Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[O:14][CH2:15][C:10]=3[C:9]([C:20]([O:22]CC)=[O:21])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>O1CCOCC1.C(O)C>[C:1]1([N:7]2[C:11]3[C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[O:14][CH2:15][C:10]=3[C:9]([C:20]([OH:22])=[O:21])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2)c2c1COc1ccccc1-2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)c1nn(-c2ccccc2)c2c1COc1ccccc1-2
Temperature: 0 °C
Yield: 91.3 %

Procedure:
1,4-Dihydro-1-phenyl-[1]-benzopyrano[4,3-c]pyrazole-3-carboxylic acid, ethyl ester (4.2 g) suspended in dioxane (60 ml) is heated with 1% KOH solution in ethanol (124 ml) at reflux temperature for 30 minutes. The reaction mixture is diluted with ice water and acidified to pH 3 with 37% HCl. The precipitate is filtered, washed with water and dried in vacuo at 50° C. to give 1,4-dihydro-1-phenyl-[1]-benzopyrano[4,3-c]pyrazole-3-carboxylic acid (3.5 g) which is reacted with thionyl chloride (1.34 ml) in dioxane (70 ml) at reflux temperature for 2 hours. After cooling the solution is evaporated to dryness in vacuo to give 1,4-dihydro-1-phenyl-[1]-benzopyrano[4,3-c]pyrazole-3-carbonyl chloride as crystalline residue. The crude product is dissolved in anhydrous dioxane (35 ml) and reacted for 2 hours under stirring at room temperature with ethyl cyanoacetate (1.5 g) carbanion, prepared by treatment with 50% sodium hydride (0.8 g) in anhydrous dimethylformamide (20 ml) at room temperature. The reaction mixture is then diluted with ice water and acidified to pH 1 with N HCl. The precipitate is filtered and dissolved in ethyl acetate, then the organic solution is washed with N HCl and water until neutral. Evaporation to dryness yields a residue which is purified over a SiO2 column using chloroform/methanol 80:20 as eluent. Crystallization from acetone gives 1.2 g of 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanoic acid, ethyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([OH:3])=O.[C:18]1([S:24]([NH2:27])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.O>[C:18]1([S:24]([N:27]=[C:1]([C:4]2[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:6][CH:5]=2)[OH:3])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(OCCn2ccnc2)cc1
Reactant: NS(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(N=C(O)c1ccc(OCCn2ccnc2)cc1)c1ccccc1

Procedure:
Treatment of 1-[2-(4-carboxyphenoxy)ethyl]imidazole with N,N'-carbonyldiimidazole followed by benzenesulphonamide as described in Example 36 above gave N-benzenesulphonyl-4-[2-(1-imidazolyl)ethoxy]benzenecarboximidic acid, m.p. 250°-252° C. (from N,N-dimethylformamide/H2O). Found: C, 58.17; H, 4.60; N, 11.08. C18H17N3O4S requires: C, 58.21; H, 4.61; N, 11.31%.
Reaction SMILES: [CH:1]1([CH2:5]O)[CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([CH:12]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:11])[CH3:8].N1C=CC=CC=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1([CH:5]=[CH:12][C:10]([O:9][CH2:7][CH3:8])=[O:11])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCC1CCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C=CC1CCC1
Temperature: 70 °C
Reaction time: 20 h
Yield: 24.4 %

Procedure:
A mixture of cyclobutyl-methanol (8.00 g, 93.02 mmol), ethoxycarbonylmethylene triphenylphosphorane (19.42 g, 55.81 mmol) and pyridine (3 mL) were dissolved in dry chloroform (100 mL) and heated at 70° C. Manganese dioxide (97.11 g, 1.12 mol) was added portion wise over a period of 5 h (with 1 h gap between each addition) and refluxing was continued for 20 h. The reaction mixture was cooled to room temperature, filtered over celite and washed with chloroform. The filtrate was concentrated and the residue subjected to column chromatography over silica gel (60-120 mesh) using 0% to 15% of ethyl acetate in pet ether as eluent to afford ethyl 3-cyclobutylprop-2-enoate (2.10 g, 15%) as a liquid.
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1>C(O)CCC>[CH2:6]([O:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:7][CH2:8][CH3:9]
Reactant: Clc1ccccn1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOc1ccccn1
Temperature: 112 °C
Reaction time: 15 h
Yield: 142.9 %

Procedure:
Into a solution of 55 g (1,38 mole) of sodium hydroxide in 245 g of n-butanol heated to 100° C., were added dropwise over four hours 113.5 g (1 mole) of 2-chloropyridine and the mixture was stirred for about 15 hours at this temperature, then heated for 2 hours at reflux (ca. 112° C.). After cooling, precipitated sodium chloride was removed by filtering and the residue was washed with about 500 ml of n-butanol. The combined filtrates were distilled in vacuum and the first fraction to distill was a butanol-water azeotrope, then followed n-butanol and a 2-chloropyridine/n-butanol intermediate run. 2-butoxypyridine distilled last at 75° C. at 10 Torr as a colorless liquid to obtain 108 g (72%) of 2-butoxypyridine with a purity of >98%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:14])[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[O:11]=[CH:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:14]
Reactant: COC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: C[C@H](C=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 165 %

