Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=1[C:13]([OH:15])=O)[C:4](=[O:6])[CH3:5])[CH3:2].C[O-].[Na+]>O1CCOCC1>[CH2:1]([N:3]1[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:13]([OH:15])=[CH:5][C:4]1=[O:6])[CH3:2]
Reactant: CCN(C(C)=O)C1=C(C(=O)O)CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1c2c(c(O)cc1=O)CCCC2

Procedure:
A solution of the ethyl and methyl esters (60:40 ratio) of 2-(N-ethyl-acetamido) cyclohex-1-ene-1-carboxylic acid (10 g; 0.043 mole) in dry dioxan (100 ml) was treated with sodium methoxide (2.54 g; 0.047 mole) and the mixture heated for 2 hrs. at 100° C. A white solid separated within a few minutes. After cooling the precipitate was filtered free of dioxan, taken up in a minimum of water and brought to pH 4 with concentrated hydrochloric acid. The product separated as a white solid which after filtration was recrystallised from glacial acetic acid, m.p. 355° -358° C (d).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:48][C:49]1([OH:53])[CH2:52][NH:51][CH2:50]1.CCN(C(C)C)C(C)C>ClCCl.CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:51]3[CH2:52][C:49]([OH:53])([CH3:48])[CH2:50]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:1])[F:23])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CC1(O)CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC1(O)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93.6 %

Procedure:
In a 25 mL 3N round-bottomed flask equipped with nitrogen inlet, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (4) (0.250 g, 1.0 eq.) was charged along with dichloromethane (5.0 mL, 20 V). The reaction mixture was cooled to 0° C. and then added HOBT (0.119 g, 1.1 eq.) followed by EDC HCl (0.149 g, 1.1 eq.) and 3-methyl azetidin-3-ol HCl (0.096 g g, 1.1 eq.). DIPEA (0.101 g, 1.1 eq) was added to this reaction mixture dropwise at the same temperature. The clear reaction mixture was stirred at 0° C. for 1.5 h. The progress of the reaction was followed by TLC analysis on silica gel with 10% methanol in dichloromethane as mobile phase and visualization with UV. Reaction mixture was quenched in 20 mL ice-water slurry. Organic layer was separated and aqueous layer was extracted with dichloromethane (2×10 mL) to ensure complete extraction. The organic layer was washed with brine solution and dried over anhydrous Na2SO4 and concentrated by rotary evaporation under reduced pressure (35° C., 20 mm Hg) to afford 0.280 g of crude compound. (cis: 61.9%, trans: 16.46%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1>CN(C=O)C.C(Cl)Cl>[CH2:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[N+:8]([O-:10])=[O:9])[CH2:18][CH2:17]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of 2.03 g (11.6 mmol) of 4-chloro-2-fluoro-nitrobenzene in DMF (12.0 mL) at rt was added 2.00 g (11.6 mmol) of ethyl 4-amino-1-piperidinecarboxylate. A yellow precipitate formed within 30 min and the reaction was further diluted with DMF (12.0 mL) and CH2Cl2 (5.0 mL) and was shaken at 300 RPM overnight. The solvent was removed under reduced pressure and the resulting solid was dried under vacuum. The crude product was purified by flash chromatography (silica, 0-5% MeOH/CH2Cl2) to afford 2.83 g (81%) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.4. MS (electrospray): m/z calculated for C14H18ClN3O4 [M++Na] 350.09, observed 350.0. 1H NMR (400 MHz, CDCl3): 8.13 (apparent d, J=9.1 Hz, 2H), 6.84 (d, J=2.0 Hz, 1H), 6.62 (dd, J=9.4, 2.3 Hz, 1H), 4.15 (q, J=14.9, 7.3 Hz, 2H), 4.08 (br d, J=12.4 Hz, 2H), 3.70-3.58 (m, 1H), 3.17-3.05 (m, 2H), 2.07 (br dd, J=13.1, 3.1 Hz, 2H), 1.63-1.50 (m, 2H), 1.28 (t, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]=O)=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[C:3]=1[O:13][CH3:14].[C:15]([CH2:17][C:18]([O:20]CC)=[O:19])#N.[OH-:23].[Na+].Cl>O>[O:23]=[C:15]1[C:17]([C:18]([OH:20])=[O:19])=[CH:11][C:10]2[CH:9]=[C:5]3[CH:6]=[CH:7][O:8][C:4]3=[C:3]([O:13][CH3:14])[C:2]=2[O:1]1
Reactant: [OH-]
Reactant: CCOC(=O)CC#N
Reactant: COc1c(O)c(C=O)cc2ccoc12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1c2occc2cc2cc(C(=O)O)c(=O)oc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The aldehyde of Example 5 (192 mg., 1 mmole) in 1 ml. of water was added to a solution of ethyl cyanoacetate (125 mg., 1.1 mmole) in 1 ml. of water containing 200 mg. of sodium hydroxide. The mixture was stirred at room temperature for 20 hours then treated with 8 ml. of 2N HCl under reflux for 30 minutes. After cooling, the product was isolated by centrifugation followed by crystallization from ethanol to yield a yellow solid, m.p. 227°-228°.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21][N:29]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH3:28])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCN12
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)n1
Yield: 64 %

