Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=O)[CH2:2][CH3:3].[NH2:24]/[C:25](/[CH3:34])=[CH:26]\[C:27]([O:29][CH2:30][CH2:31][C:32]#[N:33])=[O:28]>CC(O)C>[Cl:23][C:19]1[CH:18]=[C:17]([CH:16]2[C:26]([C:27]([O:29][CH2:30][CH2:31][C:32]#[N:33])=[O:28])=[C:25]([CH3:34])[NH:24][C:1]([CH2:2][CH3:3])=[C:5]2[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH:22]=[CH:21][CH:20]=1
Reactant: CCC(=O)C(=Cc1cccc(Cl)c1)C(=O)OCc1ccccc1
Reactant: C/C(N)=C/C(=O)OCCC#N
Solvent: CC(C)O
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
1.00 g (3.08 mmol) of benzyl 2-propionyl-3-(3-chlorophenyl)acrylate (mixture of E:Z=1:1) and 475 mg (3.08 mmol) of 2-cyanoethyl 3-aminocrotonate were heated under reflux in 10 ml of 2-propanol at 80° C. for 2 days. 2-Propanol was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (dichloromethane/methanol=100/1) to obtain the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17]>>[CH2:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH3:17]
Reactant: O=C1CCNCC1
Reactant: CCOCCCCCCCl
Product: CCOCCCCCCN1CCC(=O)CC1

Procedure:
1-(6-Ethoxyhexyl)4-piperidone is prepared from 4-piperidone and 1-chloro-6-ethoxyhexane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)(=[O:3])[CH3:2].[Br:26]Br>C(OCC)(=O)C.Br>[Br:26][CH2:2][C:1]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Agent: Br
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)CBr)c3c2)c1=O
Temperature: 25 °C

Procedure:
To a solution of 3-(3-acetyl-1,2-benzisothiazol-5-yl)-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.800 g, 0.00217 mol) in ethyl acetate at room temperature is added hydrobromic acid (48%, 3 drops) followed by bromine in ethyl acetate (0.522 M, 4.35 ml, 0.00277 mol). The resultant mixture is stirred two hours at reflux, cooled to room temperature, diluted with ethyl acetate, washed sequentially with sodium thiosulfate, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a white solid. The solid is recrystallized from hexanes:ethyl acetate to give the title compound as a white, crystalline solid (mp 191-193° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([OH:14])[CH:5]=[CH:4][C:3]1=2.[H-].[Na+].[CH3:18][O:19][CH2:20]Cl.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:18][O:19][CH2:20][O:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1
Reactant: COCCl
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
10 ml of a solution of 4.0 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol in N,N-dimethylformamide was dropwise added to 70 ml of a suspension of 1.01 g of sodium hydride (604 solution in oil) in anhydrous N,N-dimethylformamide at 0° C. The obtained mixture was stirred at room temperature for one hour and cooled to 0° C., followed by the addition thereto of 5 ml of a solution of 2.36 g of chloromethyl methyl ether in N,N-dimethylformamide. The temperature of the mixture was gradually raised to room temperature (in 10 minutes). The resulting mixture was further stirred for one hour, followed by the addition thereto of 30 ml of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 5% ethyl acetate/n-hexane) to give 5.2 g of the title compound as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ(ppm); 1.26(s, 6H), 1.29(s, 6H), 1.70(s, 4H), 3.50(s, 3H), 5.18(s, 2H), 6.87(dd, J=8.4, 2.4 Hz, 1H), 6.97(d, J=2.4 Hz, 1H), 7.23(d, J=8.4 Hz, 1H)
Reaction SMILES: Br.[C:2]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[C:13]([CH2:14][O:15]C(=O)C)=[CH:12][N:11]=[CH:10]2)=[CH:6][C:5]=1[F:21])#[N:3].O.[OH-].[Li+]>C1COCC1.O>[C:2]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[CH:10]2)=[CH:6][C:5]=1[F:21])#[N:3]
Reactant: CC(=O)OCc1cncn1Cc1ccc(C#N)c(F)c1
Agent: Br
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(Cn2cncc2CO)cc1F
Reaction time: 2 h

