Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[I-].[Na+].[Cl:10][C:11]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:12]=1[CH2:13][CH:14]([O:23][C@@H:24]1[O:29][C@@H:28]([CH2:30]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][CH2:26][CH2:25]1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>CN(C)C=O>[Cl:10][C:11]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:12]=1[CH2:13][CH:14]([O:23][C@@H:24]1[O:29][C@@H:28]([CH2:30][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH2:27][CH2:26][CH2:25]1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(C(Cc2ccc(Cl)cc2Cl)O[C@H]2CCC[C@H](COS(=O)(=O)c3ccc(C)cc3)O2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(Cc2ccc(Cl)cc2Cl)O[C@H]2CCC[C@H](Cn3cncn3)O2)cc1
Yield: 11.9 %

Procedure:
97.5 mg of 1,2,4-triazole and 62 mg of 55% sodium hydride, 142 mg of sodium iodide, 533 mg of trans-6-[α-(2,4-dichlorobenzyl)-4-methoxybenzyloxy]-2-tosyloxymethyltetrahydropyran and 6 ml of dimethylformamide were reacted and treated essentially as described in Example 3(b) and then the product was purified by column chromatography through silica gel eluted with a 1:2 by volume mixture of benzene and ethyl acetate, to give 244 mg of an isomer of lesser polarity, 109 mg of an isomer of greater polarity and 52 mg of a mixture of the two isomers (in which the ratio of the isomers of lesser to greater polarity was about 2:1).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([OH:16])[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:5]=2[O:4]1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>C(OCC)(=O)C>[CH3:15][O:14][C:10]1[C:9]([OH:16])=[C:8]([CH3:17])[C:6]2[CH2:7][C:3]([CH3:18])([CH2:2][N:28]3[CH2:29][CH2:30][CH:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[O:4][C:5]=2[C:11]=1[O:12][CH3:13]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1c(O)c(C)c2c(c1OC)OC(C)(CBr)C2
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(O)c(C)c2c(c1OC)OC(C)(CN1CCC(c3ccccc3)CC1)C2
Temperature: 180 °C
Reaction time: 16 h
Yield: 39.9 %

Procedure:
A mixture of 2-bromomethyl-2,3-dihydro-6,7-dimethoxy-2,4-dimethylbenzofuran-5-ol (1.2 g), 4-phenylpiperidine (1.2 g) and triethylamine (1.1 ml) was stirred at under an atmosphere of argon in a sealed tube at 180° C. for 16 hours. After the reaction mixture was cooled, water, triethylamine and ethyl acetate were added, and the mixture was shaken. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the title compound (0.6 g, 40%).
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([N:15]1[CH2:22][C:21]([F:24])([F:23])[CH2:20][C@@:16]1([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH2:39][CH2:40][CH:41]([OH:48])[CH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][CH3:45].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl>[F:23][C:21]1([F:24])[CH2:22][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[C:16]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=3)=[CH:28][CH:27]=2)([C:17]([NH:39][CH2:40][CH:41]([OH:48])[CH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][CH3:45])=[O:19])[CH2:20]1
Reactant: CCC(C)(C)CC(O)CN
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@@]1(Cc1ccc(-c2ccc(F)cn2)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(C)(C)CC(O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CC(F)(F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-methylmorpholine (0.2 mL, 1.8 mmol) was added to a solution of 1-(tert-butoxycarbonyl)-4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]proline (175 mg, 0.40 mmol), 1-amino-4,4-dimethylhexan-2-ol (58 mg, 0.40 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (92 mg, 0.48 mmol), and hydroxybenzotriazole (65 mg, 0.48 mmol) in dichloromethane (40 mL). After stirring at ambient temperature overnight, the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated in vacuo to afford tert-butyl 4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]-2-{[(2-hydroxy-4,4-dimethylhexyl)amino]carbonyl}-pyrrolidine-1-carboxylate which was used in the subsequent step without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1)CCC>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:4]2[C:5]3[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=3[C:2]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[CH:3]2)=[N:15][CH:16]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC1(C)CC(=O)c2c(Br)cn(-c3ccc(Cl)cn3)c2C1
Product: CC1(C)CC(=O)c2c(-c3nccs3)cn(-c3ccc(Cl)cn3)c2C1
Yield: 37 %

