Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[N:4]=[CH:3][CH:2]=1.[NH:17]([C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)[C:18]([NH2:20])=[NH:19].[OH-].[Na+]>CO>[N:25]1[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[NH:22][C:21]=1[N:17]=[C:18]1[NH:20][C:7]2([C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=3)[NH:20][C:18](=[N:17][C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)[NH:19][C:9]2([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:16]=2)[NH:19]1
Reactant: O=C(C(=O)c1ccccn1)c1ccccn1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccccn2)NC(=Nc2nc4ccccc4[nH]2)N3)nc1
Reaction time: 96 h
Yield: 71.7 %

Procedure:
A mixture of 2,2′-pyridil (15.8 g, 74.4 mmol) and 2-guanidinobenzimidazole (19.5 g, 111.7 mmol) in methanol (440 mL) was treated with a solution of sodium hydroxide (2.97 g, 74.4 mmol) in 74 mL and the resulting mixture was left standing at room temperature for 4 days. The crystalline material was filtered and dried under vacuum to yield 21.1 g of the title compound as off-white crystals (72%). mp: 305-307° C. (dec); HPLC retention time 4.5 min (reversed phase, Beckman ultrasphere ODS 4.6 mm×25 cm column, 20 min gradient elution with 20:80 to 60:40 acetonitrile:water containing 0.1% TFA@2 mL/min); 1H NMR (300 MHz, d6-DMSO) d 11.5 (br s, NH, 2 H), 10.0 (br s, NH, 2 H), 8.6 (br s, NH, 2 H), 8.38 (d, J=4.2 Hz, 2 H), 7.55 (t,J=7.8 Hz, 2 H), 7.29 (d, J=7.8 Hz, 2 H), 7.27-7.21 (m, 4 H), 7.14 (br s, 2 H), 6.98 (dd, J=5.8, 3.2 Hz, 4 H); MS (ESI) m/z 527 [M+H]+; Anal. Calcd. for C28H22N12. ⅔H2O: C, 62.44; H, 4.37, N, 31.21; Found: C, 62.72; H, 4.08; N, 30.86.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.[OH:18][CH2:19][C:20]([NH:22][NH2:23])=O>C(O)CCC>[OH:18][CH2:19][C:20]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:23][N:22]=1
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: NNC(=O)CO
Solvent: CCCCO
Product: OCc1nnc2ccc(-c3cccc(C(F)(F)F)c3)nn12