Procedure:
To a solution of 1-(4-cyano-3-fluorobenzyl)-5-(acetoxymethyl)imidazole hydrobromide (as described in Example 14, Step C) (31.87 g, 89.77 mmol) in 300 mL of 2:1 THF/water at 0° C. was added lithium hydroxide monohydrate (7.53 g, 179 mmol). After two hours, the reaction was concentrated in vacuo to a 100 mL volume, stored at 0° C. for 30 minutes, then filtered and washed with 700 mL of cold water to provide a brown solid. This material was dried in vacuo over P2O5 to provide the titled product as a pale brown powder which was sufficiently pure for use in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([NH:20][NH:21][C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=O)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:49])=CC=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:32][CH:31]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:49][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:21][N:20]=1)=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(=O)NNC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCc3ccccc3)c2[nH]1
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(-c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCc4ccccc4)c3[nH]2)s1
Temperature: 50 °C
Reaction time: 5 h
Yield: 74.1 %

Procedure:
Ethyl [2-({7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}carbonyl)hydrazino](oxo)acetate (420 mg) was dissolved in tetrahydrofuran (15 mL), Lawesson's reagent (308 mg) was added, and the mixture was stirred at 50° C. for 5 hr. Lawesson's reagent (300 mg) was added again to the reaction solution, and the mixture was further stirred at 50° C. for 1 hr. The reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=10:90-40:60, volume ratio), and the obtained yellow oil was crystallized from methanol to give the title compound (310 mg, yield 74%) as pale-yellow crystals. The obtained crystals was recrystallized from ethyl acetate-diethyl ether to give pale-yellow crystals. melting point 194-195° C. MS 550 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]2[N:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]4Cl)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.[NH2:38][NH2:39].C1(N2C3C=CC(C(O)=O)=CC=3N=C2C2C=C3C(=CC=2)N=C(C2C=CC=CC=2)C=C3N(C)C)CCCCC1>>[CH:30]1([N:10]2[C:9]3[CH:36]=[CH:37][C:6]([C:4]([OH:3])=[O:5])=[CH:7][C:8]=3[N:12]=[C:11]2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[C:16]3[NH:38][NH2:39])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Cl)c3c1)n2C1CCCCC1
Reactant: NN
Agent: CN(C)c1cc(-c2ccccc2)nc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)cc12
Product: NNc1cc(-c2ccccc2)nc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)cc12

Procedure:
In this reaction 102 mg (0.2 mmol) of crude 2-(4-chloro-2-phenyl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester was reacted with hydrazine as the nucleophile as described for the preparation of Compound 481. Yield: 3.7 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].[OH-].[K+].Cl[CH2:22][C:23]([OH:25])=[O:24]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:22][C:23]([OH:25])=[O:24])[CH2:12][CH2:13]1)=[O:7]
Reactant: O=C(O)CCl
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(CC(=O)O)CC2)cc1OC
Temperature: 50 °C

Procedure:
32 Grams of 4-(3,4-dimethoxybenzoyl)piperazine and 13.1 g of potassium hydroxide were dissolved in 300 ml of dimethylformamide (DMF), then under an ice-cooled condition with stirring, 10 g of α-chloroacetic acid was added thereto, next the reaction mixture was heated at 50° C. for 5 hours with stirring. After completion of the reaction, the reaction mixture was concentrated to dryness, the residue obtained was dissolved in water. The solution obtained was washed with chloroform, the aqueous layer was neutralized with concentrated hydrochloric acid, crystals formed were collected by filtration to obtain 9.8 g of α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.CN(C)CCN(C)C.[Li]CCCC.[CH2:25]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCCCCCC.CCCCCC>[CH2:25]([N:32]1[CH2:37][CH2:36][C:35]([C:10]2[C:4]3[O:3][C:2]([CH3:11])([CH3:1])[CH2:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)([OH:38])[CH2:34][CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)Cc2ccccc2O1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCCCCCC
Product: CC1(C)Cc2cccc(C3(O)CCN(Cc4ccccc4)CC3)c2O1
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 19.3 %

