Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].C(O[N:28]=O)CC(C)C.C(N(CC)CC)C.[C:37]([O:41][C:42]([O:44]C(OC(C)(C)C)=O)=O)([CH3:40])([CH3:39])[CH3:38].CN(C1C=CC=CN=1)C>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][CH:8]=1)[N:6]([C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:44])[N:28]=[CH:9]2
Reactant: CC(C)CCON=O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1cc(I)ccc1N
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccn1
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1ncc2cc(I)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice bath cooled solution of 4-iodo-2-methylaniline (20 g, 83.24 mmol) in chloroform (250 mL) was added dropwise with an addition funnel a solution of acetic anhydride (21.2 g, 208.11 mmol) in chloroform (50 mL). Upon completion of the addition, the mixture was stirred at room temperature for 1 hour. Potassium acetate (2.5 g, 24.97 mmol) and isoamylnitrite (22.3 mL, 166.48 mmol) were added, and the mixture was heated at 70° C. for 20 hour. The mixture was then cooled and quenched with saturated aqueous NaHCO3 to pH 7. The mixture was extracted with dichloromethane, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude solid was washed with methanol, dissolved in tetrahydrofuran (200 mL) and treated with a warm solution of KOH (60 g) in water (200 mL). The mixture was stirred for 15 minutes and was treated with 6 N HCl to pH 1. The layers were separated, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The crude material was dissolved in dichloromethane (500 mL) and triethylamine (23 mL, 166.48 mmol), and di-tert-butyldicarbonate (23.6 g, 108.2 mmol), and a catalytic amount of dimethylaminopyridine (˜5 mg) were added. The mixture was stirred at room temperature for 2 hours, quenched with water, extracted with dichloromethane, and dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure to afford the title compound. MS (ESI+) m/z 344.9 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.[C:23](=O)([O-])[O-:24].[K+].[K+].C(OCC)(=O)C>C(O)=O>[CH:23]([NH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)=[O:24]
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(CN)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(CNC=O)nc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a stirred solution of methyl 3-(6-(aminomethyl)pyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (0.24 g, 0.80 mmol) in formic acid (3 mL) was added potassium carbonate (0.2 g) portionwise. The reaction mixture was stirred at 90° C. overnight under argon and then concentrated. The residue was made basic with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with dichloromethane (3×20 mL). The combined dichloromethane extracts were dried (Na2SO4) and concentrated. Silica gel flash chromatography (20-100% ethyl acetate in hexanes) gave methyl 3-(6-(formamidomethyl)pyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (0.19 g, 0.58 mmol, 73% yield) as a solid. MS found: (M+H)+=327.35.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:15]=[C:14]([CH2:16][C:17](=O)[CH3:18])[CH:13]=[CH:12][CH:11]=3)=[CH:6][C:5]=12.Cl.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[BH3-]C#N.[Na+].C1COCC1>CO>[N:21]1([CH:17]([CH3:18])[CH2:16][C:14]2[N:15]=[C:10]([C:7]3[CH:8]=[CH:9][N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: CC(=O)Cc1cccc(-c2ccn3ccnc3c2)n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(Cc1cccc(-c2ccn3ccnc3c2)n1)N1CCOCC1
Reaction time: 24 h
Yield: 71.9 %

Procedure:
In a well mixed round bottomed flask under N2 charge 1-(6-Imidazo[1,2-a]pyridin-7-yl-pyridin-2-yl)-propan-2-one (1.8 g, 7.2 mmol), morpholine mono HCl salt (16 g, 129 mmol), 3 Å molecular sieves (powdered, vacuum oven dried 110° C. for 24 hours., 3.6 g), methanol (200 mL), and 1 M NaCNBH3 solution in THF (12.9 mL, 12.9 mmol). Stir for 24 hours. at room temp. Filter through Celite® strip off solvents under reduced pressure. Take up into DCM and adjust pH to 10 with 5N NaOH and extract with DCM (5×). Concentrate DCM under reduced pressure and chromatograph on (120 g ISCO®) SiO2 eluting with a slow gradient of 0% to 10% 2 M NH3 in MeOH with the balance DCM. Strip off solvents under reduced pressure to give clear oil 1.67 g (72%) MS(ES), m/z 323 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1>C(#N)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:15]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: Nc1ccc(F)cn1
Solvent: CC#N
Product: Oc1ccc(-c2cn3cc(F)ccc3n2)cc1
Temperature: 110 °C
Yield: 66 %

