Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][C:20]=1[O:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:27])=[CH:21][C:20]=1[O:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(CC(=O)O)ccc1OCc1ccccc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(CC(=O)N2CCc3ccoc3C2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.33 g (1.2 mmol) of 4-benzyloxy-3-methoxyphenylacetic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1) to yield the desired product.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][NH2:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:12]1[N:13]=[N+:14]([O-:25])[C:15]2[CH:24]=[C:23]3[C:19]([CH2:20][CH2:21][CH2:22]3)=[CH:18][C:16]=2[N:17]=1>COCCOC>[N:1]1([CH2:8][CH2:9][NH:10][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: NCCN1CCCCCC1
Solvent: COCCOC
Product: [O-][n+]1nc(NCCN2CCCCCC2)nc2cc3c(cc21)CCC3
Yield: 53.8 %

Procedure:
2-(1-Azepanyl)ethylamine (289) (0.52 g, 3.6 mmol) was added to a stirred solution of chloride 21 (322 mg, 1.5 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 46 (264 mg, 56%) as a yellow solid: mp (MeOH) 121-123° C.; 1H NMR δ 8.08 (s, 1H, H-9), 7.40 (s, 1H, H-5), 5.93 (br s, 1H, NH), 3.47-3.52 (m, 2H, CH2N), 2.97-3.03 (m, 4H, H-6, H-8), 2.74 (dd, J=6.0, 5.8 Hz, 2H, CH2N), 2.65-2.68 (m, 4H, 2×CH2N), 2.15 (p, J=7.4 Hz, 2H, H-7), 1.58-1.68 (m, 8H, 4×CH2); 13C NMR δ 158.8, 154.5, 148.8, 143.1, 129.7, 120.5, 114.6, 55.9, 55.1 (2), 38.8, 33.1, 32.3, 28.4 (2), 26.9 (2), 25.7. Anal. calcd for C18H25N5O: C, 66.0; H, 7.7; N, 21.4. Found: C, 66.0; H, 7.6; N, 21.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:20][C:21]#[N:22])[C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:4][CH:3]=1.CN(C=O)C.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH2:20][C:21]2[NH:30][N:29]=[N:28][N:22]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCN(c1ccc(Cl)cc1)c1nc(=O)c2cccnc2s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(N(Cc2nnn[nH]2)c2ccc(Cl)cc2)sc2ncccc12
Yield: 35.1 %

Procedure:
A mixture of 74 mg (0.23 mmol) of 2-[N-(4-chlorophenyl)-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl]amino]acetonitrile and 1 ml of DMF was put in a 20 ml flask. To the mixture were then added 146 mg of sodium azide and 120 mg of ammonium chloride with stirring. The mixture was then stirred at a temperature of 120° C. for 4 hours. The resulting reaction mixture was allowed to cool, poured into water, and then extracted with ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then washed with cold ethanol to obtain 30 mg of 2-[N-(4-chlorophenyl)-N-(1H-tetrazol-5-ylmethyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[Br:16][C:17]1[CH:18]=[C:19]([N+]([O-])=O)[C:20]([C:23]#[N:24])=[N:21][CH:22]=1>O>[Br:16][C:17]1[CH:18]=[C:19]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:20]([C:23]#[N:24])=[N:21][CH:22]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncc(Br)cc1Oc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 113.2 %

Procedure:
A flask was charged with 4-fluorophenol (44 g, 365 mmol) and DMF (500 mL). The reaction was cooled to 0° C. Sodium hydride (16.6 g, 414 mmol) was added and stirred for 10 minutes. 5-Bromo-3-nitropicolinonitrile (90 g, 395 mmol) was added and the mixture stirred at ambient temperature for 30 minutes. The reaction was poured into a flask containing water (5000 mL) and stirred for 10 minutes. The pH was adjusted to 10 to give 5-bromo-3-(4-fluorophenoxy)picolinonitrile (121 g, 413 mmol, 105% yield) as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>O1CCCC1>[CH3:20][N:21]([CH3:25])[C:22]([N:8]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9]1)=[O:23]
Reactant: c1cc(-c2n[nH]c(-c3ccncc3)n2)ccn1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)n1nc(-c2ccncc2)nc1-c1ccncc1