Procedure:
In the same way as described in Example 15, Step 4 using 3-bromo-1-(5-chloropyridin-2-yl)-6,6-dimethyl-4,5,6,7-tetrahydroindol-4-one and 2-tributylstannylthiazole, the title compound (73 mg, 37%) was isolated as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 1.06 (6H,s), 2.44 (2H,s), 3.01 (2H,s), 7.63 (1H,d, J=3Hz), 7.80-7.84 (2H,m), 8.00 (1H,s), 8.20 (1H,dd, J=8.6 and 2.6 Hz), 8.69 (1H,d, J=2.6Hz). MS (ES+) 358/360 (M+1). 1H NMR (400 MHz, d6-DMSO) δ 1.02 (6H,s), 2.33 (2H,s), 2.97 (2H,s), 7.56 (1H,s), 7.71 (1H,d, J=8.6 Hz), 8.18 (1H,dd, J=8.7Hz and 2.6 Hz), 8.64 (1H,d, J=2.6 Hz). MS (ES+) 353/355 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[NH:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:4]2([NH:8][C:7](=[O:9])[NH:6][C:5]2=[O:10])[CH2:3]1.[O:17]1[CH2:41][CH:18]1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH:24]([C:27]([CH:30]2[CH2:35][CH2:34][CH:33]([O:36][CH2:37][CH:38]3[O:40][CH2:39]3)[CH2:32][CH2:31]2)([CH3:29])[CH3:28])[CH2:23][CH2:22]1.[OH-:42].[K+]>CO>[OH:17][CH:18]([CH2:41][N:6]1[C:5](=[O:42])[C:4]2([CH2:3][C:2]([CH3:1])([CH3:16])[NH:13][C:12]([CH3:15])([CH3:14])[CH2:11]2)[NH:8][C:7]1=[O:9])[CH2:19][O:20][CH:21]1[CH2:22][CH2:23][CH:24]([C:27]([CH:30]2[CH2:31][CH2:32][CH:33]([O:36][CH2:37][CH:38]([OH:40])[CH2:39][N:6]3[C:5](=[O:10])[C:4]4([CH2:3][C:2]([CH3:16])([CH3:1])[NH:13][C:12]([CH3:15])([CH3:14])[CH2:11]4)[NH:8][C:7]3=[O:9])[CH2:34][CH2:35]2)([CH3:29])[CH3:28])[CH2:25][CH2:26]1
Reactant: CC(C)(C1CCC(OCC2CO2)CC1)C1CCC(OCC2CO2)CC1
Reactant: [OH-]
Reactant: CC1(C)CC2(CC(C)(C)N1)NC(=O)NC2=O
Agent: [K+]
Solvent: CO
Product: CC1(C)CC2(CC(C)(C)N1)NC(=O)N(CC(O)COC1CCC(C(C)(C)C3CCC(OCC(O)CN4C(=O)NC5(CC(C)(C)NC(C)(C)C5)C4=O)CC3)CC1)C2=O

Procedure:
40.0 g of 7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione, 17.5 g of 2,2-bis[4-(2,3-epoxypropoxy)cyclohexyl]propane and 2.0 g of potassium hydroxide were reacted in 300 ml of methanol, following substantially the same procedure as was described in Example 1. The desired Compound No. 118 was obtained in the form of a white powder, having an Rf value of 0.56 on thin-layer chromatography on silica gel using a 8:1:1:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine as developing solvent.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:9][C:10]#[N:11])(=[O:3])[CH3:2].Cl.N1CCC[C@@H]1CC#N>>[C:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@@H:5]1[CH2:9][C:10]#[N:11])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC[C@H]1CC#N
Agent: Cl
Agent: N#CC[C@H]1CCCN1
Product: CC(=O)N1CCC[C@@H]1CC#N

Procedure:
Prepared by proceeding in a similar manner to Intermediate 137, starting from ((R)-pyrrolidin-2-yl)acetonitrile hydrochloride (Intermediate 143) and used without further characterisation.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]([S:11](Cl)(=[O:13])=[O:12])[CH3:10].[CH3:15][N:16]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:35]3[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=3)[CH:22]=2)[C:17]1=[O:41]>>[CH3:15][N:16]1[CH:25]=[C:24]([C:2]2[CH:7]=[C:6]([NH:8][S:11]([CH2:9][CH3:10])(=[O:13])=[O:12])[CH:5]=[CH:4][N:3]=2)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:35]3[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=3)[CH:22]=2)[C:17]1=[O:41]
Reactant: Cn1cc(-c2ccc3c(=O)n(C)cc(B4OC(C)(C)C(C)(C)O4)c3c2)cn1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccnc(Cl)c1
Product: CCS(=O)(=O)Nc1ccnc(-c2cn(C)c(=O)c3ccc(-c4cnn(C)c4)cc23)c1