Procedure:
A mixture of 2,3-dihydro-2,2-dimethylbenzofuran (25 g) and tetramethylethylenediamine (46 g) in heptane (250 ml) was treated dropwise at room temperature with 1.6M BuLi in hexane (250 ml). After stirring for 1.5 h at 30°-40° C. the mixture was cooled to -40° C. and 1-benzyl-4-piperidinone (32 g) was added dropwise at -40° C. The reaction mixture was allowed to warm to room temperature during 3 h followed by quench with water. After concentrating the reaction mixture in vacuo dichloromethane (500 ml) was added followed by wash with water (3×500 ml). Removal of solvent in vacuo gave an oil which was purified by flash chromatography (silica gel, heptane/ethyl acetate/triethylamine 50:48:2) giving an oil. Addition of heptane gave the product, 7-(1-benzyl-4-hydroxy-4-piperidinyl)-2,3-dihydro-2,2-dimethylbenzofuran as a solid (11 g).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:5]2[N:6]=[C:7]([CH3:21])[C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11](=O)[NH:10][C:9]=3[N:4]2[N:3]=1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:11]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:13][C:8]2[C:7]([CH3:21])=[N:6][C:5]3[N:4]([N:3]=[C:2]([CH3:1])[CH:22]=3)[C:9]=2[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2nc(C)c3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Product: Cc1cc2nc(C)c3cc(-c4ccccc4)c(Cl)nc3n2n1

Procedure:
In a 20 mL scintillation vial Compound (19-1) (0.08 g, 0.275 mmol, 1.0 eq.) was heated with 2 mL of POCl3 at 80° C. for 2 hours. The reaction was cooled and concentrated and the residue by silica gel chromatography using CHCl3/MeOH (10%) as eluant to give Compound (19-2).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([N:7]1[C:13](=[O:14])[CH:12]([CH3:15])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[C:9]2[C:20]([NH2:24])=[CH:21][CH:22]=[CH:23][C:8]1=2)=[O:6])[CH3:4].N1C=CC=CC=1.[F:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>C1COCC1>[F:31][C:32]1[CH:33]=[C:34]([S:38]([NH:2][C@H:3]([C:5]([N:7]2[C:13](=[O:14])[CH:12]([CH3:15])[C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=3[C:9]3[C:20]([NH2:24])=[CH:21][CH:22]=[CH:23][C:8]2=3)=[O:6])[CH3:4])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1C(=O)N(C(=O)[C@H](C)NS(=O)(=O)c2cccc(F)c2)c2cccc(N)c2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7B) (0.1500 g, 0.434 mmol) in THF (4 ml) was added pyridine (0.088ml, 1.09 mmol) and 3-fluorobenzenesulfonyl chloride (Fluorochem Limited) (0.0928 ml, 0.477 mmol), stirred at RT overnight. The reaction mixture was evaporated to dryness. Water was added, filtered. The solid was purified with flash chromatography (silica, 6% MeOH/CH2Cl2, crystallized with CH2Cl2/hexane and washed with Et2O/hexane (1:1, v/v) to give the title compound (0.0580 g, 29%) as a white solid.
Reaction SMILES: [CH3:1][C@@:2]([S:14]([CH3:17])(=[O:16])=[O:15])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH3:13])[CH:10]=[N:9]1)[C:3]([OH:5])=O.CN1CCOCC1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].O>C1COCC1>[CH3:1][C@@:2]([S:14]([CH3:17])(=[O:16])=[O:15])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH3:13])[CH:10]=[N:9]1)[C:3]([NH:32][O:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][O:25]1)=[O:5]
Reactant: Cc1cnn(CC[C@](C)(C(=O)O)S(C)(=O)=O)c1
Reactant: NOC1CCCCO1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1cnn(CC[C@](C)(C(=O)NOC2CCCCO2)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of (2R)-2-methyl-4-(4-methyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoic acid (20 mg, 0.077 mmol, 1 eq) and CDMT (17.6 mg, 0.10 mmol, 1.3 eq) in THF (1 mL) was added N-methylmorpholine (10.9 mg, 0.108 mmol, 0.0120 mL, 1.4 eq) and the reaction mixture was stirred at RT for one hour. O-Tetrahydro-2H-pyran-2-yl-hydroxylamine (9.00 mg, 0.077 mmol, 1 eq) was added to the reaction mixture which was stirred overnight at RT. Water was added and the organic phase was separated. The aqueous phase was extracted with Et2O. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to give (2R)-2-methyl-4-(4-methyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, (19 mg, 68%).
Reaction SMILES: [O:1]1[CH:8]2[CH:2]1[CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=12.C[Si](C)(C)[N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[O:20]=[C:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C@@H:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH2:3][C@H:2]1[OH:1]
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: c1ccc2c(c1)OCCC1OC21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCCN1[C@@H]1c2ccccc2OCC[C@H]1O
Temperature: 100 °C

