Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].O.[NH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1.C(Cl)(=O)OCC.[C:22](=S)=[S:23]>>[N:4]([CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10]1)=[C:22]=[S:23]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: S=C=S
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N1CCC(N=C=S)CC1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred and cooled mixture of 4 parts of sodium hydroxide in 60 parts of water were added successively 7.9 parts of carbon disulfide and 17.2 parts of ethyl 4-amino-1-piperidinecarboxylate at a temperature below 10° C. Stirring was continued for 30 minutes at this temperature. Then there were added dropwise 10.9 parts of ethyl carbonochloridate (exothermic reaction: temp. rises to about 35° C.). Upon completion, stirring was continued for 2 hours at 60° C. The reaction mixture was cooled and the product was extracted with methylbenzene. The extract was dried, filtered and evaporated, yielding 22 parts (100%) of ethyl 4-isothiocyanato-1-piperidinecarboxylate (4).
Reaction SMILES: CC1N=C(C2C=CC=CC=2)C=CC=1C(OCC)=O.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(OC)(=O)CS.[H-].[Na+].[C:53]1([C:59]2[N:68]=[C:67]3[C:62]([C:63](=[O:73])[CH:64](C(OC)=O)[S:65][CH2:66]3)=[CH:61][CH:60]=2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(Cl)(Cl)(Cl)Cl.Cl.C(OCC)(=O)C.CCCCCC>[C:53]1([C:59]2[N:68]=[C:67]3[C:62]([C:63](=[O:73])[CH2:64][S:65][CH2:66]3)=[CH:61][CH:60]=2)[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: COC(=O)C1SCc2nc(-c3ccccc3)ccc2C1=O
Agent: CCOC(=O)c1ccc(-c2ccccc2)nc1C
Agent: COC(=O)CS
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1CSCc2nc(-c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of ethyl 2-methyl-6-phenylnicotinate (prepared according to Spath et al. [Monatsh. Chem. (1928) 49:265]) (1.00 g, 4.10 mmol) in carbon tetrachloride (10 mL) was added N-bromosuccinimide (0.81 g, 4.60 mmol) and benzoyl peroxide (0.05g). The reaction was heated at reflux for 18 h, cooled and filtered. The filtrate was concentrated and redissolved in anhydrous tetrahydofuran (10 mL). Methyl thioglycolate (0.37 mL, 4.10 mmol) was added, followed by sodium hydride (80%, 0.12 g, 4.1 mmol). The reaction mixture was allowed to stir at room temperature for 3 h. Additional sodium hydride (80%, 0.14 g, 4.6 mmol) was added and the solution was heated to gentle reflux for 18 h. The reaction was cooled to 0° C. and quenched with water (20 mL). The mixture was washed with ethyl acetate (50 mL). The aqueous layer was acidified to pH 5 with acetic acid and the product extracted with ethyl acetate (3×40 mL). The organic extract was washed with brine (10 mL), dried and evaporated to provide an orange oil. Chromatography on silica gel using 6:1 hexane:ethyl acetate as eluant afforded a mixture of uncyclised compound as a yellow oil (20%) and the desired methyl 7-phenyl-8-aza-isothiochroman-4-one-3-carboxylate (23%) as a yellow solid, mp 78°-81° C. This material was heated at reflux in 3N aqueous hydrochloric acid (30 mL) for 12 h, then cooled and made basic. Extraction with ethyl acetate (4×50 mL) afforded a semi-solid mass after drying and evaporation. Chromatography on silica gel using 7:1 hexane/ethyl acetate as eluant afforded 7-phenyl-8-aza-isothiochroman-4-one as a yellow solid (68%), mp 97°-99° C.; 1H NMR (CDCl3) δ3.58 (s, 2H), 4.14 (s, 2H), 7.48 (m, 4H), 7.78 (d, 1 H), 8.04-8.07 (m, 2H), 8.40 (d, 1H); IR (KBr) 1680 cm-1 ; Mass spectrum m/z 242 (M+H); Anal. calcd. for C14H11NOS: C 69.68 H 4.54 N 5.80; Found C 69.39 H 4.58 N 5.69.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:8])=[CH:5][CH2:6]Br.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>>[CH3:3][C:4]([CH3:8])=[CH:5][CH2:6][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: c1c[nH]cn1
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)=CCn1ccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.4 %

Procedure:
Sodium hydride (1.37 g 60% dispersion in oil, 0.82 g; 34.2 mmol) was weighed out in a 100 mL round bottom flask, and washed with hexane (3×15 mL) to remove the mineral oils. DMF (anhydrous, 15 mL) was added to the sodium hydride and the whole was stirred at room temperature for a couple of minutes under N2. 3,3-Dimethylallyl bromide (1.05 g, 7.02 mmol) was added to the reaction mixture, followed by slow addition of imidazole (2.28 g, 33.5 mmol) while cooling in an ice bath. The mixture was a milky cream colour initially, turning into a homogeneous brown solution. Stirring was continued at room temperature for 20 h. When the TLC showed complete consumption of the dimethylallyl bromide, the DMF was distilled off at 120° C. under high vacuum (Kugelrohr), leaving a viscous yellow heterogeneous mixture. This was triturated with chloroform to give a brown organic layer after removing the precipitated solids by filtration. The organic layer was washed with brine (3×20 mL), dried (Na2SO4) and the solvent was removed under reduced pressure and then under high vacuum. This gave the product as a dark brown oil (0.52 g, 54%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][Cl:18]>>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[CH:3][C:4]1=[O:12]