Procedure:
439 mg (corresponding to 2.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 224 mg (corresponding to 2.0 mmol) of 2-amino-5-fluoropyridine were dissolved in 20 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 8 mL of water and 8 mL of methanol. Then, about 10 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 302 mg (corresponding to 1.32 mmol) of 6-fluoro-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine (FIG. 7, Step 2).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[O:15]=[C:16]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39]>C(#N)C.C(OCC)(=O)C>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:27][CH2:26][C:25]4([C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][CH2:17][C:16]4=[O:15])[CH2:30][CH2:29]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: O=C1CCc2ccccc2C12CCNCC2
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1CCc2ccccc2C12CCN(CCCOc1cccc3[nH]ccc13)CC2

Procedure:
A solution of 1-chloro-3-(1H-indole-4-oxy)propane, 3,4-dihydro-2-oxospiro[naphthalene-1(2H),4'- piperidine] and 3 equivalents of potassium carbonate in acetonitrile was heated at reflux for 12 h. The mixture was cooled, diluted with ethyl acetate, and the organic layer was separated and washed with brine. The crude residue was purified by silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent). The resulting free base was dissolved in ethyl acetate and precipitated with one equivalent of oxalic acid in ethyl acetate, to give the title compound in 37% overall yield. FDMS m/e=388 (M+ of free base).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:20]([NH2:23])[C:21]#[CH:22].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[S:15][C:14]([S:16]([NH:23][CH2:20][C:21]#[CH:22])(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: C#CCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNS(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared in Step II (200 mg; 0.59 mmol; 1 eq) is dissolved in anhydrous DCM (10 ml). The reaction is put under nitrogen. Prop-2-ynylamine (0.08 ml; 1.19 mmol; 2 eq), diisopropylethylamine (0.61 ml; 3.56 mmol; 6 eq) are added successively and the reaction mixture is stirred for 3 hours at room temperature. Solvents are evaporated and the resulting crude product is purified by preparative HPLC. Compound (1) is isolated as a beige powder (25 mg; 12%).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][CH:12]([N:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:24])[C:18]=3[C:17]3=[N:25][O:26][C:27]([CH3:28])=[C:16]3[C:15]2=[O:29])[CH:11]=[CH:10]1)(C(C)(C)C)(C)C.N1C=CC=CC=1.N1C=CC=CC=1.C1COCC1.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C1COCC1>[Cl:24][C:19]1[C:18]2[C:17]3[C:16](=[C:27]([CH3:28])[O:26][N:25]=3)[C:15](=[O:29])[N:14]([CH:12]3[CH2:13][CH:9]([OH:8])[CH:10]=[CH:11]3)[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1onc2c1c(=O)n(C1C=CC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1onc2c1c(=O)n(C1C=CC(O)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.9 %