Procedure:
A mixture of 7.76 g. of 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine, 6.66 g. of hydroxyacethydrazide and 200 ml. of n-butyl alcohol is heated at reflux temperature for 18 hours. The mixture is evaporated in vacuo and the residue is triturated with dichloromethane-hexane. The mixture is filtered and the solid is recrystallized from ethyl acetate to give the product of the Example as off-white crystals, m.p. 224°-226° C.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[N:14]=2)[CH2:5][C:4](=[O:21])[CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:22]([C:3]1[C:2](=[O:1])[CH2:7][CH:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[N:14]=2)[CH2:5][C:4]=1[OH:21])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(-c2ccsc2C2CC(=O)C=C(O)C2)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(-c2ccsc2C2CC(=O)C(C(C)=O)=C(O)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To a 200 mL recovery flask was added 3-hydroxy-5-(3-(6-methoxypyridin-2-yl)thiophen-2-yl)cyclohex-2-enone (30F, 4.9 g, 16.3 mmol, 1.0 eq.), CH2Cl2 (100 mL), acetic anhydride (2.15 g, 21.1 mmol, 1.3 eq.), Et3N (6.8 mL, 48.8 mmol, 3.0 eq.), and DMAP (catalytic). The reaction mixture was stirred overnight at room temperature whereupon LC/MS showed two signals corresponding to M+H=344. Additional acetic anhydride (0.5 mL, 5.3 mmol, 0.32 eq.) was added and the reaction mixture was heated for 6 h at 40° C. LC/MS analysis showed the reaction to be complete whereupon the mixture was concentrated to a solid and purified via flash chromatography (70% CH2Cl2/Hex to 100% CH2Cl2) to yield a dark orange solid 30G (1.72 g, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52-2.57 (m, 3H) 2.83 (m, 2H) 3.09 (m, 2H) 3.78 (s, 3H) 4.68 (m, 1H) 6.74 (d, J=8.34 Hz, 1H) 7.32 (d, J=7.33 Hz, 1H) 7.41-7.47 (m, 1H) 7.51 (d, J=5.31 Hz, 1H) 7.76 (t, J=7.96 Hz, 1H). ESI-MS: m/z 344.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:38]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:39])[CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCCC1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N1CCCC1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.20 mmol) (from Example 25a supra) in tetrahydrofuran (3 mL) was added triethylamine (32 mg, 0.3 mmol) (Aldrich), followed by the addition of 1-pyrrolidinecarbonyl chloride (34 mg, 0.24 mmol) (Aldrich). The mixture was stirred at 50° C. for 1 hour, then cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue were triturated with dichloromethane-hexanes to give rac-6-chloro-3-(3-chloro-benzyl)-3-[1-(pyrrolidine-1-carbonyl)-piperidin-3-yl]-1,3-dihydro-indol-2-one as a white solid. (Yield 50 mg, 50%).
Reaction SMILES: C(O[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1B1OC(C)(C)CCCCCO1)C.I[C:24]1[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][C:25]=1[NH2:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[O:22]=[C:4]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:27]2[CH:28]=[C:29]([C:31]#[N:32])[CH:30]=[CH:24][C:25]=2[NH:26]1
Reactant: N#Cc1ccc(N)c(I)c1
Reactant: CCOC(=O)c1ccccc1B1OCCCCCC(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#Cc1ccc2[nH]c(=O)c3ccccc3c2c1
Yield: 120.4 %

Procedure:
2-(4,4-Dimethyl-[1,3,2]dioxaboronan-2-yl)-benzoic acid ethyl ester (19.84 g), 2-iodo-4-cyanoaniline (18.47 g), tetrakis(triphenylphosphine)palladium (8.75 g) and potassium phosphate (35.36 g) were added to dioxane (360 ml), and the resulting mixture was heated under reflux overnight. The reaction solvent was cooled, and the produced solid was collected by filtration, washed with water and dried to thereby obtain 17.3 g (yield: quantitative) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:21])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[OH-].[Na+].[CH:24]1([C:30]([Cl:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>CC(C)=O>[ClH:32].[CH:24]1([C:30]([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:21])[CH2:16][NH:17][CH:18]([CH3:19])[CH3:20])=[C:6]3[C:11]=2[NH:10][C:9](=[O:12])[CH2:8][CH2:7]3)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)NCC(O)COc1ccc(O)c2c1CCC(=O)N2
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)NCC(O)COc1ccc(OC(=O)C2CCCCC2)c2c1CCC(=O)N2
Yield: 45.5 %