Reactant: ClCCCCBr
Reactant: O=c1cc(O)c2ccccc2[nH]1
Product: O=c1cc(O)c2ccccc2n1CCCCCl
Yield: 107.2 %

Procedure:
Analogously to the procedure described in Example I, reaction of 4-hydroxy-1H-quinolin-2-one (24.82 mmol, 4.00 g, prepared according to Monatsh. Chem. 1965, 96, 418) and bromo-4-chlorobutane (29.78 mmol, 5.11 g) afforded 6.70 g of the title compound which is contaminated with reactant. The mixture thus obtained was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4]([C:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][N:13]=2)[N:3]=1.[OH-].[Li+]>CO.O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([C:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][N:13]=2)[N:3]=1
Reactant: COC(=O)c1cc(C2=NOC(c3ccccc3)C2)nc(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(C(=O)O)cc(C2=NOC(c3ccccc3)C2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To a stirred solution of methyl 2-methyl-6-(5-phenyl-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxylate (0.15 g, 0.505 mmol, Preparation #19) in methanol (1.5 mL) and water (0.5 mL) mixture was added lithium hydroxide (0.036 g, 1.514 mmol, Sd Fine Chem). The reaction mixture was stirred for about 10 min at RT and the organic solvent was removed under reduced pressure. The aqueous layer was acidified with 10% citric acid solution. The solid was collected by filtration, washed with water and dried under vacuum to afford 2-methyl-6-(5-phenyl-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxylic acid 0.1 g, (70.0%) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 14.0 (bs, 1H), 8.16 (s, 1H), 7.42 (m, 5H), 5.92 (m, 1H), 3:98 (m, 1H), 3.45 (m, 1H), 2.72 (s, 3H), MS m/z: 284.2 (m+H)+.
Reaction SMILES: N1CCCC1.C(O)(=O)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[C:16]([CH3:27])([CH2:22][CH2:23][C:24](=[O:26])[CH3:25])[CH2:15]2>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18]([C:17]3[C:16]([CH3:27])([CH2:15]2)[CH2:22][CH2:23][C:24](=[O:26])[CH:25]=3)=[CH:19][CH:20]=1
Reactant: COc1ccc2c(c1)CC(C)(CCC(C)=O)C2=O
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC1(C)CCC(=O)C=C21
Temperature: 85 °C
Yield: 99.1 %

Procedure:
Pyrrolidine (0.159 mL, 1.9 mmol) and acetic acid (0.109 mL, 1.9 mmol) were added to a solution of 5-methoxy-2-methyl-2-(3-oxo-butyl)-1-indanone (467 mg, 1.9 mmol) in toluene (5 mL) and the resulting solution was heated in an oil bath at 85° C. for 2.5 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 mL), washed with water (20 mL), 5% NaHCO3 (20 mL), and brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum to yield 7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (430 mg) as a light brown solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([OH:17])[C@H:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][O:13][C@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH3:28])[C@H:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][O:13][C@H:10]1[O:11][CH3:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CO[C@@H]1OC[C@@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1OC[C@@H](OCc2ccccc2)[C@H](OC)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a solution of methyl 2,4-di-O-benzyl-b-D-xylopyranoside (38 g, 0.11 mole) in dry DMF (500 ml) was added 60% NaH in oil (4.4 g, 0.11 mole). After stirring at 0° C. for 30 min, methyl iodide (17 g, 0.12 mole) was added and the reaction mixture was allowed to warm to room temperature. The solution was continued to stir for 1 hr and evaporated to dryness under reduced pressure. The oily residue was partitioned between ether (300 ml) and water (300 ml). The ether layer was dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure to give methyl 2,4-di-O-benzyl-3-O-methyl-b-D-xylopyranoside (39.4 g, 100% yield) as colorless oil; EI-MS: m/z 358 (M+), 254 (M+ -Bn); 1H-NMR (CDCl3)d: 3.18 (1H,dd,J=10 & 12 Hz), 3.24 (1H,dd, J=7.5 & 9 Hz), 3.29 (1H,t,J=9 Hz), 3.50 (1H,m), 3.52 (3H, s), 3.65 (3H,s), 3.9 (1H,dd,J=5.9 & 12 Hz), 4.21 (1H,d,J=7.5 Hz), 4.62 (1H,d,J=12 Hz), 4.69 (1H,d,J=11 Hz), 4.75 (1H,d,J=12 Hz), 4.85 (1H,d,11 Hz), 7.35 (10 br.s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[C:9](=O)([O:17]C1C=CC([N+]([O-])=O)=CC=1)[O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C>C1COCC1>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:9]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.5 g of 4-piperidinylmethanol were dissolved in 170 ml of THF. 25.8 g of 2-(trimethylsilyl)ethyl 4-nitrophenyl carbonate and 15.9 ml of N,N-diisopropylethylamine were successively added thereto. The mixture was stirred at room temperature for 1 h and then the solvent was removed in vacuo. The residue was taken up in 400 ml of ethyl acetate and washed once with 300 ml of 0.5 N HCl and twice with 250 ml of 1 N NaOH each time. The organic phase was dried with MgSO4, the solvent was removed in vacuo, and the residue was purified by chromatography on silica gel.