Procedure:
To 2.13 g. (0.01 mole) of 3,5-di(4-pyridyl)-1,2,4-triazole in 200 ml. of tetrahydrofuran is added 57% sodium hydride in mineral oil (0.42 g., 0.01 moles). The reaction mixture is heated at reflux for 1 hour, cooled and a solution of dimethylcarbamoyl chloride (1g., 0.01 mole) in 10 ml. of tetrahydrofuran is added dropwise. The reaction mixture is heated at reflux for 4 hours, cooled, filtered and concentrated to an oil which solidifies. After recrystallization from benzene 1.2 g. of 1-dimethylcarbamoyl-3,5-di(4-pyridyl)-1,2,4-triazole melting at 140°-141.5°C. is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:24]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.5 %

Procedure:
To a solution of the product of Example 126A (0.20 g, 1.1 mmol) and Et3N (0.3 mL, 2.2 mmol) in 25 mL THF was added 2-bromobenzoyl chloride (Aldrich, 0.18 mL, 1.4 mmol). This mixture stirred at ambient temperature for 20 hours then was concentrated under reduced pressure and the residue was diluted with 10 mL EtOAc and washed with 5 mL NH4Cl. The layers were separated and the aqueous layer was extracted (2×5 mL EtOAc). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via recrystallization with 50% hexanes/EtOAc to afford 0.18 g of the title compound (0.49 mmol, 46% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.26 (s, 3H), 2.28 (s, 3H), 3.30 (s, 3H), 3.78 (t, J=5.1 Hz, 2H), 4.42 (t, J=5.1 Hz, 2H), 7.22 (dt, J=7.8, 1.7 Hz, 1H), 7.34 (dt, J=7.5, 1.4 Hz, 1H), 7.63 (dd, J=8.0, 1.2 Hz, 1H), 7.90 (dd, J=7.6, 1.9 Hz, 1H); MS (DCI/NH3) m/z 369, 371 (M+H)+; Anal. calculated for C15H17BrN2O2S: C, 48.79; H, 4.64; N, 7.59. Found: C, 48.84; H, 4.49; N, 7.40.
Reaction SMILES: [CH:1]([C:3]1[N:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:27]([O:30][CH2:31][C:32]1[CH2:39][S:38][CH:37]2[N:34]([C:35](=[O:41])[CH:36]2[NH2:40])[C:33]=1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])(=[O:29])[CH3:28]>O1CCCC1>[C:27]([O:30][CH2:31][C:32]1[CH2:39][S:38][CH:37]2[N:34]([C:35](=[O:41])[CH:36]2[NH:40][C:9](=[O:11])[CH2:8][N:4]2[CH:5]=[CH:6][CH:7]=[C:3]2[CH:1]=[O:2])[C:33]=1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])(=[O:29])[CH3:28]
Reactant: O=Cc1cccn1CC(=O)O
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)C2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)Cn3cccc3C=O)C2SC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (2-formyl-1-pyrryl)acetic acid (3.1 g, 0.02 m) in tetrahydrofuran (THF) is cooled to about 0° C. and 4.12 g (0.02 m) of dicyclohexylcarbodiimide is added in one portion with stirring for five minutes. Then 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, tert-butyl ester (6.08 g, 0.02 m) in THF is added. The temperature is maintained at 0° C. for one hour and then the temperature is increased to 20° for about 18 hours and the solution filtered. The THF is removed at reduced pressure and the residue is taken up in ethyl acetate. The ethyl acetate is extracted with 1.0% aqueous sodium bicarbonate and water. The ethyl acetate is then filtered, dried and evaporated to give the title compound.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:36])[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][C:31]1[N:36]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:30]=1
Reactant: COCCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: COCCc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 300 mg (0.720 mmol) of the compound from Example 45A and 93.6 mg (0.792 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted Yield: 231 mg (63% of theory, approx. 15% trans isomer)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH2:15])[CH:7]=[C:8]([S:11]([OH:14])(=[O:13])=[O:12])[CH:9]=2)[CH:4]=[C:3]([S:16]([OH:19])(=[O:18])=[O:17])[CH:2]=1.[OH-].[Na+:21].C(O)C>O>[Na+:21].[Na+:21].[NH2:15][C:6]1[C:5]2[C:10](=[CH:1][CH:2]=[C:3]([S:16]([O-:19])(=[O:18])=[O:17])[CH:4]=2)[CH:9]=[C:8]([S:11]([O-:14])(=[O:13])=[O:12])[CH:7]=1
Reactant: Nc1cc(S(=O)(=O)O)cc2ccc(S(=O)(=O)O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(S(=O)(=O)[O-])cc2ccc(S(=O)(=O)[O-])cc12