Procedure:
0.66 g of 8-hydroxy-5-(2-hydroxy-3-isopropylaminopropoxy)-3,4-dihydrocarbostyril was suspended in 10 ml of acetone, and 3.0 ml of 1 N sodium hydroxide was added thereto to form a homogeneous solution. To the resulting solution was added dropwise 0.35 g of cyclohexylcarbonyl chloride dissolved in a small amount of acetone under ice-cooling and stirring. After the reaction mixture was allowed to stand under ice-cooling for 30 minutes, the mixture was adjusted to a pH of 3 with 1 N hydrochloric acid. The solvent was evaporated, and the residue was dissolved in water and then extracted with chloroform. The aqueous layer was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel chromatography using chloroform-methanol (8:1 by volume) as an eluent. The solvent was evaporated, and the residue was recrystallized from methanol-diethyl ether to obtain 0.45 g of 8-cyclohexylcarbonyloxy-5-(2-hydroxy-3-isopropylaminopropoxy)-3,4-dihydrocarbostyril hydrochloride as colorless flake-like crystals having a melting point of 227°-228° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[C@@H:4]([NH:9][C:10]([O:12][C:13]([CH3:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6].O.[OH-].[Li+].[Li+].[OH-]>C1COCC1.O>[CH3:6][C:5]([CH3:8])([CH3:7])[C@H:4]([NH:9][C:10]([O:12][C:13]([CH3:19])([CH3:18])[C:14]([F:15])([F:16])[F:17])=[O:11])[C:3]([OH:20])=[O:2]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C(F)(F)F)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[C@H](NC(=O)OC(C)(C)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (S)-3,3-Dimethyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxycarbonylamino)-butyric acid methyl ester (673 mg, 2.249 mmol, from Step 1b) in THF (4 mL) was added to a pre-made solution of lithium hydroxide monohydrate (189 mg, 4.50 mmol) in water (4.00 mL). The cloudy white solution was stirred at rt for 5 hrs. Another 100 mg of LiOH in 1 mL water was added to the mixture and the solution was stirred at rt overnight. The volatiles were removed, and the reaction mixture was diluted with 5% citric acid aqueous solution, and extracted with EtOAc (3×10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The crude material (325 mg, 51%) as white solid was used in the next step reaction without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2Cl)[C:7]([CH2:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H][H]>CO.[Pt]=O>[CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:7]([CH2:10][CH:11]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1ncc(CC(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Agent: O=[Pt]
Solvent: CO
Product: CCCCc1ncc(CC(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1
Yield: 18.1 %

Procedure:
A solution of methyl 3-[2-n-butyl-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoate [Example 9] (0.75 g) in methanol (25 mL) was stirred with platinum oxide (0.07 g) at room temperature under one atmosphere of hydrogen for 18 hours. Column chromatographic separation of the crude product over silica gel with 10% methanol in ethyl acetate gave 0.52 g of the crude de-chlorinated product. This was further purified on a prep silica gel plate using 30% acetone in hexane to provide 0.125 g of methyl 3-[2-n-butyl-1-benzyl-1H-imidazol-5-yl]-2-benzylpropanoate as a syrup.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[Cl:19].CN([CH:23]=[O:24])C>C1COCC1>[Br:13][C:14]1[CH:18]=[C:17]([CH:23]=[O:24])[S:16][C:15]=1[Cl:19]
Reactant: Clc1sccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cc(Br)c(Cl)s1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
n-BuLi (2.5 M in hexanes, 105 mL) is slowly added to a solution of diisopropylamine (36.8 mL) in THF (600 mL) at 0° C. After 15 min, the mixture is cooled to −70° C. A solution of 3-bromo-2-chlorothiophene (49.4 g) in THF (20 mL) is added maintaining the internal temperature <−65° C. After 15 min, DMF (25.2 mL) is added. The mixture is stirred at −70° C. for 15 min and then allowed to warm to room temperature. The reaction mixture is quenched with saturated aq. NH4Cl solution (200 mL) and concentrated in vacuo to one-half volume. The residue is diluted with EtOAc (500 mL) and the aqueous layer is separated. The aqueous layer is extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine (100 mL), dried (MgSO4), and concentrated to afford an oil. The oil is purified by column chromatography (heptane; heptane/EtOAc, 20/1; 10/1) and the resulting solid is suspended in heptane (75 mL) and filtered to afford 30.3 g (54%) of the title compound as a light yellow solid. Physical characteristics: M.p. 61-62° C.; 1H NMR (300 MHz, DMSO-d6) δ9.82, 8.14; 13C NMR (100 MHz, CDCl3) δ181.6, 140.9, 138.5, 138.1, 112.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C:9](=[O:13])[CH2:8][C:7]=2[CH:14]=1.[N+:15]([O-])([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>>[N+:15]([C:4]1[C:3]([O:2][CH3:1])=[CH:14][C:7]2[CH2:8][C:9](=[O:13])[NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:17])=[O:16]
Reactant: COc1ccc2c(c1)CC(=O)NCC2
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(cc1[N+](=O)[O-])CCNC(=O)C2
Temperature: 0 °C