Reaction SMILES: [P:1]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].C(O)C.[C:22]([NH:30][NH2:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)C>[P:1]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]=[N:31][NH:30][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][CH:16]=1)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCSP(=O)(OCC)Oc1ccc(C=O)cc1
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: CCCSP(=O)(OCC)Oc1ccc(C=NNC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
O-Ethyl S-propyl O-(4-formylphenyl) thiophosphate (5.44 grams; 0.019 mole), ethanol (150 ml) and benzoylhydrazine (2.57 grams; 0.019 mole) were charged into a glass reaction vessel equipped with a mechanical stirrer. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then stripped of ethanol under reduced pressure having a viscous oil as the residue. The residue was then dissolved in diethyl ether resulting in the formation of a precipitate. The ether solution was decanted from the precipitate and was stripped of solvent under vacuum leaving an orange-brown oil. This oil was chromatographed on a silica gel column using methylene chloride and methylene chloride-acetone mixtures as the eluant. Fourteen fractions were recovered and fractions 3 plus 4, 7, 8 and 9 were analyzed by infra red spectroscopy revealing that fraction 8 was the desired product. This fraction was stripped of solvent to yield the desired product O-ethyl S-propyl O-[4-(benzoylhydrazonomethyl)phenyl] thiophosphate as a yellow oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:17][CH:16]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][CH:17]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCc1ccc(Br)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCc1ccc(N(c2ccccc2)c2ccccc2)cc1

Procedure:
One equivalent weight of diphenylamine, 1 equivalent weight of 1-bromo-4-dodecylbenzene, 0.1 equivalent weight of palladium(II) acetate, 0.4 equivalent weight of tri(t-butyl)phosphine and 4.8 equivalent weight of potassium t-butoxide were heated in a toluene solution at 90° C. for 2 hours to obtain 4-dodecyl-N,N-diphenylaniline. To the above resultant, 2 equivalent weight of N-bromosuccinimide was added and stirred for 30 minutes at room temperature in N,N-dimethylformamide to obtain 4-dodecyl-N,N-bis(4-bromophenyl)aniline. To the obtained compound, 3 equivalent weight of thiophene boric acid, 0.06 equivalent weight of tetrakis(triphenylphosphine)palladium and 2 equivalent weight of potassium carbonate were added, and heated and refluxed for 3 days in a mixture solvent of THF and water to obtain 4-dodecyl-N,N-bis(4-thiophene-2-yl)phenyl)aniline. To the obtained compound, 5 equivalent weight of phosphorus oxychloride and 5 equivalent weight of N,N-dimethylformamide were added and heated at 105° C. for 5 hours under nitrogen atmosphere for diformylizing the thiophene ring. An acetic acid solution composed of the above obtained diformilized compound, 4 equivalent weight of cyanoacetic acid and 5 equivalent weight of ammonium acetate was heated and refluxed for 1 hour. Thus Dye 1 could be obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:20])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)COC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CC(C)COC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.053 mMol) isobutyl chloroformate, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 331(M+1)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8](Cl)=[O:9])(=[O:3])[CH3:2]>C1(C)C(C)=CC=CC=1.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[CH:8]=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: CC(=O)Oc1cc(C=O)cc(OC(C)=O)c1
Temperature: 115 °C
Yield: 90 %

Procedure:
A mixture of 61.8 g (0.24 mole) of 3,5-diacetoxybenzoyl chloride and 6 g of 5% palladium on BaSO4 in 200 ml of dry xylene was efficiently stirred while bubbling in hydrogen gas. The reaction mixture was slowly heated to 115° C. in an oil bath and the heating was continued until the evolution of HCl gas ceased (approximately 5 hours). After cooling, the mixture was filtered and the xylene was removed in vacuo to leave 48 g (90%) of 3,5-diacetoxybenzaldehyde which was used without further purification in subsequent reactions.