Procedure:
A 45.0 g amount of (62.5%) 1-naphthylamine-3,7-disulfonic acid is suspended in 200 ml of water and 30 ml of 5N sodium hydroxide is added to it. The solution is warmed and absolute ethyl alcohol is added until a cloudy precipitate forms. The solution is cooled and the solid is collected by filtration and is washed with 85% ethyl alcohol, ethyl alcohol and ether. The product is dried in vacuo at 110° C. to give 21.0 g of 4-amino-2,6-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH2:12]([NH:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([S:33](=[O:36])(=[O:35])[NH2:34])[C:25]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:20]([NH2:22])=O)[CH2:13][CH2:14][CH3:15].C(OCC)(=O)C>N1C=CC=CC=1.O>[CH2:12]([NH:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([S:33](=[O:36])(=[O:35])[NH2:34])[C:25]=1[O:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:20][NH2:22])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1cc(C(N)=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CCCCNc1cc(CN)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
To a mixture of lithium aluminium hydride (1.6 g) and dry tetrahydrofuran (10 ml), a solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzamide (2.25 g) in dry pyridine (20 ml) is added, and the mixture is refluxed for 16 hours. After cooling, ethyl acetate (1 ml) followed by water (6 ml) are very cautiously added dropwise, whereafter the mixture is stirred for a further 30 minutes. It is then heated on a steambath and filtered hot; the filter-cake is carefully washed with hot 2-methoxyethanol (3 portions of 20 ml). The combined filtrates are evaporated in vacuo and the residue is crystallized from ethanol to give 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine with a melting point of 195°-198° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][C:30]([F:33])([F:32])[F:31])[CH:27]=2)[O:22][C:21]([CH3:35])([CH3:34])[C@H:20]1[OH:36].C(N(CC)CC)C.C(N)(=O)C1C=CC=CC=1>C1C=CC=CC=1.ClCCl>[OH:36][C@H:20]1[C@H:19]([NH:18][C:4](=[O:6])[C:3]2[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:7]=2[N+:11]([O-:13])=[O:12])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][C:30]([F:33])([F:31])[F:32])[CH:27]=2)[O:22][C:21]1([CH3:35])[CH3:34]
Reactant: CC1(C)Oc2ccc(OC(F)(F)F)cc2[C@@H](N)[C@@H]1O
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)O
Agent: NC(=O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc([N+](=O)[O-])c1C(=O)N[C@@H]1c2cc(OC(F)(F)F)ccc2OC(C)(C)[C@H]1O
Yield: 56.8 %

Procedure:
2-Methyl-6-nitrobenzoic acid (1.81 g, 10 mmol) was converted to the corresponding acid chloride by refluxing in benzene (30 mL) with thionyl chloride (1.66 g, 14 mmol) for 0.5 hours. The crude mixture was concentrated in vacuo and diluted with dichloromethane (10 mL). This solution was added to a cooled solution of (3S,4R)-4-amino-2,2-dimethyl-6-(trifluoromethoxy)-chroman-3-ol (2.75 g, 10 mmol), triethylamine (1.39 mL, 10 mmol) and dichloromethane (25 mL). The crude benzamide was worked-up in a method similar to that in Example 1 and chromatographed (1:1 hexanes/ethyl acetate) to afford 2.5 g (62%) of a white solid: m.p. 204°-206° C.; 1H NMR (CDCl3): δ 8.02 (d, 1H), 7.58 (d, 1H), 7.48 (t, 1H), 7.20 (s, 1H), 7.04 (d, 1H), 6.82 (d, 1 H), 6.06 (d, 1H), 3.80 (t, 1H), 3.70 (br s, 1H), 2.56 (s, 3H), 1.52 (s, 3H), 1.31 (s, 3H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH3:10][CH:11]([CH3:14])[CH2:12]O>>[CH2:10]([O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH2:10][CH:11]([CH3:14])[CH3:12])=[O:6])[OH:3])[CH:11]([CH3:14])[CH3:12]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: CC(C)CO
Product: CC(C)COC(=O)CC(O)C(=O)OCC(C)C
Temperature: 108 °C