Procedure:
A solution of 1.1 g (0.00281 mol) of (S)-8-chloro-1-(4-chloromethyl-thiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one in 70 ml of tetrahydrofuran was treated with 7.7 ml (0.0562 mol) of dipropylamine. After stirring at reflux for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with ethyl acetate as the eluent and recrystallized from ethyl acetate/ether. There was obtained 0.82 g (64%) of (S)-8-chloro-1-(4-dipropylaminomethyl-thiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepin-9-one as white crystals; m.p. 200°-201° and [α]D20 =-181.2° (CHCl3, c=1%).
Reaction SMILES: C([O:4][C@@H:5]1[O:22][C@@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C(O)(=O)C.NN.C(OCC)(=O)C>CN(C)C=O>[C:8]([O:7][C@H:6]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:21]([CH3:23])[O:22][CH:5]1[OH:4])(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@@H]1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: NN
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)OC(O)[C@H]1OC(C)=O
Yield: 80 %

Procedure:
A solution of 1,2,3,4-tetra-O-acetyl-α-L-fucopyranose (6.00 g, 18 mmol), prepared, for example, according to Nunez et al., supra., and hydrazine acetate (1.99 g, 21.6 mmol) in 20 ml of dry dimethylformamide is stirred at 50° C. for 4.5 h. After addition of ethyl acetate, the mixture is extracted about twice with aqueous sodium chloride solution and the concentrated organic extract is chromatographed (petroleum ether (40°-60°)/ethyl acetate 1:1). 2,3,4-Tri-O-acetyl-L-fucopyranose (1) is obtained in an anomer ratio of α:β of 3:1 with a yield of 80%. TLC analysis (petroleum ether (40°-60°)/ethyl acetate 1:1) gives Rf =0.47.
Reaction SMILES: O.[ClH:2].Cl.[NH2:4][CH2:5][C:6]([CH2:8][NH2:9])=O.Cl.[C:11]1([CH2:17][O:18][NH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:20]O>>[ClH:2].[C:11]1([CH2:17][O:18][N:19]=[C:6]2[CH2:8][NH:9][CH:20]=[N:4][CH2:5]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NOCc1ccccc1
Reactant: NCC(=O)CN
Reactant: CO
Agent: Cl
Solvent: O
Product: C1=NCC(=NOCc2ccccc2)CN1
Yield: 60 %