Procedure:
3.24 g (20 mmol) of 4,5-epoxy-2,3,4,5-tetrahydro-1-benzoxepin and 9.60 g (61 mmol) of N-trimethylsilyl-2-oxo-pyrrolidine are dissolved in 8 ml of dry THF and, while cooling, 6.31 g (20 mmol) of tetrabutylammonium fluoride trihydrate are added in one portion, and the mixture is heated at 100° C. for several hours (TLC check). The mixture is hydrolyzed with ice-water and extracted several times with diethyl ether. The combined diethyl ether extracts are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration and evaporation of the solvent in vacuo, the residue is crystallized in diisopropyl ether/ethyl acetate. Crystals of melting point 151°-153° C. are obtained.
Reaction SMILES: [C@@H:1]1([CH2:7][C:8]#[N:9])[CH2:3][C@H:2]1[CH2:4][C:5]#[N:6].N[NH:11][C:12]([NH2:14])=[S:13]>C(O)(C(F)(F)F)=O>[C@@H:1]1([CH2:7][C:8]2[S:13][C:12]([NH2:14])=[N:11][N:9]=2)[CH2:3][C@H:2]1[CH2:4][C:5]1[S:13][C:12]([NH2:14])=[N:11][N:6]=1
Reactant: NNC(N)=S
Reactant: N#CC[C@@H]1C[C@H]1CC#N
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(C[C@@H]2C[C@H]2Cc2nnc(N)s2)s1
Temperature: 100 °C

Procedure:
trans-2,2′-(cyclopropane-1,2-diyl)diacetonitrile I-4 (1 equivalent) was dissolved in TFA (2.0 mL) and thiosemicarbazide (2 equivalents) was added to it. The reaction mixture was refluxed for 3 h at 100° C. before quenching by careful addition of a saturated solution of NaHCO3 at 0° C. to bring the pH around 8-9. The solid precipitated was filtered and further purified to obtain trans-5,5′-(-cyclopropane-1,2-diylbis(methylene))bis(1,3,4thiadiazol2-amine) I-5.
Reaction SMILES: C([O:8][C:9](=[O:25])[CH2:10][C:11]1[C:15]([NH:16][C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])=[CH:14][S:13][CH:12]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=1[NH:16][C:15]1[C:11]([CH2:10][C:9]([OH:25])=[O:8])=[CH:12][S:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(Cc1cscc1Nc1c(Cl)cccc1Cl)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1cscc1Nc1c(Cl)cccc1Cl

Procedure:
393 mg (1 mmole) of 4-(2,6-dichloroanilino)-3-thiophenacetic acid benzyl ester are subjected to hydrogenolysis (in a mixture of 100 ml of ethyl acetate and 10 ml of glacial acetic acid in a circulatory hydrogenation apparatus in the presence of 50 mg of 10 percent strength palladium-on-active charcoal at room temperature and under atmospheric pressure) until the theoretical amount of hydrogen has been taken up. The catalyst is filtered off, the filtrate is concentrated in vacuo, and the residue is dissolved in 1 N sodium hydroxide solution. The aqueous solution is extracted with toluene, and the product phase is acidified with 1 N hydrochloric acid and extracted again with toluene. The organic phase is dried and concentrated. 4-(2,6-Dichloroanilino)-3-thiophenacetic acid (m. 179° to 180°) is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]1[C:33]2([CH2:34][CH2:35][NH2:36])[N:29]([CH2:30][CH2:31][CH2:32]2)[CH2:28][CH2:27]1.[NH4+].[OH-]>CO.C(Cl)(Cl)Cl.CN(C=O)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:36][CH2:35][CH2:34][C:33]23[CH2:26][CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][CH2:32]3)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: NCCC12CCCN1CCC2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)NCCC12CCCN1CCC2
Yield: 75.2 %