Procedure:
Diisobutyl-DL-malate was prepared by esterification of DL-malic acid with isobutyl alcohol. To a three-neck 1 L round-bottomed flask equipped with a reflux condenser, Dean-Stark trap, septum, thermocouple and mechanical stirrer, were added DL-malic acid (75.91 g), 2-methyl-1-propanol (210 mL) and Amberlyst®15 ion exchange resin (10 g). The mixture was placed under nitrogen and heated to reflux. At 106° C., two phases started to collect in the Dean-Stark trap. The reaction temperature was maintained at 108° C. for 2 hr 15 min and the water was continuously removed via the Dean-Stark trap. As collection in the Dean-Stark trap slowed, the reaction temperature was increased to 115° C. and fresh alcohol (50 mL) was added to the reaction. The reaction was heated to 120° C. and more alcohol (50 mL) was added. At this point, no more water collected in the Dean-Stark trap. The product was separated from the catalyst via filtration. The crude yellow liquid was purified via vacuum distillation. Diisobutyl-DL-malate was obtained as a low viscosity, clear, colorless liquid with a slight pleasant odor (120.4 g, 86.3% yield).
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[OH-].[K+].Cl[C:21]([CH:23]([CH2:35][CH2:36][CH2:37][CH:38]([O:44][C:45](=[O:47])[CH3:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:22]>CCOCC.CCOCCOCCO.O>[N+:1](=[CH:3][C:21]([CH:23]([CH2:35][CH2:36][CH2:37][CH:38]([O:44][C:45](=[O:47])[CH3:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:22])=[N-:2]
Reactant: C=[N+]=[N-]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)Cl)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOCCOCCO
Solvent: O
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)C=[N+]=[N-])OC(C)=O

Procedure:
Diazomethane (6 g., 0.143 mole) is generated via dropwise addition of a solution of Diazald® (43 g.) in ether (400 ml.) over 45 minutes to a warm (65%), stirred solution of potassium hydroxide (12 g., 0.214 mole) in carbitol-water (7:2, 90 ml.). The resulting yellow, ethereal diazomethane distillate is cooled to 0° and treated with a solution of ethyl 8-chlorocarbonyl-12-acetoxyheptadecanoate (8.1 g., 0.02 mole) (Example 7, Step D), in ether (40 ml.) added over a period of 15 minutes.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1)=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
2-(6-Methylthio-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.28 g, 1.0 mmol) obtained in Example 43 was dissolved in chloroform (30 ml). To the stirred mixture was added dropwise a solution of 3-chloroperbenzoic acid (ca. 70%, 0.25 g, 1.0 mmol) in chloroform (10 ml). The reaction mixture was stirred for 1 hr and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with 10% methanol-chloroform and recrystallized from ethanol to give the titled compound (0.19 g, 64%) as crystals.
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([O:21]CCCC)=[O:20])=[O:12])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].[ClH:26]>>[ClH:26].[NH:1]([C:5]1[S:6][C:7]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])=[O:12])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCCCOC(=O)COCCCNC(=O)c1sc(NC(=N)N)nc1C
Agent: Cl
Product: Cc1nc(NC(=N)N)sc1C(=O)NCCCOCC(=O)O

Procedure:
151 mg of butyl {3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-propoxy}-acetate are stirred for 5 hrs. in 3 ml of 25% hydrochloric acid. The reaction mixture is evaporated to dryness in a vacuum and the residue is lyophilized from acetic acid. There are obtained 144 mg of [3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-propoxy]-acetic acid hydrochloride (1:1), m.p. 48-51° C., MS: 316 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>ClCCl>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)[C:4]=2[N:5]=[C:6]([S:8]([CH3:9])=[O:33])[N:7]=1
Reactant: CSc1nc(Cl)c2ccc(=O)n(-c3ccc(C(F)(F)F)cc3)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3ccc(C(F)(F)F)cc3)c2n1
Yield: 82.1 %