Reaction SMILES: C(O[C:9](=O)[N:10]([CH:12]([C:14](=[O:46])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([CH:40]3CCOCC3)[CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])C)C1C=CC=CC=1>CO>[F:39][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[F:38])[O:31][CH:30]1[CH:24]2[N:23]([C:21]([CH:16]([NH:15][C:14](=[O:46])[CH:12]([NH:10][CH3:9])[CH3:13])[C:17]([CH3:19])([CH3:20])[CH3:18])=[O:22])[CH2:27][CH2:26][CH:25]2[N:28]([C:40]2[N:28]=[CH:29][CH:30]=[CH:24][N:23]=2)[CH2:29]1
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2C1CCOCC1)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Solvent: CO
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2c1ncccn1)C(C)(C)C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
The Cbz-protected intermediate 31 (180 mg, 0.27 mmol) was stirred vigorously with 10% Pd-on-carbon (wet, 100 mg, 0.09 mmol) in MeOH (20 mL) under 1 atm H2. After 4 h, the catalyst was removed by filtration with an Acrodisc® 0.45 μm nylon membrane syringe filter and the solvent was removed in vacuo. The crude product was purified by reverse-phase HPLC (2″ Dynamax® C18, 10-55% ACN/water containing 0.1% HOAc over 20 min; Flow: 40 mL/min) to afford 45 mg of 32 (32%, 3 steps) as a flocculent, white solid following lyophilization.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.Cl.C(N=C=NCCCN(C)C)C.C1C=C2N=NN(O)C2=CC=1.N.[NH2:41][CH2:42][C:43]1[C:44]([OH:51])=[N:45][C:46]([CH3:50])=[CH:47][C:48]=1[CH3:49]>O.ClCCl.C(N(CC)CC)C>[OH:51][C:44]1[C:43]([CH2:42][NH:41][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH:5]=2)=[O:9])=[C:48]([CH3:49])[CH:47]=[C:46]([CH3:50])[N:45]=1
Reactant: Cc1nn(C(C)c2ccccc2)cc1C(=O)O
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cn(C(C)c3ccccc3)nc2C)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
A mixture of 3-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxylic acid (60 mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (95 mg, 0.5 mmol), N-hydroxybenzotrizole (67 mg, 0.5 mmol), triethylamine (0.1 mL) and dichloromethane (5 mL) was stirred at 25° C. for 0.5 hours. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (50 mg, 0.33 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (10 ml) was added and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-3-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxamide as a white solid (56 mg, 58%). LRMS (M+H+) m/z: calcd 364.19. found 364. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 7.96 (s, 1H), 7.82 (t, J=4.5 Hz, 1H), 7.33-7.13 (m, 5H), 5.84 (s, 1H), 5.62 (q, J=7.2 Hz, 1H), 4.20 (d, J=5.1 Hz, 2H), 2.40 (s, 3H), 2.14 (s, 3H), 1.99 (s, 3H), 1.76 (d, J=7.2 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:7](C(O)=O)=[CH:6][NH:5][N:4]2[CH:11]=[CH:12][CH:13]=[C:3]12>CS(C)=O>[NH:5]1[CH:6]=[CH:7][C:2](=[O:1])[C:3]2=[CH:13][CH:12]=[CH:11][N:4]12
Reactant: O=C(O)c1c[nH]n2cccc2c1=O
Solvent: CS(C)=O
Product: O=c1cc[nH]n2cccc12
Temperature: 150 °C
Yield: 74 %

Procedure:
4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylic acid was dissolved in dimethyl sulfoxide (110 mL) and heated at 150° C. for 1 hour. After removing the solvent by distillation under reduced pressure, the resulting residue was purified by silica gel chromatography (5% ethyl acetate in dichloromethane) to give the target compound (5.3 g, 39.5 mmol, 74% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18]CC)=[O:17])(=[O:12])=[O:11].C(O)C.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([OH:18])=[O:17])(=[O:12])=[O:11]