Procedure:
1,3-Diaminoacetone dihydrochloride monohydrate (2.00 g, 11.2 mmol) was dissolved in refluxing methanol and O-phenylmethylhydroxylamine hydrochloride (3.30 g, 20.5 mmol) was added. After refluxing for 20 hours the solvent was evaporated. The crude product was dissolved in methanol and an excess of trimethylorthoformate was added to the reaction mixture which was heated to reflux. After 48 hours the solvent was removed in vacuo. Crystallization from methanol/ethyl acetate afforded 1.60 g (60%) of white material. Mp. 167.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[C:6]([F:8])[CH:7]=1.I[CH2:24][CH3:25].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:36]1COC[CH2:37]1>>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11](=[O:15])[C:12]([CH2:24][CH3:25])([CH2:36][CH3:37])[CH2:13][CH2:14]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC[C@H]1c1cc(F)cc(F)c1
Reactant: C1CCOC1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CCC1(CC)CC[C@@H](c2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2S)-2-(3,5-difluorophenyl)-6-oxopiperidine-1-carboxylate from Step C (1.53 g, 4.91 mmol) and iodoethane (0.993 mL, 12.3 mmol) in THF (15 mL) at −78° C. was added a 1 M solution of sodium bis(trimethylsilyl)amide in THF (10.8 mL, 10.8 mmol) dropwise over 15 min. The resulting mixture was stirred at −78° C. for 10 min and at 0° C. for 2 h, then quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=312 (M−C4H7).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].CN1CCCC1=O>[Cu](I)I.[Cu].O>[ClH:1].[CH2:14]([N:16]([CH2:17][CH3:18])[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1)[CH3:15]
Reactant: CCNCC
Reactant: Cc1cccc2c(Cl)cc(=O)[nH]c12
Agent: I[Cu]I
Agent: [Cu]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCN(CC)c1cc(=O)[nH]c2c(C)cccc12
Product: Cl

Procedure:
2.0 Grams of 4-chloro-8-methylcarbostyril, 5 ml of diethylamine, 0.2 g of copper iodide-copper powder mixture and 20 ml of N-methylpyrrolidone were placed in an autoclave and heated at 180°-190° C. for 10 hours. To the reaction mixture was added water, then extracted with ethyl acetate. The extract was washed with water, dried, and the solvent was removed by evaporation. The residue thus obtained was purified by a silica gel column chromatography (eluent: dichloromethane). The product was converted into hydrochloride by using ethanol-HCl, and recrystallized from acetone-diethyl ether to obtain 0.6 g of 4-diethylamino-8-methylcarbostyril hydrochloride. Light brown powdery substance. Melting point: 183°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([OH:17])[CH:10]=2.[I-].[N:24]1([C:30](N2C=C[N+](C)=C2)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([O:17][C:30]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:31])[CH:10]=2
Reactant: Cc1c(Cc2ccc(Cl)c(Cl)c2)c(=O)oc2cc(O)ccc12
Reactant: C[n+]1ccn(C(=O)N2CCOCC2)c1
Agent: [I-]
Product: Cc1c(Cc2ccc(Cl)c(Cl)c2)c(=O)oc2cc(OC(=O)N3CCOCC3)ccc12

Procedure:
The title compound was prepared from 3-(3,4-dichloro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(morpholine-4-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=448 (M+1), Rt: 4.73 min.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[OH:22]>C(OCC)C.N1C=CC=CC=1>[C:1]([O:22][C:15]1[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=1[Cl:13])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCCCC(=O)Oc1cc(Cl)c(Cl)cc1Cl

Procedure:
A solution of decanoyl chloride (Pfaltz and Bauer, 5.6 ml) and 2,4,5-trichlorophenol (5.6 g) in diethyl ether (1 L) and pyridine (120 ml) is stirred for 4 hours. The reaction mixture is filtered and dried in vacuo. The 2,4,5-trichlorophenyl n-decanoate is purified on a silica-gel column (Woelm), using toluene as the eluent. Fractions are monitored by TLC, using short-wave UV for detection. Appropriate fractions are pooled and dried in vacuo to give 10.4 g of 2,4,5-trichlorophenyl n-decanoate.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH2:19][NH2:20].C(O)(=O)C>O>[NH:19]([C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1)[NH2:20]
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Cn1cnc2c(NN)nc3ccccc3c21

