3.99 g, 55%); IR (neat, cm-1): 3330, 2240, 1700; MS (+CI): 214 (MH+, 20), 187 (76), 158 (100), 131 (44); 1H NMR (CDCl3, 400 MHz): δ 4.80 (br s, NH), 3.61 (s, 2H), 3.22 (q, J=6.5 Hz, 2H), 2.79 (t, J=6.5 Hz, 2H), 1.69 (p, J=6.5 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[Cl:9][C:10]1[C:11]([F:36])=[C:12]([CH:33]=[CH:34][CH:35]=1)[NH:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:31][CH3:32])=[C:21]([O:24][C@H:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[CH:22]=2)[N:17]=[CH:16][N:15]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:25]([O:24][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][C:20]=2[O:31][CH3:32])[N:17]=[CH:16][N:15]=[C:14]3[NH:13][C:12]2[CH:33]=[CH:34][CH:35]=[C:10]([Cl:9])[C:11]=2[F:36])[CH2:26]1)(=[O:3])[CH3:2]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCCNC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCCN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of acetic anhydride (42 μl) in methylene chloride (5 ml) was added dropwise to a stirred solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-piperidin-3-yloxy]quinazoline hydrochloride (0.175 g, 0.4 mmol; prepared as described in Example 49) and diisopropylethylamine (208 μl) in methylene chloride (20 ml) at 0° C. and the mixture was stirred for 2 hours and allowed to warm to room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution, dried (MgSO4), filtered and evaporated to give a white foam. This was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the desired product were combined and evaporated under vacuum to give the title product as a colourless foam (0.117 g, 66%); 1H NMR Spectrum: (DMSO d6 at 373K) 1.40-1.65 (m, 1H), 1.70-1.94 (m, 2H), 2.00 (s, 3H), 1.95-2.20 (m, 1H), 3.20-3.70 (m, 3H), 3.70-4.10 (m, 1H), 3.95 (s, 3H), 4.40-4.70 (m, 1H), 7.15-7.33 (m, 2H), 7.33-7.50 (m, 1H), 7.50-7.70 (m, 7.90 (s, 1H), 8.40 (s, 1H), 9.25 (s, 1H); Mass Spectrum: (M+H)+ 445.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].[F:25][C:26]([F:39])([F:38])[O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][S:34]([C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]([F:25])([F:38])[F:39])=[CH:33][CH:32]=3)(=[O:36])=[O:35])=[CH:8][CH:9]=2)[C:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:3]1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1C
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: Cn1c(C(=O)O)c(-c2ccccc2)c2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)ccc21

Procedure:
The title compound was prepared from ethyl 1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylate and 4-trifluoromethoxy-benzenesulfonyl chloride followed the procedures of Example 1 Step 2 & Step 3 as an off-white solid: 1H NMR (DMSO-d6) δ 3.95 (s, 3H), 6.98 (d, J=2.8 Hz, 1H, 7.11 (dd, J=8.8, 1.7 Hz, 1H, 7.21 (d, J=8.0 Hz, 2H, 7.30-7.45 (m, 3H, 7.50-7.60 (m, 3H, 7.74 (d, J=8.7 Hz, 2H, 9.98 (s, 1H, 13.00 (br s, 1H; MS (ESI) m/z 489[M-H]−; HRMS calcd for C23H18F3N2O5S: 491.0886; found (ESI+): 491.0878; Anal. calcd for C23H17F3N2O5S.0.4H2O: C, 55.51; H, 3.61; N, 5.63. Found: C, 55.61; H, 3.39; N, 5.77.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:4][N:3]=[CH:2]1.[N:14]1[C:22]2[C:17]3[C:18](=[CH:23][CH:24]=[CH:25][C:16]=3[C:15]=1S)[CH:19]=[CH:20][CH:21]=2>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][O:12][CH3:13])[C:15]2[C:16]3[CH:25]=[CH:24][CH:23]=[C:18]4[C:17]=3[C:22](=[CH:21][CH:20]=[CH:19]4)[N:14]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COCCNCCCn1ccnc1
Reactant: SC1=Nc2cccc3cccc1c23
Solvent: CCO
Product: COCCN(CCCn1ccnc1)C1=Nc2cccc3cccc1c23

Procedure:
The reaction of 2-methoxyacetyl chloride and 3-(1H-imidazol-1-yl)propanamine in the presence of triethylamine leads to the formation of N-(3-(1H-imidazol-1-yl)propyl)-2-methoxyacetamide, which by reduction with borane gives N-(3-(1H-imidazol-1-yl)propyl)-2-methoxyethylamine. The latter amine reacts with molar equivalents of benz(cd)indol-2-thiol and mercuric acetate in refluxing ethanol, under the conditions of Example 55 to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6](O)[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.BrC1C=C2C(C(=O)CCO2)=CC=1.[BH4-].[Na+].C1(P([N:41]=[N+:42]=[N-:43])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C(O)C.C1(C)C=CC=CC=1>[N:41]([CH:6]1[C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[O:9][CH2:8][CH2:7]1)=[N+:42]=[N-:43]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OC1CCOc2cc(Br)ccc21
Agent: O=C1CCOc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NC1CCOc2cc(Br)ccc21

