Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]([C:14]1[N:15]=[CH:16][NH:17][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][C:23]=1[Cl:35])=[O:20])=[O:13].C=O.[CH3:38]CN(C(C)C)C(C)C.ClCCl>C1COCC1>[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]([C:14]1[N:15]=[CH:16][NH:17][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:38])[CH2:31][CH2:30]2)=[CH:24][C:23]=1[Cl:35])=[O:20])=[O:13]
Reactant: O=C(Nc1nc2ccccc2[nH]1)c1nc[nH]c1C(=O)Nc1ccc(OC2CCNCC2)cc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CCC(Oc2ccc(NC(=O)c3[nH]cnc3C(=O)Nc3nc4ccccc4[nH]3)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.2 %

Procedure:
A flask was charged with N4-(1H-benzo[d]imidazol-2-yl)-N5-(2-chloro-4-(piperidin-4-yloxy)phenyl)-1H-imidazole-4,5-dicarboxamide hydrochloride (115 mg, 0.22 mmol), formaldehyde, 30% wt (0.030 mL, 4 mmol), DIEA (0.080 mL, 0.5 mmol), dichloromethane (20 mL) and THF (20 mL), and the reaction mixture was stirred for 15 hours at room temperature. The reaction mixture was filtered, and the precipitate was discarded. The product was purified by reverse phase HPLC using ammonium acetate and acetonitrile as eluent to afford 60 mg (55% yield) of N4-1H-benzimidazol-2-yl-N5-(2-chloro-4-{[1-(methyl)piperidin-4-yl]oxy}phenyl)-1H-imidazole-4,5-dicarboxamide. 1H-NMR (400 MHz, DMSO-d6): δ 8.06 (s, 1H), 7.91 (d, 9 Hz, 1H), 7.46 (s, br, 2H), 7.21 (d, 3 Hz, 1H), 7.12-7.03 (m, 3H), 4.44-4.42 (m, 1H), 2.61-2.50 (m, 2H), 2.20-2.17 (m, 5H), 1.96-1.89 (m, 2H), 1.67-1.61 (m, 2H). MS (EI): 494 (MH+).
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].OCC[C:14]#[N:15]>C(O)C>[C:1]([CH2:5][C:6]([O:8][CH2:9][CH2:10][C:14]#[N:15])=[O:7])(=[O:4])[CH2:2][CH3:3]
Reactant: N#CCCO
Reactant: CCOC(=O)CC(=O)CC
Solvent: CCO
Product: CCC(=O)CC(=O)OCCC#N
Temperature: 202.5 °C
Yield: 73.5 %

Procedure:
A mixture of ethyl propionylacetate (25 g, 0.173 mol) and 3-hydroxypropionitrile (18.48 g, 0.26 mol) was stirred and heated at 200-205° C. for 2 hours and the ethanol formed was removed by distillation. The residue was subjected to high vacuum distillation and the fraction distilling at 120-125° C. at 0.4 mm Hg was collected to get 2-cyanoethyl propionylacetate (21.5 g, 73.4%). A mixture of 4-nitrobenzaldehyde (14.46 g, 0.957 mol), 2-cyanoethyl propionylacetate (17.0 g, 0.1005 mol), piperidine (0.41 g, 476 mL, 4.8 mmol), and acetic acid (0.288 g, 274 mL, 4.8 mmol) in 2-propanol (400 mL) was stirred at room temperature for 24 h. The white solid, 2-cyanoethyl 3-{(4-nitrophenyl)methylene}-4-oxopentanoate, was filtered, washed with 2-propanol (2×50 mL) dried and used without further purification (Yield: 28.34 g, 97%); m.p. 98-100° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][O:9][CH2:10][CH2:11][OH:12])[CH:2]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCNCC1)=O)=NC(N1CCNCC1)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][O:9][CH2:10][CH2:11][O:12][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:44])=[CH:16][CH:15]=2)[CH:2]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCON=Cc1cccnc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCNCC1)N1CCNCC1
Product: O=C1NC(=O)C(Cc2ccc(OCCON=Cc3cccnc3)cc2)S1
Yield: 85.9 %

Procedure:
Following a procedure similar to that described in Example 3(a), but using 0.90 g of 2-(3-pyridylmethyleneaminooxy)ethanol (prepared as described in Preparation 5), 2.00 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 1.32 ml of tributylphosphine and 1.23 g of 1,1'-(azodicarbonyl)dipiperazine, 1.37 g of the title compound were obtained as a crystalline powder, melting at 155°-157° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]([C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][CH:29]=2)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][S-:32].[Na+]>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]([C:24]2[CH:25]=[N:26][C:27]([S:32][CH3:31])=[CH:28][CH:29]=2)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccc(Cl)nc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Temperature: 70 °C