Procedure:
4-Chloro-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (10.0 g, 0.0385 moles, U.S. Pat. No. 4,689,338 Example 77) was added to hydrazine (30 ml). The mixture heated rapidly to reflux. The solid dissolved with a vigorous heat of reaction then a precipitate formed as the reaction mixture refluxed. The reaction mixture was diluted with water. The precipitate was isolated by filtration then suspended in water (100 mL). The solid was brought into solution by the addition of acetic acid. The solution was filtered to remove traces of undissolved solid. The filtrate was made basic by the addition of ammonium hydroxide. The resulting precipitate was isolated by filtration, washed with water then dried to provide 8.0 g of crude product as a white solid. A sample of this material was recrystallized from methanol to provide 4-hydrazino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline, m.p. 202-205° C. Analysis: Calculated for C14H17N5 : %C, 65.86; %H, 6.71; %N, 27.43; Found: %C, 65.20; %H, 6.6; %N, 27.5.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=[C:20]4[S:24][C:23](SC)=[N:22][C:21]4=[O:27])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)=[C:7]([C:30]([F:33])([F:32])[F:31])[CH:6]=1)(=[O:4])=[O:3].[CH3:34][NH:35][CH2:36][CH:37]([OH:40])[CH2:38][OH:39]>>[OH:40][CH:37]([CH2:38][OH:39])[CH2:36][N:35]([CH3:34])[C:23]1[S:24][C:20](=[CH:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:10]([CH2:9][C:8]2[CH:28]=[CH:29][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][C:7]=2[C:30]([F:32])([F:31])[F:33])[N:11]=[CH:12]3)[C:21](=[O:27])[N:22]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(S(C)(=O)=O)cc3C(F)(F)F)c2)S1
Reactant: CNCC(O)CO
Product: CN(CC(O)CO)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(S(C)(=O)=O)cc3C(F)(F)F)c2)S1

Procedure:
2-[(2,3-Dihydroxy-propyl)-methyl-amino]-5-[1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one was prepared from 5-[1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 3-Methylamino-propane-1,2-diol following General Procedure C.
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH:25]([CH3:29])[NH:24]1>N1C=CC=CC=1>[CH3:22][CH:23]1[NH:24][CH:25]([CH3:29])[CH2:26][N:27]([C:2]2[C:3]([F:21])=[CH:4][C:5]3[C:6]([CH:20]=2)=[N:7][C:8]2[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=2[CH:14]=3)[CH2:28]1.[OH2:15].[CH3:22][CH:23]1[NH:24][CH:25]([CH3:29])[CH2:26][N:27]([C:2]2[C:3]([F:21])=[CH:4][C:5]3[C:6]([CH:20]=2)=[N:7][C:8]2[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=2[CH:14]=3)[CH2:28]1.[CH3:22][CH:23]1[NH:24][CH:25]([CH3:29])[CH2:26][N:27]([C:2]2[C:3]([F:21])=[CH:4][C:5]3[C:6]([CH:20]=2)=[N:7][C:8]2[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=2[CH:14]=3)[CH2:28]1
Reactant: CC1CNCC(C)N1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Product: CC1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)CC(C)N1
Product: O

Procedure:
8-(3,5-Dimethyl-1-piperazinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 3 but starting from 1.7 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 2.5 g of 2,6-dimethylpiperazine in 20 cm3 of pyridine. 1.1 g of 8-(3,5-dimethyl-1-piperazinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid hemihydrate are obtained in the form of a yellow solid melting at 294°-295° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2C(C#N)=[C:15]3[C:10]([CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([CH:19]4[CH2:21][CH2:20]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[OH-:25].[Na+].[CH2:27]([OH:29])[CH3:28]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:28]([C:27]([OH:25])=[O:29])=[C:15]3[C:10]([CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([CH:19]4[CH2:21][CH2:20]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Br)cc1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Br)cc1
Temperature: 90 °C
Yield: 63 %

Procedure:
To a stirred suspension of compound (vi) (3.3 g, 8.6 mmol) in ethanol (35 mL) was added aqueous NaOH (3.44 g, 86 mmol) and the reaction mixture was heated to 90° C. and maintained for 15 h when TLC and LCMS showed the absence of SM and formation of product. Concentration of the solvent gave a crude residue which was dissolved in water and filtered. The filtrate was acidified with dilute HCl at which time the product precipitated and was filtered to give the crude product which was purified by acid-base treatment to give 2-(4-bromophenyl)-5-cyclopropyl-6-nitro-2H-indazole-3-carboxylic acid (vii) (2.2 g, 63%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C@@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[NH3:17].C1COCC1>S(Cl)(Cl)=O.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C@@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([NH2:17])=[O:16])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2ccncc2)CC1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)[C@H]1CC[C@@H](Nc2ccncc2)CC1
Reaction time: 1 h