Procedure:
A solution of 4-Chloro-2-methylsulfanyl-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.7 mmol) in dichloromethane (50 mL) was mixed with m-CPBA (0.63 g, 4.0 mmol). The resultant mixture was stirred at room temperature for 10 minutes and concentrated under vacuum. Flash chromatography (EtOAc/Hexane, 3:1) then provided the title compound (0.86 g, 82%): MS (ES) m/z 388 (M+H)+; 1H-NMR(CDCl3) δ 2.80 (s, 3H), 7.03 (d, J=9.9 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 2H), 8.19 (d, J=9.9 Hz, 1H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][CH:23]=[C:24]([CH:26]=O)[N:25]=2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[O:22][CH:23]=[C:24]([CH2:26][N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[N:25]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1coc(-c2ccc(F)cc2)n1
Product: CC(C)(C)OC(=O)N1CCN(Cc2coc(-c3ccc(F)cc3)n2)CC1
Yield: 42 %

Procedure:
This compound was synthesized from tert-butyl piperazine-1-carboxylate and 2-(4-fluorophenyl)oxazole-4-carbaldehyde as described for example 82 step 3 (240 mg, yield 42%). 1H NMR (400 MHz, CDCl3) δ 8.07-8.03 (dd, J=9.1 Hz, 5.3 Hz, 2H), 7.59 (s, 1H), 7.16-7.12 (t, J=8.8 Hz, 2H), 3.54 (s, 2H), 3.49-3.47 (m, 4H), 2.52-2.49 (m, 4H), 1.46 (s, 9H). MS (ESI) m/z: Calculated for C19H24FN3O3: 361.18. found: 362.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([Br:18])[C:6]([Br:17])=[C:7]3[C:15](=[O:16])[O:14][C:12](=[O:13])[C:8]3=2)[C:3]=1[Br:19].C12C(=O)OC(=[O:31])C1=CC=C1C=2C=CC=C1.BrBr>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([Br:18])[C:6]([Br:17])=[C:7]([C:15]([OH:14])=[O:16])[C:8]=2[C:12]([OH:31])=[O:13])[C:3]=1[Br:19]
Reactant: O=C1OC(=O)c2c1c(Br)c(Br)c1c(Br)c(Br)ccc21
Reactant: O=C1OC(=O)c2c1ccc1ccccc21
Agent: BrBr
Product: O=C(O)c1c(Br)c(Br)c2c(Br)c(Br)ccc2c1C(=O)O

Procedure:
Tetrabromonaphthalene-1,2-dicarboxylic anhydride: 2.0 g of naphthalene-1,2-dicarboxylic anhydride, 0.05 g of ferrum reductum and 5.2 ml of bromine are heated at 210° C. for 6 hours using a long intensive condenser. Working up analogously to Example 61a) gives 5.0 g of tetrabromonaphthalene-1,2-dicarboxylic acid, which is converted into the anhydride with acetic anhydride. Yield: 4.8 g (94%), bromine content: 62.4% (theoretical 62.7%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH:8]([CH3:12])[CH2:7][C:5]=2[N:6]=1.BrBr.N12CCCN=C1CCCCC2.CCOC(C)=O>C(O)(=O)C.ClCCl>[Br:1][C:2]1[S:3][C:4]2[C:10]([OH:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC1CC(=O)c2sc(Br)nc2C1
Agent: BrBr
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(O)c2sc(Br)nc2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-5-methyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one (17.5 g, 71.24 mmol) in acetic acid (142 mL) at 80° C. was added dropwise bromine (3.30 mL, 64.12 mmol) over 30 minutes. Reaction mixture was stirred for 1 h at 80° C., cooled to room temperature and resulting solid collected by filtration. The filter cake was partitioned between dichloromethane/saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried (MgSO4), filtered and concentrated. The residue was dissolved in dichloromethane (250 mL) and added dropwise over 2.5 h to a solution of 1,8-Diazabicyclo[5.4.0]undec-7-ene (19.5 mL, 130 mmol) in dichloromethane (1.5 L) at 0° C. Reaction mixture was stirred for 30 minutes, quenched with 1N HCl and stirred for 5 minutes. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. Purification by CombiFlash (220 g, 5 to 40% EtOAc/Hex) gave impure product. Recystallization from hot EtOAc/Hex gave pure product. NMR (400 MHz, CDCl3): δ 7.42 (s, 1H), 6.65 (s, 1H), 2.44 (s, 3H).