Procedure:
To a stirred solution of 5-[4-(t-butyl-dimethylsilanyl-oxy)cyclopent-2-en-1-yl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (3.4 g, 7.9 mmol) in THF (60 mL) was added HF pyridine/pyridine/THF (1:2:8; 50 mL). The mixture was stirred at r.t. for 6 hours. Solid NaHCO3 (6 g) and ethyl acetate (60 mL) were added. Aqueous NaHCO3 was then added until the reaction was quenched The layers were separated and the organic fraction was washed (brine, water, aqueous CuSO4), dried (Na2SO4), filtered and concentrated. Column chromatography (silica gel, hexanes/ethyl acetate, gradient) gave desired product (2.2 g, 88%). 1H NMR (CDCl3, 400 MHz) δ; 7.59 (d, 1H); 7.37 (t, 1H); 7.30 (d, 1H); 6.15 (m, 1H); 5.91 (m, 1H); 5.78 (broad, 1H); 4.82 (broad, 1H); 2.81 (s, 3H); 2.82 (m, 1H); 2.18 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:16][O:17][NH:18][CH3:19]>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[CH3:16][O:17][N:18]([CH3:19])[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1ccc[nH]1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc[nH]1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
Method 7 General Experimental: Pyrrole-2-carboxylic acid (27.0 mmol, 3.00 g) in CH2Cl2 (100 ml) was treated with oxalyl chloride (54.0 mmol, 4.70 ml) and DMF (1 drop), then heated to reflux for 1 h, then concentrated under reduced pressure. The residue was diluted with CH2Cl2 (100 ml) and pyridine (6.50 ml), and treated with O,N-dimethyl-hydroxylamine hydrochloride (27.0 mmol, 2.65 g), then held at room temperature overnight. The resulting solution was diluted with ethyl acetate (250 ml), washed with 10% aqueous citric acid (2×30 ml), saturated aqueous sodium bicarbonate (2×30 ml), then brine (2×30 ml). The organics were concentrated under reduced pressure. Purification of the residue by silica gel chromatography provided 3.42 g (82%) of 1H-pyrrole-2-carboxylic acid methoxy-methyl amide. 1H NMR (CDCl3) δ 6.90-6.80 (1H, m), 6.79-6.60 (1H, m), 6.18 (1H, dd, J=3.7, 1.3), 3.81 (3H, s), 3.01 (3H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[NH:19])([O-:18])=[O:17]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCNCc1ncccn1
Product: N=C(NCCNCc1ncccn1)N[N+](=O)[O-]

Procedure:
Reaction of N-(2-pyrimidylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(2-pyrimidylmethylamino)-ethyl]guanidine. Similarly, from the same starting material, according to the procedure of Example 2(iii), there is produced N-methyl-N'-nitro-N"-[2-(2-pyrimidylmethylamino)ethyl]guanidine.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([S:30][C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)C.C(=O)(O)[O-].[Na+].[S:40]([O-:44])([O-])(=[O:42])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:40]([C:15]1[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([S:30][C:31]([F:33])([F:34])[F:32])=[CH:26][N:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:44])=[O:42])[CH3:3]
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1cccnc1C(=O)Nc1ccc(SC(F)(F)F)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cccnc1C(=O)Nc1ccc(SC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.24 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 0.18 g of 3-ethylsulfanyl-N-(5-trifluoromethylsulfanylpyridin-2-yl)picolinamide (Compound of Present Invention 48) and 5 mL of chloroform under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.17 g of 3-ethylsulfonyl-N-(5-trifluoromethylsulfanylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 49).
Reaction SMILES: [CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=2)[CH2:15][C@H:14]1[C:26]([O:28][CH3:29])=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:30][C:31]([F:37])([F:36])[CH:32]([OH:35])[CH:33]=[CH2:34].[CH2:38]([N:50]([CH2:68][CH2:69]CC(OCC)=O)[CH2:51][CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57](/[CH:60]=[CH:61]/[CH:62]([OH:67])[C:63]([F:66])([F:65])[F:64])=[CH:56][CH:55]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>>[CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:34]=[CH:33]/[CH:32]([OH:35])[C:31]([F:37])([F:36])[F:30])=[CH:21][CH:20]=2)[CH2:15][C@H:14]1[C:26]([O:28][CH3:29])=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:38]([N:50]1[CH2:51][C@@H:52]([O:53][C:54]2[CH:55]=[CH:56][C:57]([CH2:60][CH2:61][C:62](=[O:67])[C:63]([F:64])([F:66])[F:65])=[CH:58][CH:59]=2)[CH2:69][C@H:68]1[C:26]([O:28][CH3:29])=[O:27])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(/C=C/C(O)C(F)(F)F)cc1
Reactant: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(I)cc2)C[C@H]1C(=O)OC
Reactant: C=CC(O)C(F)(F)F
Product: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(/C=C/C(O)C(F)(F)F)cc2)C[C@H]1C(=O)OC
Product: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(CCC(=O)C(F)(F)F)cc2)C[C@H]1C(=O)OC
Yield: 9 %
Yield: 72 %