Procedure:
The title compound was prepared after 2-chloropyridin-4-amine was sulfonylated with ethanesulfonyl chloride and the resulting product was coupled to the title compound of Example 46, step 2. 1H NMR (CDCl3, 400 MHz) δ 10.65 (brs, 1H), 8.56 (s, 1H), 8.29 (d, J=8.4 Hz, 1H), 8.22 (s, 1H), 8.01-7.73 (m, 4H), 7.37 (s, 1H), 7.18 (s, 1H), 3.87 (s, 3H), 3.59 (s, 3H), 1.25 (t, J=7.2 Hz, 3H). LCMS: 424.0 (M+1)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]([CH3:33])[CH2:18][CH2:19][CH2:20][N:21]([CH3:32])[C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:16])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:36]I.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH3:36])[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]([CH3:33])[CH2:18][CH2:19][CH2:20][N:21]([CH3:32])[C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:16])=[N:13][CH:14]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CI
Reactant: CN(CCCN(C)C(=O)c1ccc(NC(=O)OC(C)(C)C)cn1)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCCN(C)C(=O)c1ccc(N(C)C(=O)OC(C)(C)C)cn1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
The compound (170 mg, 0.372 mmol) obtained in Example 6a was dissolved in tetrahydrofuran (4 mL), sodium hydride (55%; 20 mg, 0.447 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. Methyl iodide (35 μL, 0.558 mmol) was added, and then the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate (×3), and the organic layer was washed with saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to give the title compound (178 mg; yield, 100%) as a yellow oily substance.
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][OH:5].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:8][CH2:7][O:6][CH2:11][CH3:10]
Reactant: C1=COCCC1
Reactant: OC[C@H]1CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: C1CCOCC1
Product: OCC1CO1
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
(S)-Glycidol (2 g, 27.0 mmol) in dihydropyran (40 mL, 438.0 mmol) was treated with para-toluenesulphonic acid (0.3 g, 1.5 mmol) at 0° C. with magnetic stirring. The reaction was complete in 10 minutes (TLC, ether). The reaction mixture was diluted with ether (100 mL), washed with water (10 mL), saturated NaHCO3 solution (20 mL), brine (20 mL) and dried over MgSO4. Concentration and flash chromatography gave the title compound (3 g, 70%).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:37][C:38](=[O:57])[NH:39][CH:40]([C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1)[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[C:13]([NH:15][C@@H:16]([C@H:20]([NH:22][C@H:23]([C:34]([OH:36])=[O:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[CH3:21])[C:17]([OH:19])=[O:18])=[O:14])=O)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[NH2:11][C@@H:12]([CH2:37][C:38](=[O:57])[NH:39][CH:40]([C:49]1[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=1)[C:41]1[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=1)[C:13]([NH:15][C@@H:16]([C@H:20]([NH:22][C@H:23]([C:34]([OH:36])=[O:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[CH3:21])[C:17]([OH:19])=[O:18])=[O:14]
Reactant: COc1ccc(C(NC(=O)C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@H](C(=O)O)[C@@H](C)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c2ccc(OC)cc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(C(NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)O)[C@@H](C)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c2ccc(OC)cc2)cc1
Yield: 69.4 %

Procedure:
A solution of (2S,3R)-2-[[(2S)-2-benzyloxycarbonylamino-3-[N-[bis(4-methoxyphenyl)methyl]carbamoyl]propionyl]amino]-3-[[(1S)-1-carboxy-2-(3-indolyl)ethyl]amino]butyric acid (800 mg) in acetic acid (20 ml) was hydrogenated under medium pressure (3 atm.) for 8 hours at room temperature in the presence of 10% palladium on carbon (120 mg). After removal of the catalyst, the solution was evaporated in vacuo and the residue was solidified with water to give (2S,3R)-2-[[(2S)-2-amino-3-[N-[bis(4-methoxyphenyl)methyl]carbamoyl]propionyl]amino]-3-[[(1S)-1-carboxy-2-(3-indolyl)ethyl]amino]butyric acid (460 mg) as a yellow brown powder.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([O:11][C:12](=[O:14])[CH3:13])(=[O:10])[CH3:9]>C(OCC)C>[C:8]([O-:11])(=[O:10])[CH3:9].[C:12]([NH:1][CH:2]1[CH2:7][CH2:6][NH2+:5][CH2:4][CH2:3]1)(=[O:14])[CH3:13]
Reactant: NC1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)NC1CC[NH2+]CC1
Product: CC(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 714.5 %