Procedure:
cis-4-(Pyridin-4-ylamino)cyclohexanecarboxylic acid (600 mg, 2.74 mmol) was dissolved in thionyl chloride (2 ml) at room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to yield the crude acid chloride, which was added to liquid ammonia/THF (1:1, 15 ml) and allowed to stir at room temperature. The reaction mixture was diluted with DCM and filtered. The filtrate was concentrated under reduced pressure to afford 400 mg (68%) of cis-4-(pyridin-4-ylamino)cyclohexanecarboxamide as white solid.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[O:9][CH:8]=[C:7]([C:10]2[CH:22]=[CH:21][C:13]3[NH:14][C:15](=[O:20])[O:16][C:17]([CH3:19])([CH3:18])[C:12]=3[CH:11]=2)[CH:6]=1)C.Cl>C1COCC1>[CH3:18][C:17]1([CH3:19])[O:16][C:15](=[O:20])[NH:14][C:13]2[CH:21]=[CH:22][C:10]([C:7]3[CH:6]=[C:5]([CH:4]=[O:3])[O:9][CH:8]=3)=[CH:11][C:12]1=2
Reactant: CCOC(OCC)c1cc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)co1
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)OC(=O)Nc2ccc(-c3coc(C=O)c3)cc21

Procedure:
A solution of 6-(5-diethoxymethyl-furan-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (1.1 g, 3 mmol) was stirred in THF (20 mL) and 2N HCl (2 mL) for 1 hour. The crystalline product was filtered and dried (0.52 g, 69%): mp 262-263° C.; 1H NMR ( DMSO-d6 ) δ10.3 (s, 1H), 9.65 ( s, 1H), 8.59 (s, 1H), 8.04 (s, 1H), 7.65-7.64 (d, 1H, J=1.5 Hz),7.61-7.60 (d, 1H, J=1.8 Hz), 7.59-7.58 (d, 1H, J=1.8 Hz), 6.94-6.91 (d, 1H, J=8.2 Hz), 1.65 (s, 6H). .MS (ESI) m/z 270 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][NH:7][C:8]([O:10][C@H:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH:34]3[CH2:36][CH2:35]3)[CH:23]=2)[CH2:12][C:13]2[C:18]([Cl:19])=[CH:17][N+:16]([O-:20])=[CH:15][C:14]=2[Cl:21])=[O:9])=[CH:4][CH:3]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[Cl:19][C:18]1[CH:17]=[N+:16]([O-:20])[CH:15]=[C:14]([Cl:21])[C:13]=1[CH2:12][C@@H:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:30])[F:31])=[C:24]([O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[CH:23]=1)[O:10][C:8](=[O:9])[NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([N:1]([S:40]([CH3:39])(=[O:42])=[O:41])[S:40]([CH3:39])(=[O:42])=[O:41])=[CH:38][CH:37]=1
Reactant: Nc1ccc(CNC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc(CNC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 90.1 %

Procedure:
A mixture of (S)-4-(2-(4-aminobenzylcarbamoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (190 mg, 0.334 mmol) and TEA (0.102 ml, 0.735 mmol) in DCM (7 ml) was cooled to 0° C., and methanesulfonyl chloride (0.051 ml, 0.669 mmol) was added. The cold bath was removed and the solution was stirred at RT for 5 hours. The reaction mixture was concentrated under reduced pressure and the resulting crude product (218 mg, 0.301 mmol, 90% yield, MS/ESI+ 646.3 [MH]+) was used in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:53])[CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si](C(C)(C)C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])=[CH:17][CH:18]=1)[CH3:9]>ClCCl>[CH2:8]([O:10][C:11](=[O:53])[CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:26][CH3:27])([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([OH:43])[C:39]([CH3:40])([CH3:41])[CH3:42])=[C:32]([CH3:51])[CH:31]=3)[CH2:28][CH3:29])=[CH:21][C:20]=2[CH3:52])=[CH:17][CH:18]=1)[CH3:9]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(CCC(O)C(C)(C)C)c(C)c3)cc2C)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
Trifluoroacetic acid (0.03 mL) was added to a solution of {6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid ethyl ester (Example 23-(2); 2.1 mg, 0.0033 mmol) in dichloromethane (0.15 mL) at room temperature, and the mixture was stirred at room temperature for one hour and 15 minutes. The solvent in the reaction solution was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (1.7 mg, 100%).