Procedure:
(2S, 4S)-1-N-Dodecyl-4-(4-iodophenoxy)pyrrolidine-2-carboxylic acid, methyl ester (800 mg, 1.55 mmol) and 4,4,4-trifluorobut-1-en-3-ol (complex with 1 tetrahydrofuran, 620 mg, 3.1 mmol) were reacted by the general procedure as described in the preparation of 4-[N-dodecyl-N-2-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-1-en-1-yl]phenoxy]ethylamino]butanoic acid, ethyl ester and afforded the title compound (575 mg, 72%) as a colorless oil [[a]D=−28.7° (c 0.8, CHCl3)] and (2S, 4S)-1-N-dodecyl-4-[4-(3-oxo-4,4,4-trifluorobut-1-yl)phenoxy]pyrrolidine-2-carboxylic acid, methyl ester (68 mg, 9%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]#[N:11].[S:12]([OH:16])(=[O:15])(=[O:14])[CH3:13].[CH2:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])[CH3:18].ClC1C=CC=CC=1>>[NH2:9][C:10]([NH2:11])=[NH:22].[S:12]([OH:16])(=[O:15])(=[O:14])[CH3:13].[CH2:17]([C:19]1[CH:20]=[C:21]([NH:22][C:10]([NH:9][C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])=[NH:11])[CH:23]=[CH:24][CH:25]=1)[CH3:18]
Reactant: N#CNc1cc(Cl)ccc1Cl
Reactant: CCc1cccc(N)c1
Agent: CS(=O)(=O)O
Solvent: Clc1ccccc1
Product: CCc1cccc(NC(=N)Nc2cc(Cl)ccc2Cl)c1
Product: N=C(N)N

Procedure:
A mixture of 2,5-dichlorophenylcyanamide (1.02 g, 5.5 mmol), 3-ethylaniline mesylate (1.1 g, 5 mmol), and chlorobenzene (15 mL) were combined in a dry round bottom flask equipped with a water cooled condenser under nitrogen and placed in a preheated oil bath (150-160° C.). The reaction mixture was heated for 2 hours. After cooling, the crude reaction product was purified by crystallization from chlorobenzene/diethylether. The resulting crystals were collected by filtration, washed with diethylether, and dried in a vacuum oven (40° C., hours) to yield the title compound, N-(3-ethylphenyl)-N'-(2,5-dichlorophenyl)guanidine mesylate, as a white solid (1.5 g, 75% yield).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].N[C:14]1[CH:25]=[CH:24]C=C[C:15]=1[CH2:16]C1NC=CN=1>C(Cl)Cl>[N:10]1[CH:11]=[CH:12][N:8]2[C:9]=1[CH2:24][C:25]1[CH:14]=[CH:15][CH:16]=[CH:6][C:7]=1[NH:3][C:1]2=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1Cc1ncc[nH]1
Solvent: ClCCl
Product: O=C1Nc2ccccc2Cc2nccn21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Alternately, 0.75 g of 1,1'-carbonyldiimidazole was added at once to a suspension of 0.79 g of 2-(2-aminobenzyl)imidazole in 38 ml of methylene chloride and the mixture was stirred at room temperature overnight. The resulting precipitate was collected and recrystallized from methylene chloride to give the crude 11H-imidazo[1,2-c][1,3]benzodiazepin-5(6H)-one, m.p. 238°-40°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:3]([O:8][CH:7]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[CH2:2][CH2:9][CH3:6]
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(OCCCC)c1cc(F)ccc1[N+](=O)[O-]
Yield: 189.2 %