Procedure:
4-tert-Butyl-N-[4-chloro-2-(6-chloro-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (231 mg, 0.5 mmol) was dissolved in dry THF (5 mL) and treated with sodium thiomethoxide (175 mg, 2.5 mmol) and the mixture was heated at 70° C. for 4 h. The solvent was evaporated and the residue suspended in water (5 mL) and the product was precipitated by the drop wise addition of 3M HCl and purified by HPLC. 1H-NMR (400 MHz, CDCl3): δ 1.19 (s, 9H), 2.60 (s, 3H), 7.21-7.28 (m, 3H), 7.31 (m, 1H), 7.50-7.54 (m, 3H), 7.65 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.78 (d, 1H, J=8.8 Hz), 8.19 (m, 1H), 9.62 (s, 1H). MS: m/z 476.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10].[O:21]1C[CH2:24][CH2:23][CH2:22]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(O)CCO.C(P(CCCC)CCCC)CCC>C(OCC)C>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:24][CH2:23][CH2:22][OH:21])(=[O:10])=[O:11]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2c(C)nn(C)c2Cl)c1
Reactant: C1CCOC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: OCCCO
Solvent: CCOCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2c(C)nn(C)c2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a solution of 318 mg (0.951 mmol) of 3-(5-chloro-1,3-dimethyl-pyrazole-4-sulfonyloxy)-5-methylphenol, as prepared in the preceding step, in 5 mL of anhydrous tetrahydrofuran containing 360 mg (1.42 mmol) of 1,1'-(azodicarbonyl)dipiperidine and 150 μL (2.07 mmol) of 1,3-propanediol was added slowly 350 μL (1.41 mmol) of tri-n-butylphosphine. The reaction mixture was stirred for 1 h at ambient temperature, diluted with diethyl ether, and filtered. The filtrate was concentrated and purified by flash chromatography (ethyl acetate/dichloromethane (2:1)) to give 227 mg (64% yield) of the title compound as an oil. 1H-NMR (300 MHz, CDCl3) δ 6.64-6.65 (m, 1H), 6.52-6.54 (m, 1H), 6.46-6.47 (t, 1H), 4.06 (t, 2H, J=6 Hz), 3.83 (t, 2H, J=6 Hz), 3.82 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H), 2.00 (pentet, 2H, J=6 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C15H19ClN2O5S: 375.1 (M+H), 397.1 (M+Na). Found: 374.9, 397.1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6](=[S:28])[NH2:8])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16]
Reactant: NC(=O)c1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: NC(=S)c1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 4-chloro-3,5-bis(trifluoromethyl)benzamide (1.2 g) in toluene (20 mL) was added Lawesson's reagent (3.32 g, 2.0 eq.). The reaction mixture was stirred at 90° C. for 8 h before being cooled to room temperature and filtered. The filtrate was poured into water and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (3×50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford 2 g of crude compound. The crude compound was purified by combi-flash chromatography (eluting with 7% EtOAc:hexane) to afford 1.0 g of desired compound (yield: 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH:11][C:12]([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CNC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1ccc(Cl)nc1)C(C)(C)C
Temperature: 80 °C
Yield: 56.1 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (570 mg, 3.52 mmole) in 7 mL of dry acetonitrile is 608 mg (7.04 mmol) of N-methyl-t-butylamine followed by 486 mg (3.52 mmol) of potassium carbonate. The reaction is heated at 80° C. for 12 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 420 mg (56% yield) of N-methyl-tert-Butyl-(6-chloro-pyridin-3-ylmethyl)-amine. Diagnostic 1H NMR (400 MHz, CDCl3) 1.14 (s, 9H), 2.06 (s, 3H), 3.48 (s, 2H), 7.26 (d, 1H, J=6.2 Hz), 7.68 (d, 1 h, J=6.6 Hz), 8.28 (d, 1H, J=2.5 Hz); MS 213.3 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH3:22])[CH2:17]1>>[CH3:22][N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([CH2:15][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:17]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: CN1CCCC(CCl)C1
Product: CN1CCCC(Cn2cnc(-c3cc(C#N)ccn3)c2)C1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 3-chloromethyl-methyl piperidine according to the procedure for the preparation of Example 43, part A (heating to 120°). [M+H] Calc'd for C16H19N5, 282. Found, 282.
Reaction SMILES: [C:1](=[N:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH3:15])([CH3:3])[CH3:2].Cl[O:18][N:19]=[CH:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1.C(Cl)(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>O>[CH3:28][C:23]1[CH:22]=[C:21]([C:20]2[N:4]([NH:5][C:6](=[O:16])[C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=3[CH3:15])[C:1]([CH3:3])([CH3:2])[O:18][N:19]=2)[CH:26]=[C:25]([CH3:27])[CH:24]=1
Reactant: COc1cccc(C(=O)NN=C(C)C)c1C
Reactant: Cc1cc(C)cc(C=NOCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cccc(C(=O)NN2C(c3cc(C)cc(C)c3)=NOC2(C)C)c1C
Reaction time: 24 h
Yield: 37.5 %