Procedure:
765 mg (4 mmol) of 8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one were added to a mixture of 15 ml of concentrated nitric acid and 1.5 ml of fuming nitric acid at a temperature between 3° and 5° C., while stirring. After stirring at this temperature for 30 minutes more, the mixture was poured into ice water, and the aqueous mixture was neutralized with potassium carbonate. The precipitate formed thereby was suction-filtered off, washed with water and dried. The yellow crystals were purified by chromatography on silica gel, using ethyl acetate as the eluant, to separate the corresponding 9-nitro- and 7,9-dinitro-isomers.
Reaction SMILES: C(O[C:6]([N:8](C)[C:9]([C:11]1[C:12]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[N:13][N:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([CH3:32])=[N:22][C:23]([O:30][CH3:31])=[C:24]([CH:29]=3)[C:25]([O:27][CH3:28])=[O:26])=[C:16]([F:33])[C:15]=12)=[O:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:33][C:16]1[C:15]2[N:14]([N:13]=[C:12]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[C:11]=2[C:9](=[O:10])[NH:8][CH3:6])[CH:19]=[CH:18][C:17]=1[C:20]1[C:21]([CH3:32])=[N:22][C:23]([O:30][CH3:31])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1cc(-c2ccn3nc(-c4ccc(F)cc4)c(C(=O)N(C)C(=O)OC(C)(C)C)c3c2F)c(C)nc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cc(C(=O)OC)c(OC)nc3C)c(F)c12

Procedure:
To a solution containing methyl 5-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-2-methoxy-6-methylnicotinate (0.07 g, 0.13 mmol) and dichloromethane (2.5 mL) was added TFA (0.39 mL, 5.0 mmol) at room temperature. The solution was maintained for 15 minutes and concentrated to dryness to afford Methyl 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)-2-methoxy-6-methylnicotinate as a tan solid which was used without further purification. LCMS retention time: 1.777 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% methanol/90% H2O/10 mM TFA and solvent B was 10% H2O/90% methanol/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 489 (MNa+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2O.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2ncc([N+](=O)[O-])c(O)c2c1
Product: Cc1ccc2ncc([N+](=O)[O-])c(Cl)c2c1
Temperature: 25 °C

Procedure:
6-Methyl-3-nitroquinolin-4-ol (Compound of step 2, 610 mg) in POCl3 (5 mL) was stirred for 45 min at 120° C. The mixture was cooled to RT and poured slowly into ice-water. The precipitate was filtered, washed with ice-cold water and dissolved in CH2Cl2. The organic phase was washed with cold brine, and the aqueous phase was discarded. After drying over Na2SO4, the organic solvent was evaporated to dryness to obtain the title compound. Yield: 600 mg (90%); 1HNMR (DMSO-d6, 300 MHz: δ 9.299 (s, 1H), 8.192 (s, 1H,), 8.096-8.124 (d, 1H, J=8.4 Hz), 7.893-7.927 (dd, 1H, J=8.4 Hz, 1.8 Hz), 2.604 (s, 3H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:50][CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:50][CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)CCCCl
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCCS(C)(=O)=O)c4ccc(OC(F)F)cc34)nc12
Temperature: 65 °C
Yield: 88.2 %