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Nc2c(F)cccc2F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(S(=O)(=O)Nc2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the product of Step A was added ethanol (8 mL) followed by a solution of 50% NaOH (0.96 g, 12.1 mmol) in water (8 mL). The reaction was stirred at ambient temperature for 1.5 hours. To the mixture was added dropwise 1 N HCl (28 mL), and the mixture was stirred at ambient temperature overnight. The solids were collected by filtration, washed with water (2×5 mL), and dried in a vacuum oven at 50° C. overnights to give 3-{[(2,6-difluorophenyl)amino]sulfonyl}benzoic acid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.11 (t, J=8.1 Hz, 2H), 7.33-7.41 (m, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.92 (dt, J=8.4, 1.1 Hz, 1H), 8.19 (dt, J=7.8, 1.1 Hz, 1H), 8.27 (t, J=1.51 Hz, 1H), 10.20 (s, 1H), 13.48 (s, 1H); MS (ESI) m/z 312 (M−H)−.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[C:4](=[O:14])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1.[ClH:30]>C(OCC)(=O)C>[ClH:30].[NH:20]1[CH2:21][CH2:22][CH:17]([CH2:16][CH2:15][N:3]2[C:4](=[O:14])[C:5]3[CH:6]=[C:7]4[O:13][CH2:12][O:11][C:8]4=[CH:9][C:10]=3[C:2]2=[O:1])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)c3cc4c(cc3C2=O)OCO4)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1c2cc3c(cc2C(=O)N1CCC1CCNCC1)OCO3
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To 500 ml reaction vessel, 20 g (0.05 mol) compound XI and 400 ml 10% solution of hydrogen chloride in ethyl acetate were added, the reaction was kept at room temperature for 2 h, filtrated, washed, oven-dried, and 15.5 g compound II-1 was obtained, with yield of 92.3%. 1H NMR (D2O): δ 1.40-1.64 (m, 5H), 2.02 (d, 2H, J=13.4 Hz), 2.96-3.03 (m, 2H), 3.45-3.50 (m, 4H), 6.12 (s, 2H), 6.79 (s, 2H); MS (ESI): m/z 303 [M−Cl]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH:11]=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)C.[Cl-].[NH4+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[OH:12])[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: O=Cc1cc2cc(Cl)ncc2[nH]1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OC(c1ccccc1)c1cc2cc(Cl)ncc2[nH]1
Temperature: -15 °C
Reaction time: 5 h
Yield: 49 %

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (156 mg, 0.86 mmol) in tetrahydrofuran (5 mL) was added 3.0 M phenylmagnesium bromide in diethyl ether (0.58 mL, 1.74 mmol) at −78° C. under a nitrogen atmosphere. The reaction mixture was slowly warmed to −15° C. After stirring for ca. 5 h, additional 3.0 M phenylmagnesium bromide in diethyl ether (0.15 mL, 0.45 mmol) was added. The reaction mixture was stirred for another 1 h, warming to 0° C. The reaction mixture was poured into a 2:1 solution of saturated ammonium chloride and water, and extracted with ethyl acetate (3×). The combined organic extracts were washed with water and brine, and dried over sodium sulfate. After filtration and concentration, the crude product was purified by Biotage chromatography (1 to 100% ethyl acetate in hexanes) to give (5-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methanol (109 mg, 49%) as a yellow foam: 1H NMR (300 MHz, CDCl3) 8.69 (1H, s), 6.23 (1H, s), 7.33-7.61 (6H, m), 8.49 (1H, s), 8.69 (1H, br s); ESI MS m/z 259 [C14H11ClN2O+H]+.