Procedure:
3-Methoxy-2-methyl-benzoic acid isopropylidene-hydrazide (1.71 g, 7.77 mmol) and 3,5-dimethyl-benzaldehyde chlorooxime (2.29 g, 12.4 mmol), both as CHCl3 solutions (total volume 40 mL), were added to a 250 mL round bottom flask equipped with a magnetic stirrer. An aqueous K2CO3 solution (5 g in 30 mL) was added, the vessel was placed in a 50° C. water bath, and the reaction was stirred vigorously for 24 hours. The reaction was monitored by 1H NMR. Chloroform (100 μl) and water (50 mL) were added, and the mixture was shaken in a separatory funnel. The organic phase was separated, dried, and the solvent was removed in vacuo. Column chromatography on silica gel using a gradient of 10-30% ethyl acetate in hexane yielded 1.07 g of N-[3-(3,5-dimethyl-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-3-methoxy-2-methyl-benzamide (32%). An analytical sample was obtained by crystallization from CH2Cl2/hexane under refrigeration. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.4 (s, 2H), 7.1 (t, 1H), 7.07 (s, 1H), 6.85 (d, 1H), 6.65 (d, 1H), 3.78 (s, 3H), 2.30 (s, 6H), 2.07 (s, 3H), 1.65 (s, 6H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)=[O:39]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)=[O:39])=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: NCC(=O)Nc1ccccn1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCC(=O)Nc2ccccn2)cc1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
4-geranyloxybenzoic acid(1.81 g) was dissolved in chloroform(40 ml) and triethylamine(1.84 ml), and then diphenylphosphinic chloride(1.26 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 2-(aminoacetylamino)pyridine(1.00 g) added thereto, was stirred for 2 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.84 g of the aimed compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]([F:28])[F:27])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.C[O-].[Na+].CO.[C:34](OCC)(=[O:36])C>CO.CCCCCC>[F:28][CH:26]([F:27])[CH2:25][O:24][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([O:36][CH3:34])[CH:3]=1)[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:21])[F:23])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: O=C1c2c(Cl)cc(OCC(F)F)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: COc1cc(OCC(F)F)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 100 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A mixture of 7-chloro-5-(2,2-Difluoro-ethoxy)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.057 g, 0.14 mmol), and 30% sodium methoxide-methanol (0.12 mL) in methanol (4 mL) was stirred at 100° C. for 1 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-(2,2-Difluoro-ethoxy)-7-methoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.030 g, 51%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.96 (s, 3H), 4.22 (m, 4H), 4.73 (s, 2H), 5.94-6.32 (m, 1H), 6.45 (d, 2H), 7.17 (d, 2H), 7.35 (d, 2H). GC-MS: m/z 417 (M)+, 399 (M−18)+.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C1(C)C=CC=CC=1>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:7]([CH2:6][CH2:5][CH2:4][NH2:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Brc1ccccn1
Reactant: NCCCNc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NCCCN(c1ccccn1)c1ccccn1
Temperature: 90 °C
Yield: 38.8 %

Procedure:
A mixture of sodium hydride (0.92 g) and 2-(3aminopropylamino)pyridine (5 g) in toluene (100 ml) was heated under nitrogen to 90° C. until initial reaction ceased, and then under reflux for 2 hr. After cooling, 2-bromopyridine (5.53 g) was added and the mixture heated under reflux for 10 hr. The mixture was poured on to ice/water (100 ml), extracted at pH 14 with chloroform, and these extracts washed with 2N HCl. The acidic aqueous solution was adjusted to pH 9 and extracted with ether and the extracts were discarded. The aqueous phase was adjusted to pH 14 and extracted with ether and the latter ethereal extracts were washed with water, dried (K2CO3) and concentrated to give 3-(N,N-dipyrid-2-ylamino)propylamine (2.93 g, 39%) as an oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12]([CH3:17])=[N:13][NH:14][C:15]=1[CH3:16].[H-].[Na+].[CH2:26](I)[CH3:27]>CN(C)C=O>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:15]([CH3:16])=[N:14][N:13]([CH2:26][CH3:27])[C:12]=1[CH3:17]
Reactant: CCI
Reactant: COc1ccc(OCCCCCCc2c(C)n[nH]c2C)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc(C)c(CCCCCCOc2ccc(OC)cc2Cl)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To a solution of 6.8 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-dimethyl-1H-pyrazole (Example 7) in 100 ml of dimethylformamide was added 1.13 g of sodium hydride. The mixture was stirred one hour at room temperature, and then 3.8 g of ethyl iodide was added and the reaction mixture stirred for six hours longer. The reaction mixture was concentrated to remove the solvent, the residue partitioned between dilute hydrochloric acid and methylene dichloride, and the organic layer washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica with hexane:ethyl acetate:acetonitrile 4:2:1 to give 2.6 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-1-ethyl-3,5-dimethyl-1H-pyrazole as a pale yellow oil; MIC=0.7-1.5 microg/ml (herpes 1 and 2).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:20]=[C:21](CCN)[CH:22]=[CH:23][CH:24]=1>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[C:23]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH:22]=[CH:21][CH:20]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Solvent: CN(C)C=O
Product: S=C(NCCc1cccc(Cl)c1)Nc1nc2ccccc2s1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A solution of 1-[(2-benzothiazolyl)-thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(3-chlorophenyl)ethylamine (0.63 g, 4 mmol) in dimethylformamide (15 mL) was stirred at 100° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.88 g (63%) of the title product:
Reaction SMILES: [NH2:1][C:2]1[C:11]([I:12])=[C:10]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][C:14]=2[CH3:19])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:20].S(Cl)([Cl:24])(=O)=O>C(O)(=O)C>[NH2:1][C:2]1[C:11]([I:12])=[C:10]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][C:14]=2[CH3:19])[C:9]([Cl:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:20]
Reactant: Cc1nnn(C)c1-c1cc2c(c(N)c1I)CCNC2=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: Cc1nnn(C)c1-c1c(Cl)c2c(c(N)c1I)CCNC2=O
Reaction time: 2 h
Yield: 202.6 %