Procedure:
To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.156 mmol) in DMF (5 mL) was added 1-chloro-3-(methylsulfonyl)propane (30 mg, 0.187 mmol) followed by K2CO3 (65 mg, 0.468 mmol). The mixture was heated at 65° C. for 3 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (105 mg, 88%). The crude product was used to the next step without purification. MS: (M+H)+=763.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:32])=[C:16]([N:20]3[CH2:23][C:22]([CH3:31])([NH:24]C(=O)C(F)(F)F)[CH2:21]3)[C:17]=2[F:19])[C:12](=[O:33])[C:11]([C:34]([OH:36])=[O:35])=[CH:10]1.[OH-].[Na+].C(O)C>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:32])=[C:16]([N:20]3[CH2:23][C:22]([NH2:24])([CH3:31])[CH2:21]3)[C:17]=2[F:19])[C:12](=[O:33])[C:11]([C:34]([OH:36])=[O:35])=[CH:10]1
Reactant: CC1(NC(=O)C(F)(F)F)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(N)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)C1
Yield: 22.6 %

Procedure:
A solution of 1.1 g (2.1 mmoles) of 1-(2,4-difluorophenyl)-6,8-difluoro-7-(3-methyl-3-trifluoroacetamido-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (example 34), 4 ml of 10% sodium hydroxide, 5 ml of ethanol and 25 ml of water is heated under reflux for 3 hours. It is cooled, filtered, acetic acid is added and the product filtered and washed with water and cold ethanol. 0.2 g (22%) of 1-(2,4-difluorophenyl)-6,8-difluoro-7-(3-amino-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 185°-6° C.
Reaction SMILES: [OH:1][C:2]([CH3:9])([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[O:10]1[CH:11]=[CH:12][CH2:13][CH2:14][CH:15]1[O:1][C:2]([CH3:9])([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(C)(C)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: COC(=O)CC(C)(C)OC1CCC=CO1

Procedure:
In 50 ml of 7 wt. % hydrochloric acid methanol solution was dissolved 1.18 g of β-hydroxyisovaleric acid, and an reaction was allowed to proceed at room temperature overnight. The solvent was removed from the solution as reacted by distillation under a reduced pressure to obtain 1.30 g of crude methyl β-hydroxyisovalerate. The crude methyl β-hydroxyisovalerate was dissolved in diethyl ether, and 0.91 g of 3,4-dihydro-2H-pyran and a catalytic amount of p-toluenesulfonic acid were added thereto. Stirring was continued at room temperature overnight for reaction. The resultant reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water and dried over magnesium sulfate. The solvent was removed from the dried reaction mixture by distillation under a reduced pressure to obtain 1.98 g of crude methyl β-dihydropyranyloxyisovalerate.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5](#[N:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Cl-].[Zn+2].[Cl-]>[C:6]1([C:5]2[NH:12][N:3]=[N:2][N:1]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Product: c1ccc(-c2nnn[nH]2)cc1

Procedure:
As outlined in Scheme 9, benzonitrile is treated with sodium azide and zinc chloride to give 5-phenyltetrazole 22 which is convened to the N-trityl derivative 23 by treatment with triphenylmethyl chloride and triethylamine. The zinc reagent 24 was prepared by treatment with n-butyl lithium followed by zinc chloride. Coupling with 4-iodotoluene using the catalyst bis(triphenylphosphine)nickel(II) dichloride gives the biphenyl product 25 in high yield. Treatment with N-bromosuccmimide in refluxing carbon tetrachloride in the presence of a radical initiator such as benzoyl peroxide or 2,2'-azobisisobutyronitrile (AIBN) gives bromide 26.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>O.C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-c2ccc(C)cc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc(C)c(C(=O)O)s2)cc1
Yield: 88 %

Procedure:
The mixture of ethyl 4-methyl-2-p-tolylthiazole-5-carboxylate (0.200 g; 0.765 mmol) and sodium hydroxide (0.0643 g; 1.61 mmol) in water (4 mL) and ethanol (8 mL) was irradiated in a microwave oven at 130° C. for 5 min. The mixture was concentrated (removal of ethanol), and the pH of the solution was adjusted to 3 by addition of 6N hydrochloric acid. The acidic solution was extracted with (3×10 mL) of ethyl acetate. Combined organic layers were dried over magnesium sulfate, and evaporated to afford 0.157 g (88%) of 4-methyl-2-p-tolylthiazole-5-carboxylic acid as a white solid which was directly used in the next step.