Procedure:
Dissolve 5-fluoro-2-nitrobenzaldehyde (9.43 g, 55.81 mmol), 1-butanol (12.41 g, 167.4 mmol) and 4toluenesulfonic acid monohydrate (0.9 g, 4.7 mmol) in toluene (84 mL). Heat the reaction mixture to reflux, and remove the water using a Dean-Stark apparatus. Continue to heat the reaction mixture for 3 hours. Add water and extract the aqueous layer with ethyl acetate. Combine the organic layers and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure and purify by flash column chromatography (1% v/v triethylamine buffered silica gel, 5% ethyl acetate/hexane) to obtain 15.8 g (95%) of the title compound as colorless oil.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[C:13]([NH:22][S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)([O-])=O.[Cl-].[Na+]>O.O1CCCC1>[NH2:9][C:12]1[C:13]([NH:22][S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=1
Reactant: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1N
Yield: 93.4 %

Procedure:
An alternative process will be described. To a solution prepared by dissolving 34.9 g of sodium hydrosulfite in 400 ml of water, a solution prepared by dissolving 5.0 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide in 80 ml of tetrahydrofuran, was dropwise added at room temperature. After completion of the dropwise addition, the mixture was reacted for further 3 hours. After completion of the reaction, sodium chloride was added until the tetrahydrofuran layer was separated. The separated tetrahydrofuran layer was dried, and tetrahydrofuran was distilled off under reduced pressure to obtain 4.2 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide.
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][O:29][CH2:28]1>O.ClCCl>[CH:1]([CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:31](=[O:32])[CH2:30][O:29][CH2:28][C:27]([OH:34])=[O:33])[CH2:18][CH2:19]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C1COCC(=O)O1
Solvent: O
Solvent: ClCCl
Product: O=C(O)COCC(=O)NCCCCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 2 h

Procedure:
A 1.02 gram (2.10 millimoles) sample of sodium {2-[6-(4-benzhydrylpiperidino)hexyl]amino-2-oxoethoxy}acetate (prepared as described in Example XIII) and 7.3 milliliters of 5 N aqueous NaOH is heated under reflux temperature for 1.5 hours to obtain 6-(4-benzhydrylpiperidino)hexanamine and diglycolate in the reaction mixture; the mixture is then diluted with 25 milliliters of water and extracted with ether. The ether solution is washed with aqueous NaCl, dried with Na2SO4, and concentrated to obtain as residue, 6-(4-benzhydrylpiperidino)hexanamine. To a solution of 0.685 gram (1.96 millimoles) of the thus prepared 6-(4-benzhydrylpiperidino)hexanamine in 14 milliliters of dichloromethane is added drop by drop during about 10 minutes, a warm solution of 0.227 gram (1.95 millimole) of diglycolic anhydride in 26 milliliters of dichloromethane. After the addition, the mixture is stirred at a temperature range of 25°-30° C. for two hours to obtain the desired {2-[ 6-(4-benzhydrylpiperidino)hexyl]amino-2-oxoethoxy}acetic acid; the latter is isolated by volatilization of the solvent.
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH2:27][NH2:28])=[O:20])([CH3:17])([CH3:16])[CH3:15]>CC(C)=O>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH2:27][NH:28][C:11]([NH2:12])=[S:10])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCCCC1CNC(N)=S
Temperature: 25 °C
Yield: 76.4 %

Procedure:
Benzoyl chloride (1.2 ml) was added dropwise to sodium thiocyanate (0.90 g) in acetone (50 ml). When the addition was complete the mixture was refluxed for 15 minutes, cooled to room temperature and (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) in acetone (5 ml) added. The mixture was refluxed for 2 hours, cooled to room temperature and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane eluant) to give the title product (1.95 g).