Procedure:
To a solution of 4-aminopiperidine (524 μL, 5.00 mmol) in diethyl ether (20 mL) was added a solution of acetic anhydride (567 μL, 0.600 mmol)) in diethyl ether (20 mL) over 10 minutes and the resulting mixture was stirred for 1 h at RT. The solid was collected on a Buchner funnel, washed with diethyl ether (50 mL), and dried under vacuo to give 867 mg (86%) of the title compound as a white solid. 1H-NMR (400 MHz, CDCl3): δ 7.82 (d, 1H, J=10.5 Hz), 4.20-4.16 (m, 1H), 3.78-3.71 (m, 2H), 3.45 (br s, 1H), 3.09 (m, 1H), 2.69 (m, 1H), 1.98 (s, 3H), 1.79 (s, 3H), 1.78-1.69 (m, 2H), 1.28-1.13 (m, 2H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[C:13]([O-])(=[O:15])[CH3:14].[Na+].BrCCO.O>CS(C)=O>[OH:15][CH2:13][CH2:14][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(=O)[O-]
Agent: OCCBr
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCCO
Temperature: 70 °C
Reaction time: 5 h
Yield: 66.5 %

Procedure:
To a solution of N-hydroxyphthalimide (2.20 g, 13.5 mmol) and sodium acetate (3.30 g) in dimethylsulfoxide (40 mL) was added 2-bromoethanol (2.88 mL) under an argon atmosphere at room temperature. The reaction mixture was stirred at 70° C. for 5 hours, followed by cooling to room temperature, adding water (40 mL), and extracting with methylene chloride. The resulting organic layer was washed with water, 2.5M hydrochloric acid, and saturated brine. The washed organic layer was dried over magnesium sulfate, the residue resulting from distilling off the solvent under reduced pressure was recrystallized with ethanol and water to afford 1.86 g of the title compound (yield 66%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[CH:10]=2)[C:5]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:4][CH:3]=1.[NH3:20]>O>[NH2:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[CH:10]=2)[C:5]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:4][CH:3]=1.[NH2:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=S(=O)(O)c1ccc2c(S(=O)(=O)O)ccc(Cl)c2c1
Solvent: O
Product: Nc1ccc(S(=O)(=O)O)c2ccc(S(=O)(=O)O)cc12
Product: Nc1cccc2ccc(S(=O)(=O)O)cc12

Procedure:
Process of claim 1 wherein 1-aminonaphthalene-4,7-disulphonic acid is prepared from 1-chloronaphthalene-4,7-disulphonic acid at temperatures below 220° C, and then the temperature of the reaction mixture is raised to 220° to 350° C in the presence of ammonia and water so as to obtain 1-aminonaphthalene-7-sulphonic acid.
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].C(OCC)(=O)C.CCCCCC>C1COCC1.Cl>[OH:1][C:2]1([C:12]2[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=2)[CH2:3][CH2:4][C:5](=[O:6])[CH2:10][CH2:11]1
Reactant: N#Cc1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(O)CCC(=O)CC2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
4-(8-Hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)benzonitrile (520 mg, 2.0 mmol) was dissolved in the mixed solvent of 10 mL of THF and 10 mL of 1 N HCl aqueous solution at room temperature. The reaction mixture was then stirred at 60° C. for 1 h. The solution was cooled down to room temperature, adjusted to pH 7-8 with saturated NaHCO3 aqueous solution. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc (20 mL×2). The combined organic extracts were dried over MgSO4 and evaporated to give an oil residue. Chromatography on silica gel (flash chromatography grade) with 40% ethyl acetate-hexane gave 410 mg (95%) of the desired product: 1H NMR (CDCl3) δ 7.7 (2H, d, J=11.0 Hz), 7.42 (2H, d, J=10.7 Hz), 4.10 (H, s), 2.79-2.74 (2H, m), 2.63-2.49 (2H, m), 1.95-1.89 (2H, m), 1.67-1.59 (2H, m); MS: 216 (M+1)+.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][CH:9]([O:16][CH3:17])[CH:10]([CH3:15])/[C:11](/[F:14])=[CH:12]\[OH:13]>[O-2].[O-2].[O-2].[Cr+6].C(Cl)Cl>[CH3:7][O:8][CH:9]([O:16][CH3:17])/[C:10](/[CH3:15])=[C:11](/[F:14])\[CH:12]=[O:13]
Reactant: COC(OC)C(C)/C(F)=C\O
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(OC)/C(C)=C(/F)C=O
Reaction time: 2 h