Procedure:
4-Amino-5-chloro-2-methoxybenzoic acid (1.0 g, 0.005 moles) and 1,1'-carbonyldi-imidazole (892 mg, 0.00055 moles) were suspended in the DMF (10 ml) and the mixture was stirred until solution occurred (three hours). At this time, tetrahydro-1H-pyrrolizin-7a(5H)-ethylamine [amine Heterocycles 16, 755, 1981](771 mg; 0,005 moles) was added and the mixture was stirred for 1 hour. Tlc 30% MeOH/CHCl3 /1/10% NH4OH indicated that the reaction was complete. Concentration afforded a residue which was partitioned between Et2O/H2O . The product crystallized. The solid was filtered and dissolved in CHCl3, washed with dilute K2CO3, dried over MgSO4 and concentrated to a solid. The solid was triturated with Et2O and converted to the HCl salt with MeOH/HCl to yield 1.27g (69%) of the product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH:21]1[CH:22]=C[C:24]2[N:29](O)N=[N:27][C:25]=2[CH:26]=1.NC1C=NC=CC=1>CN(C=O)C>[N:29]1[CH:22]=[CH:21][CH:26]=[C:25]([NH:27][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:24]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cccnc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
To a solution of (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid (3 g, 12.99 mmol) in DMF (25 mL) is added EDC (2.73 g, 14.29 mmol) and HOBT (1.93 g, 14.29 mmol). The resulting solution is stirred at 25° C. for 0.5 h and 3-aminopyridine (1.83 g, 19.48 mmol) is; added and the reaction is heated to 50° C. for 18 h. The mixture is concentrated, diluted with EtOAc (50 mL), and washed with saturated aqueous sodium bicarbonate. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to provide (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid 3-pyridylamide as a foam (1.6 g, 40% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:6]=1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=1[F:20])(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pt]>[C:1]([NH:4][C:5]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:6]=1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[F:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(F)cc1OCCOc1ccc([N+](=O)[O-])cc1F
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(F)cc1OCCOc1ccc(N)cc1F
Reaction time: 2 h
Yield: 71 %

Procedure:
A mixture of nitro compound 15 (1.0 g, 3.1 mmol) in ethyl acetate (20 mL) and Pt/C (200 mg) was stirred for 2 hrs under H2 (1 atm). The reaction mixture was filtered through Celite and concentrated under reduced pressure. The crude product was recrystalized with benzene providing amino ethane 16 as a white solid (709 mg, 78%), m.p. 134°-136° C. 1H NMR (CDCl3): 2.12 (s, 3H), 4.29 (s, 4H) (s, 4H), 6.4-6.3 (m, 1H), 6.46 (dd, J=12.5, 2.5 Hz, 1H), 6.7-6.6 (m, 2H), 6.85 (dd, J=9, 9 Hz, 1H), 8.30 (dd, J=9, 6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:22](F)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH:18]4[CH2:20][CH2:19]4)[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[CH3:24][S:25]([OH:28])(=[O:27])=[O:26].CS(O)(=O)=O.[NH2:34][C:35]1([CH2:39][CH3:40])[CH2:38][NH:37][CH2:36]1.CS(O)(=O)=O>C(O)C>[CH3:24][S:25]([OH:28])(=[O:27])=[O:26].[NH2:34][C:35]1([CH2:39][CH3:40])[CH2:38][N:37]([C:22]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:21]=2)=[N:6][C:7]2[N:8]([CH:18]4[CH2:19][CH2:20]4)[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:36]1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: CCC1(N)CNC1
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CCC1(N)CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)C1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 19.6 %

Procedure:
8-(3-Amino-3-ethyl-1-azetidinyl)-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid methanesulphonate was prepared under the conditions of Example 15, but starting with 1.8 g of 7,8-difluoro-1-cyclopropyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 2.94 g of 3-amino-3-ethylazetidine dimethanesulphonate. After recrystallization in dimethylformamide, the product obtained, suspended in 20 cm3 of ethanol, is treated with 3.4 cm3 of a solution at a concentration of 9.6 g % of methanesulphonic acid in ethanol. The suspension is stirred for 5 minutes at approximately 80° C., cooled to a temperature in the region of 20° C., drained and washed with 3 times 10 cm3 of ethanol. 0.55 g of 8-(3-amino-3-ethyl-1-azetidinyl)-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid methanesulphonate is obtained in the form of a yellow solid, which decomposes at 248° C.