Procedure:
To a cooled solution of (R)-methyl 2-(tert-butoxycarbonylamino)propanoate (40.0 g, 98.0 mmol) in DCM (200 mL) at −78° C. was added diisobutylaluminium hydride (208 mL, 1.0 M in THF) dropwise over 30 min. The reaction mixture was stirred at −78° C. for 1.5 h then quenched with water (50 mL). After warmed to rt, the white precipitate was removed by filtration over Celite. The organic layer was then washed with brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography (petroleum ether: EtOAc, 10:1) to give (R)-tert-butyl 1-oxopropan-2-ylcarbamate (28.0 g, 82%). 1H NMR (DMSO-d6, 400 MHz) δ 9.43 (s, 1H), 7.33 (d, J=6.0 Hz, 1H), 3.85 (m, 1H), 1.39 (s, 9H), 1.12 (d, J=7.2 Hz, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH2:14][C:15]([NH:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]([NH:17][CH3:18])=[O:16])=[CH:19][CH:20]=1
Reactant: CNC(=O)COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CNC(=O)COc1ccc(O)cc1
Yield: 94 %

Procedure:
A solution of 4.7 g of 2-(4-benzyloxy-phenoxy)-N-methyl-acetamide [Example 2c)] in 150 ml of tetrahydrofurane was hydrogenated at atmospheric pressure and room temperature using 470 mg of palladium on charcoal (10%) as the catalyst. For the working-up, the reaction mixture was filtered over a Dicalite layer and the resulting solution was evaporated under reduced pressure. The residue was triturated in ether and the solid collected on a filter funnel. After drying there were obtained 2.95 g (93% of theory) of 2-(4-hydroxy-phenoxy)-N-methyl-acetamide as white crystals; MS: m/e=181 (M)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1.COC(=O)OC>CS(C)=O>[CH3:22][CH:23]1[NH:24][CH2:25][CH2:26][N:27]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[C:7](=[O:18])[C:8]3=[CH:9][C:10]=2[F:17])[CH2:28]1
Reactant: CC1CNCCN1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CS(C)=O
Solvent: COC(=O)OC
Product: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 55 °C
Yield: 70 %

Procedure:
Forty grams of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid and 28.4 g (2.1 eq) of 2-methyl piperazine were suspended in DMSO (800 mL) under nitrogen atmosphere. The mixture was heated to 55° C. during 24 hours. Thereafter, dimethylcarbonate (200 mL) was added, the reaction mixture was cooled to 5° C., and held at this temperature overnight. The mixture was then filtered under vacuum and the compound was then dried under vacuum to obtain 35.5 g after assay (70% yield) of gatifloxacin.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:13][C:14]([F:32])([F:31])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([N:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:14]([F:13])([F:31])[F:32])=[CH:17][CH:18]=1)[S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: Cc1ccccc1SNc1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1SN(C(=O)NC(=O)c1ccccc1Cl)c1ccc(OC(F)(F)F)cc1
Temperature: -5 °C

Procedure:
A solution of 2.0 g of 2-chlorobenzoyl isocyanate in 5 ml of dry toluene was added to a stirred suspension of 3.0 g of N-[4-(trifluoromethoxy)phenyl]-2-methyl-benzenesulphenamide in 40 ml of dry light petroleum at room temperature. After a few minutes, the reaction mixture became clear and subsequently the product came out of solution as an oil which eventually crystallized. After 24 hours the reaction mixture was cooled to -5° C. and filtered, and the pale purple product was washed with cold light petroluem. Recrystallization from ether/light petroleum gave 4, as colorless crystals, m.p.: 79°-80° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4]2[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:17]=[CH:18][C:3]=12.[BH4-].[Na+].[Cl-].[NH4+]>C1COCC1.C(O)C>[Cl:1][C:2]1[C:7]([CH:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[OH:9])=[CH:6][N:5]=[C:4]2[N:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[CH:18][C:3]=12
Reactant: O=C(c1ccccc1)c1cnc2c(cnn2-c2ccccc2)c1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cnc2c(cnn2-c2ccccc2)c1Cl
Yield: 100 %