Procedure:
Two batches of 5-amino-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-iodo-3,4-dihydroisoquinolin-1(2H)-one (293e, 2.5 g/6.5 mmol each batch, 5.0 g/13 mmol total) in glacial acetic acid (100 mL each batch) were treated with sulfuryl chloride (1 g, 75 mmol each batch), added dropwise at 20-25° C. The mixtures were stirred for 2 hours, then combined and concentrated under vacuum to remove volatiles. The residue was purified by silica gel chromatography (10:1 dichloromethane/methanol) to give 5-amino-8-chloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-iodo-3,4-dihydroisoquinolin-1(2H)-one (293f, 5.5 g, 90% purity, 90% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.Cl.Cl[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([NH:34][CH3:35])=[O:33])[CH:27]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:22][CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32]([NH:34][CH3:35])=[O:33])[CH:27]=2)[C:5]([C:20]#[N:21])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CNC(=O)c1cc(CCl)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc(CSc2nc(N)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.16 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-sulfanylpyridine-3,5-dicarbonitrile (Example 10A), 38.9 mg (0.18 mmol) of 4-(chloromethyl)-N-methylpyridine-2-carboxamide hydrochloride (Example 41A) and 53.8 mg (0.64 mmol) of sodium bicarbonate were dissolved in 1 ml of DMF and the mixture was stirred at RT overnight. 30 ml of water were added to the reaction mixture, and the precipitate was filtered off. The precipitate was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH:6]([CH:8]=O)[CH2:5][CH2:4][O:3]1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH:6](/[CH:8]=[CH:11]/[C:12]([OH:14])=[O:13])[CH2:5][CH2:4][O:3]1
Reactant: C[C@H]1CC(C=O)CCO1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C[C@H]1CC(/C=C/C(=O)O)CCO1
Temperature: 100 °C

Procedure:
A mixture of (2S)-2-methyltetrahydro-2H-pyran-4-carboxaldehyde (4.0), malonic acid (6.495 g) and piperidine (0.1 ml) in pyridine (10 ml) was heated to 100° C. for 4 hours. The reaction mixture was concentrated and partitioned between ethyl acetate (100 ml) and 1N HCl. The organic layer was dried, evaporated and recrystallised form toluene to give the title compound. Yield 2.48 g. NMR CDCl3 1.2 (m, 4H), 1.5 (m, 1H), 1.7 (m, 2H), 2.45 (m, 1H), 3.5 (m, 2H), 4.05 (m, 1H), 5.8 (d, 1H), 7.0 (dd, 1H).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:33]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (20 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (2.0 g) and triethylamine (2.0 ml), and 3-chlorobenzoyl chloride (2.0 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>O1CCCC1>[C:19]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[CH:10]=1)(=[O:21])[CH3:20]
Reactant: Cc1nc2ccc(O)cc2o1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2nc(C)oc2c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A slurry of 2-methyl-1,3-benzoxazol-6-ol (7.1 g, 47.8 mmol) in tetrahydrofuran was cooled to 10° C. and triethylamine (5.8 mL, 81.3 mmol) was added in one portion, followed by the addition of acetyl chloride (11.3 mL, 81.6 mmol) in small portions. After stirring at room temperature over night the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed twice with water and concentrated to give the titled compound (8.2 g, 90%) as a beige solid.