Procedure:
Chromium trioxide (145 g., 1.45 mol) was added to 5 l. of methylene chloride in a 12 l. round bottomed flask fitted with argon inlet and mechanical stirrer. Pyridine (230 ml., 2.9 mol) was added and the mixture was stirred for 2 hours. Celite (290 g.) was added and then E-4,4-dimethoxy-2-fluoro-3-methyl-buten-1-ol was added in one portion and stirred for 30 minutes. The mixture was filtered, evaporated at 30° C. to ~5% of its volume and diluted with 500 ml. of ether. This mixture was filtered and evaporated to ~100 ml. at 30° C. The resulting E-4,4-dimethoxy-2-fluoro-3-methyl-buten-1-al was used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12](C(OC(C)(C)C)=O)=[C:11]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[N:10]([CH3:34])[N:9]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.[Cl-].[NH4+]>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:12]=[C:11]([NH:20][S:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:28][CH:29]=2)(=[O:22])=[O:23])[N:10]([CH3:34])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCCOc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n(C)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To tert-butyl 3-[2-(acetyloxy)ethoxy]-5-({[4-(tert-butyl)phenyl]sulfonyl}amino)-1-methyl-1H-pyrazole-4-carboxylate (Preparation 9) (1.48 g) in dichloromethane (20 ml) was added trifluoroacetic acid (10 ml), at room temperature. The reaction mixture was stirred at room temperature for 2.5 hours and then refluxed for 3 hours. The reaction mixture was then diluted with a saturated solution of aqueous ammonium chloride (20 ml), and the aqueous was then extracted with ethyl acetate (2×20 ml). The organics were dried with magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by chromatography on a suction column packed with silica eluted with ethyl acetate:hexane (3:5) to yield the desired product as an off white solid (200 mg).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:26]([NH:28][C:29](=[N:37][CH2:38][CH2:39][S:40][CH2:41][C:42]1[N:43]=[C:44]([NH:47][C:48]([NH2:50])=[NH:49])[S:45][CH:46]=1)OC1C=CC=CC=1)#[N:27]>>[C:26]([NH:28][C:29]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:24]=[CH:25][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:23])=[N:37][CH2:38][CH2:39][S:40][CH2:41][C:42]1[N:43]=[C:44]([NH:47][C:48]([NH2:50])=[NH:49])[S:45][CH:46]=1)#[N:27]
Reactant: CN(CCCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Product: CN(CCCCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.51 g (1.5 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,5-pentanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=626 ([M+H]+, 3), 154 ([m-NO2 benzylOH] 100); IR (KBr): 2162 cm- (C≡N). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystallised from isopropanol/petroleum ether; m.p.: 103° C. (isopropanol/petroleum ether).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=S.C[O:32]C1C=CC([C@H]2O[C@@H]2C(OC)=O)=CC=1>C(O)C>[CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:32]
Reactant: CNC(=S)N1CCSC1c1ccccc1OCCN1CCN(c2ccccc2)CC1
Reactant: COC(=O)[C@H]1O[C@@H]1c1ccc(OC)cc1
Solvent: CCO
Product: CNC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2ccccc2)CC1
Yield: 75.7 %

Procedure:
480 mg of (+)-N-methyl-2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carbothioamide and 339 mg of methyl trans-3-(4-methoxyphenyl)glycidate are dissolved in 40 ml of ethanol, and the solution is refluxed for 11 hours under heating. 339 mg of methyl trans-3-(4-methoxyphenyl)glycidate are added to the mixture, and the mixture is further refluxed for 3 hours. The mixture is concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform:ethanol=40:1), and the resultant product is recrystallized from a mixture of ethyl acetate and n-hexane. 350 mg of (+)-N-methyl-2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide are obtained. Yield: 75.7%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5](=O)[NH:6][C:7]=1[CH3:8].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>>[Cl:14][C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=1
Reactant: Cc1cc([N+](=O)[O-])c(=O)[nH]c1C
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1cc([N+](=O)[O-])c(Cl)nc1C
Temperature: 140 °C
Reaction time: 0.58 h
Yield: 90.2 %

Procedure:
5,6-Dimethyl-3-nitro-2-pyridone (1-013-04)(841 mg) and phosphorus pentachloride (1.25 g) was heated with stirring in an oil bath at 140° C. under nitrogen atmosphere. After 35 min, the reaction mixture was cooled under ice-cooling, poured into ice-water, extracted with twice with chloroform, and washed once with water and a saturated aqueous solution of sodium bicarbonate. To the extract was added a decolorzing charcoal, and the extract was dried over magnesium sulfate, and evaporated under reduced pressure to give 2-chloro-5,6-dimethyl-3-nitropyridine (1-013-05) (842 mg, 90.2%) as a crystalline residue.