Procedure:
To a stirred solution of (4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone (0.16 g, 0.48 mmol) in THF (1.5 mL) and ethanol (95%, 1.5 mL) was added sodium borohydride (30 mg, 0.79 mmol). The mixture was stirred at rt for 30 min before saturated ammonium chloride aqueous solution was added with caution. The mixture was concentrated and partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. Combined organic solutions were dried (Na2SO4), filtered through a pad of silica gel, and concentrated to give (4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanol (0.16 g, 0.48 mmol, 100% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.Cl>O.CC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:9][S:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:8])=[O:7])=[O:21])=[CH:15][CH:14]=1
Reactant: CCCCCS(N)(=O)=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCS(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Reaction time: 8 h
Yield: 73.5 %

Procedure:
The general method of procedure A was followed with 1-pentanesulfonamide (10 g), acetone (200 ml), 1N NaOH (66 ml) and 4-chlorophenyl isocyanate (9.6 g). 1N HCl (66 ml) was used to acidify the solution. Additional water was added and after standing overnight the solid was isolated and dried to provide 14 g of product.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:17]=[CH:16][CH:15]=[CH:14][C:8]=1[C:9]([O:11][CH2:12]C)=[O:10])[C:2]([CH3:5])([CH3:4])[CH3:3].C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:26])C>>[CH2:1]([N:6]1[C:7]2[N:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9](=[O:10])[O:11][C:12]1=[O:26])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cccnc1NCC(C)(C)C
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Product: CC(C)(C)Cn1c(=O)oc(=O)c2cccnc21

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 30A for the product of Example 3A (0.182 g, 89%). 1H NMR (300 MHz, CDCl3) δ 1.12 (s, 9H), 4.28 (s, 2H), 7.25 (dd, J=6.99, 4.04 Hz, 1H), 8.41 (dd, J=7.91, 2.02 Hz, 1H), 8.69 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O: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][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[NH2:32]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:26]3[O:27][N:32]=[C:31]([C:33]4[N:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[N:30]=3)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1ncccn1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ncccn3)no2)C1

Procedure:
150 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 77 mg (0.56 mmol) of N′-hydroxypyrimidine-2-carboximidamide were reacted according to the General Method 2. Yield: 100 mg (51% of theory).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]([CH3:60])[C:57](Cl)=[O:58]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:57]([N:56]([CH3:60])[CH3:55])=[O:58])[CH2:49][CH2:48]1
Reactant: CN(C)C(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 84 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and N,N-dimethylcarbamoyl chloride as starting materials in 84% yield. LCMS for C27H32ClN8O2 (M+H)+: m/z=535.2.
Reaction SMILES: [CH3:1][C:2](=[CH:32][O:33]C)[C:3]([N:5]([CH2:9][C@@H:10]1[O:22][C@H:21]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11]1)[C:6]([NH2:8])=[O:7])=O.Cl>C(O)(=O)C>[CH2:25]([O:24][C@@H:23]1[C@@H:21]([CH2:12][O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:22][C@@H:10]([CH2:9][N:5]2[CH:3]=[C:2]([CH3:1])[C:32](=[O:33])[NH:8][C:6]2=[O:7])[CH2:11]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC=C(C)C(=O)N(C[C@H]1C[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O1)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cn(C[C@H]2C[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)O2)c(=O)[nH]c1=O
Yield: 74.7 %

Procedure:
1-[N-(2-methyl-3-methoxypropenoyl)ureido]-2,5-anhydro-4,6-di -O-benzyl-1,3-dideoxy-D-allitol (2.3 g) was stirred in acetic acid (36 ml)--concentrated hydrochloric acid (3.6 ml) at room temperature overnight. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (chloroform→1% methanol/chloroform) to provide 1.6 g of the desirable compound as pale-yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.[CH2:25]([N:28]=[C:29]=S)[CH2:26][CH3:27].[Cl-].[NH4+].IC.Cl>CO.O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:29]([NH:28][CH2:25][CH2:26][CH3:27])[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]=2[CH:11]=1
Reactant: COC(=O)CCCCCOc1ccc(N)c(Nc2ccccc2)c1
Reactant: CCCN=C=S
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: CI
Product: CCCNc1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccccc1

Procedure:
200 mg of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl ester was dissolved in 2 ml of methanol, the solution was mixed with 90 μl of propylisothiocyanate, and the mixture was heated for 3 hours to 50° C. After cooling, it was mixed with saturated ammonium chloride solution, diluted with water, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 140 mg of a thiourea derivative, which was dissolved in 1.5 ml of methanol, was obtained. 0.16 ml of iodomethane was added to this solution, and it was refluxed for 4 hours. After cooling, it was mixed with 1N aqueous hydrochloric acid, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 72 mg was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH:4]([N:6]1[C:19]2[CH:18]=[C:17]([C:20](=[S:22])[NH2:21])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:5].[CH:24]1([CH2:30]N)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.S>C(O)C>[CH:24]1([CH2:30][NH:21][C:20]([C:17]2[CH:16]=[CH:15][C:14]3[S:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]([CH:4]([CH3:5])[CH2:3][N:2]([CH3:1])[CH3:23])[C:19]=3[CH:18]=2)=[S:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(CN(C)C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: NCC1CCCCC1
Agent: S
Solvent: CCO
Product: CC(CN(C)C)N1c2ccccc2Sc2ccc(C(=S)NCC3CCCCC3)cc21
Temperature: 125 °C
Reaction time: 1 h