Procedure:
In analogy to the procedures described fort he preparation of intermediates A-2 [B] and A-2 [C], (rac)-7-bromo-chroman-4-ol prepared from 7-bromo-chroman-4-one with sodium borohydride in ethanol at 60-70° C., was treated with diphenylphosphoryl azide, DBU in toluene to give (rac)-4-azido-7-bromo-chroman, which was subsequently reduced with triphenylphosphine in THF/water to yield the title compound as light yellow oil. MS: 227 (M+, 1Br).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:18]([N+:24]([O-:26])=[O:25])[C:19](=O)[N:20]=[CH:21][CH:22]=1>CN(C=O)C>[Cl:3][CH:19]1[CH:18]([N+:24]([O-:26])=[O:25])[C:17]([C:8]2[CH:9]=[CH:10][C:11]([O:13][CH:14]([F:16])[F:15])=[CH:12][C:7]=2[Cl:6])=[CH:22][CH:21]=[N:20]1
Reactant: O=C1N=CC=C(c2ccc(OC(F)F)cc2Cl)C1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])C1C(c2ccc(OC(F)F)cc2Cl)=CC=NC1Cl
Temperature: 25 °C
Yield: 96 %

Procedure:
To 10 mL of POCl3 was added 4-(2-chloro-4-difluoromethoxy-phenyl)3-nitro-3H-pyridin-2-one (0.20 g, 0.63 mmol), followed by the addition of DMF (1–2 mL) and the reaction refluxed overnight. The reaction mixture was cooled to room temperature and poured over ice/H2O (200 mL). The solution was extracted with EtOAc, washed H2O, brine, dried Na2SO4, filtered, and concentrated in vacuo to give 0.176 g (96%) of 2-chloro-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridine as brown viscous oil.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:53][CH2:54][CH2:55][C:56]#[N:57].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:56]([CH2:55][CH2:54][CH2:53][O:51][C:42]1[CH:41]=[C:40]([CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=1)[CH2:39][N:4]([CH:1]1[CH2:3][CH2:2]1)[C:5]([C@@H:7]1[C@@H:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=3[Cl:31])=[CH:17][CH:18]=2)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]1)=[O:6])#[N:57]
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCC#N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.2 M) was added 4-bromobutanenitrile (1.2 eq.) and cesium carbonate (1.3 eq.). The reaction was stirred at rt for 18 h, then heated to 65° C. for 4 h. After cooling to rt, the reaction was diluted with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NH4Cl solution, 5% aqueous HCl, saturated aqueous NaHCO3 solution, and brine. The organic solution was dried over MgSO4 and concentrated in vacuo to afford the title compound as an oil.
Reaction SMILES: [Cl:1][SiH:2]([CH3:4])[CH3:3].[C:5]([CH2:7][C:8]([O:10][CH2:11][C:12]#[CH:13])=[O:9])#[N:6]>C1(C)C=CC=CC=1.[Pt]>[C:5]([CH2:7][C:8]([O:10][CH2:11][CH:12]=[CH:13][Si:2]([Cl:1])([CH3:4])[CH3:3])=[O:9])#[N:6]
Reactant: C#CCOC(=O)CC#N
Reactant: C[SiH](C)Cl
Agent: [Pt]
Solvent: Cc1ccccc1
Product: C[Si](C)(Cl)C=CCOC(=O)CC#N
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Chlorodimethylsilane (29.59 g, 0.313 mol) was added dropwise at 80° C. to a solution of 35.0 g (0.284 mol) propargyl cyanoacetate, 0.1 g of a solution of 1,3 divinyl- 1,1,3,3-tetramethyldisiloxane/Pt(0) complex containing 5 wt % platinum in xylenes (Karstedt catalyst) and 50 ml toluene under a nitrogen blanket. The reaction was stirred 3 hours at 80° C. after the addition. An IR spectrum confirmed disappearance of Sill at 2160 cm-1. After removing low-boiling volatiles by rotary evaporation, the crude product was purified by vacuum distillation. Upon removal of a small forecut at 80° C. at 0.1 mm Hg, the product distilled at 100°-115° C. at 0.1 m Hg. Yield: 47.1 g (76%) of a clear, greenish tinged liquid. Its structure was confirmed to be cyanoacetoxypropenylchlorodimethylsilane by IR and proton NMR.
Reaction SMILES: [NH2:1][CH2:2][C:3]1C=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]1[C:13]([F:30])=[CH:14][C:15]3[C:25](=[O:26])[C:24]([C:27]([OH:29])=[O:28])=[CH:23][N:17]4[CH:18]([CH3:22])[CH2:19]OC=1[C:16]=34)[CH2:6]2.C(OC(C1C(=O)C2C(=NC(Cl)=C(F)C=2)[N:38](C2CC2)C=1)=O)C.NC1C=CC=C2C=1CNC2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([C:12]1[N:38]=[C:16]3[C:15]([C:25](=[O:26])[C:24]([C:27]([OH:29])=[O:28])=[CH:23][N:17]3[CH:18]3[CH2:22][CH2:19]3)=[CH:14][C:13]=1[F:30])[CH2:8]2
Reactant: CC1COc2c(N3Cc4ccc(CN)cc4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: Nc1cccc2c1CNC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Nc1cccc2c1CN(c1nc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2

Procedure:
310 mg of 1 cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 270 mg of 4-aminoisoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform were processed in a similar manner as in Example 107 to produce 88 mg of 7-(4-amino-2- isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[NH:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:23][C:24]([CH3:26])=O.[OH-].[K+].C(Br)C=C>O>[N+:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH2:26][CH:24]=[CH2:23])[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])cnc2n1-c1ccc2c(c1)OCO2
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: C=CCBr
Solvent: O
Product: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2ncc([N+](=O)[O-])cc21
Reaction time: 1.5 h

Procedure:
To a mixture of 1.1 g. (0.0036 mole) of the nitro product of Step C in 175 ml. of refluxing acetone, was added 400 mg. (0.0068 mole) of powdered potassium hydroxide. The mixture was stirred and heated for 15 minutes, 1 ml. of allyl bromide was added and reflux was continued for 1.5 hours. About 50 ml. of water was then added and the resulting solution was concentrated to about 75 ml. The product, 1.2 g. crystallized and melted at 152°-153° C.