Procedure:
A mixture of 10-[(2RS)-1-dimethylamino-2-propyl]-2-phenothiazinecarbothioamide (2 g) and cyclohexylmethylamine 11.4 cc) in absolute ethanol (30 cc) is saturated with hydrogen sulphide and heated for 16 hours to a temperature in the region of 125° C. After cooling, the orange solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil is purified by chromatography on a column (height: 25 cm; diameter: 4 cm) of silica gel (0.06-0.04 mm) under a slight excess pressure of nitrogen (40 kPa) eluting with a 60:40 by volume mixture (1 litre) of ethyl acetate and cyclohexane and collecting 60-cc fractions. The combined fractions 6 to 13 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange gum (2.5 g) is dissolved in isopropanol (8 cc) under reflux and treated, with stirring, with a solution at 50° C. of fumaric acid (0.6 g) in isopropanol (8 cc). The mixture is allowed to cool and stirring is continued for 1 hour at a temperature in the region of 5° C. The solid formed is drained, washed with isopropanol (2×1 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. N-Cyclohexylmethyl-10-[(2RS)-1-dimethylamino-2-propyl]-2-phenothiazinecarbothioamide neutral fumarate (2.53 g) is thereby obtained in the form of a yellow solid, m.p. 167° C.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)=[C:2]=[S:3].[CH3:14][C:15]1[N:19]([CH2:20][CH2:21][CH2:22][NH2:23])[CH:18]=[N:17][CH:16]=1>>[CH3:14][C:15]1[N:19]([CH2:20][CH2:21][CH2:22][N:23]2[C:6](=[O:8])[C:5]3[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:1][C:2]2=[S:3])[CH:18]=[N:17][CH:16]=1
Reactant: COC(=O)c1ccccc1N=C=S
Reactant: Cc1cncn1CCCN
Product: Cc1cncn1CCCn1c(=S)[nH]c2ccccc2c1=O

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanatobenzoate (0.276 g, 1.43 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.198 g, 1.43 mmol) as described above.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[N:12]1[N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[N:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Cn2nccn2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Cn2nccn2)cc1
Yield: 96.7 %

Procedure:
A 25-mL round bottomed flask was charged with 2-((4-nitrophenyl)methyl)triazole (195 mg, 0.95 mmol, 1 eq.), palladium on carbon (206 mg, 10 wt. % loading, 0.2 eq.) and ethanol (3 ml). The resulting mixture was stirred under H2 over night. The mixture was passed through a plug of celite and washed with methanol (5 ml). Removal of solvent under reduced pressure gave the crude product (160 mg, two regioisomers, 97% yield). The product thus obtained was forwarded to the next step without any further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]1[CH2:15][CH2:14]1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:26]C=2C=1.N.CO>CN(C=O)C.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH:13]1[CH2:15][CH2:14]1)[C:10]([NH2:26])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Agent: N
Solvent: O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](C(N)=O)C1CC1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid (430 mg, 2 mmol) in DMF (6 ml) was added EDC (461 mg, 2.4 mmol) and HOBt. H2O (367 mg, 2.4 mmol) at room temperature, 20 min later, it was added ammonia in MeOH (7N, 0.6 mL, 4 mmol) at room temperature. After stirring for 30 min, it was diluted with water and EtOAc, organic layer was separated and washed with Sat. NaHCO3, brine, dried and concentrated to give (R)-tert-butyl-2-amino-1-cyclopropyl-2-oxoethylcarbamate (330 mg) as crude oil, which was treated with 4N HCl in Dioxane (2 mL). 30 min later, it was concentrated to give (R)-2-amino-2-cyclopropylacetamide hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16](F)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])=[C:4]([F:22])[CH:3]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O-:27].[Na+].O1CCCC1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([O:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])=[C:4]([F:22])[CH:3]=1
Reactant: CN(C)CC[O-]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cl)cc1F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCOc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2cn1
Yield: 64 %

Procedure:
To 250 mg of 4-(4-chloro-2-fluoro-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere was added 8 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofaran. After refluxing for 2 hours, the reaction was stripped of tetrahydrofuran and water was added. The product was filtered, washed with water, dried, and recrystallized from chloroform/ether/hexanes to give 204 mg (64%) of 4-(4-chloro-2-fluoro-phenylamino)-6-(2-dimethylamino-ethoxy)-[1.7]naphthyridine-3-carbonitrile as a yellow solid: melting point 150-152° C.; mass spectrum (m/e): M+H 385.9.