Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20](Cl)=[O:21]>C1COCC1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([F:26])=[C:17]([F:16])[CH:18]=2)=[CH:3][N:4]=1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: Nc1cnc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cnc(Cl)nc1)c1ccc(F)c(F)c1
Yield: 61.8 %

Procedure:
A solution of 450 g (3.49 mol) of 5-amino-2-chloropyrimidine and 790 g (6.98 mol) of triethylamine in anhydrous THF was cooled to less than 5° C. in an ice bath. To this solution was added 3,4-difluorobenzoyl chloride at a rate (2 h) that maintained the temperature of the reaction mixture below 10° C. Once the addition was complete the reaction was monitored for full conversion of the starting material to product by HPLC. Following confirmation of complete conversion, the reaction mixture was concentrated under reduced pressure. The viscous residue was dissolved in ethyl acetate (4 L) and washed with water (4 L) and 2M HCl (4 L). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dissolved in ethanol (4 L) and 250 g of charcoal was added. The mixture was heated to reflux for 10 minutes and filtered through a bed of Celite® and the filtrate was concentrated under reduced pressure. The solids were recrystallized twice from acetonitrile (1 L) to yield 580 g (61.8%) of the desired product as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([CH:6]1[C:18]2[CH:17]=[C:16]([CH2:19]O)[CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[C:8]([O:22][CH3:23])[CH:9]=[CH:10][C:11]=2[F:21])([CH3:5])[CH:3]=[CH2:4].S(Cl)([Cl:26])=O>C(Cl)Cl>[Cl:26][CH2:19][C:16]1[CH:17]=[C:18]2[C:13]([C:12]3[C:11]([F:21])=[CH:10][CH:9]=[C:8]([O:22][CH3:23])[C:7]=3[CH:6]2[C:2]([CH3:5])([CH3:1])[CH:3]=[CH2:4])=[CH:14][CH:15]=1
Reactant: C=CC(C)(C)C1c2cc(CO)ccc2-c2c(F)ccc(OC)c21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: C=CC(C)(C)C1c2cc(CCl)ccc2-c2c(F)ccc(OC)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 21.8 (40 mg, 128 μmol) in DCM (0.8 mL), was added thionyl chloride (30 mg, 256 μmol). The resulting mixture was stirred at room temperature for 1 hour. Solvent was removed in vacuo to give a residue which was used without purification (40 mg, 94%).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>O1CCCC1.C(OCC)(=O)C>[CH3:21][N:22]([CH3:26])[C:23](=[O:24])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reaction time: 0.5 h

Procedure:
A solution of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) in dry tetrahydrofuran (THF, 8 ml) was added to the stirred solution of sodium hydride in dry THF at −10° C. during 5 minutes under nitrogen environment. The reaction mixture was stirred for 30 minutes. Then, N,N-dimethyl carbamoyl chloride (265 mg/ml, 3.14 mM) was added to the stirring reaction mixture. The mixture was stirred further for 7 hours during which the temperature was allowed to reach the room temperature (35° C.). The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vacuum and chromatographed using ethyl acetate:hexane (1:49) to afford 8k as solid. Yield: 0.796 g, 76.19%.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4].O[Li].O>O1CCCC1.O>[F:27][C:24]([F:25])([F:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[N:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH2:12][CH2:13]1)=[O:28]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a suspension of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid methyl ester (1.000 g, 2.535 mmol) in a mixture of tetrahydrofuran-water (1:1, 5 mL), LiOH.H2O (0.106 g, 2.535 mmol) was added in one portion. The mixture was stirred at room temperature overnight. The clear solution was then cooled to 0° C. and quenched with 1 N HCl solution to pH 4-5. The solid separated was filtered. The residue was washed with cold water and dried under vacuum to obtain 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (0.771 g, 2.027 mmol, 80%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.82 (t, J=9.6 Hz, 2H), 7.74 (t, J=7.4 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.52 (d, J=7.4 Hz, 1H), 7.27 (t, J=9.6 Hz, 1H), 3.87-3.60 (m, 6H), 3.31-3.10 (m, 2H), 13C NMR (75 MHz, DMSO-d6) δ 166.8, 165.7, 160.0, 143.7, 134.9, 134.9, 133.4, 130.1, 129.0, 128.0, 127.1, 127.0, 127.0, 126.0, 125.9, 125.5, 122.4, 112.5, 46.3, 44.3, 44.1. MS (ES+) m/z 381.2 (M+1).
Reaction SMILES: [NH2-].[Na+].C([O:10][C:11](=O)[C@H:12]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:13]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C.[CH3:55][S:56]([CH3:58])=[O:57]>O1CCCC1>[CH2:14]([N:13]([C@@H:12]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:11](=[O:10])[CH2:55][S:56]([CH3:58])=[O:57])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CS(C)=O
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 74.5 °C
Yield: 85.6 %

Procedure:
3.76 g (96.39 mmol) of sodium amide was suspended in 40 ml of dimethylsulfoxide and heated at from 74 to 75° C. for 30 minutes. 40 ml of tetrahydrofuran was added to the resulting solution and cooled to 0° C. To this was dropwise added a solution of 15.47 g (90.5 wt. %, 32.14 mmol) of N,N-dibenzyl-(L)-phenylalanine benzyl ester as dissolved in 20 ml of tetrahydrofuran, while keeping it at 0° C. After these were reacted at 0° C. for 30 minutes, 120 ml of an aqueous solution of 10% citric acid and 100 ml of ethyl acetate were added to the reaction mixture, which was thus subjected to phase separation. The aqueous layer thus separated was extracted once with 50 ml of ethyl acetate, and the resulting extract was combined with the previously-separated organic layer and then washed with 60 ml of a saturated saline solution. This was dried with anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=from 2/1 to 1/3) and then crystallized in toluene/hexane to obtain 11.16 g of the above-entitled compound. The yield was 85.6%. The integral ratio in 1H-NMR of the compound verified that the ratio of the diastereomers constituting it is about 1:1.
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[S:17]([CH3:20])(=[O:19])=[O:18].[H-].[Na+].[Cl:23][C:24]1[CH:37]=[CH:36][C:27]2[S:28][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:30]([CH3:31])[C:26]=2[CH:25]=1>CN(C=O)C>[Cl:23][C:24]1[CH:37]=[CH:36][C:27]2[S:28][C:29]([S:32]([NH:6][C:7]3[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=3[S:17]([CH3:20])(=[O:19])=[O:18])(=[O:33])=[O:34])=[C:30]([CH3:31])[C:26]=2[CH:25]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: COC(=O)c1ccc(N)c(S(C)(=O)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Into a mixed solvent of 20 mL of THF and 3 mL of DMF was dissolved 985 mg of methyl 4-amino-3-methanesulfonylbenzoate, followed by addition of 170 mg of sodium hydride (oily, 60%) at 0° C. After 20 minutes of stirring at the same temperature, 1.28 g of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene was added at 0° C., followed by 1 hour of stirring at room temperature. Further, 150 mg of sodium hydride (oily, 60%) was added at room temperature and the mixture was stirred for 2 hours at the same temperature. After confirmation of disappearance of the starting material, the reaction was terminated by adding saturated aqueous ammonium chloride solution at 0° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1) to obtain 911 mg of the title compound as colorless powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].CN1CCOCC1.[C:20](Cl)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C(Cl)Cl>[CH2:23]([O:22][C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(O)CCCCN
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)C(O)CCCCNC(=O)OCc1ccccc1

Procedure:
To a well stirred mixture of 0.05 moles of ethyl 6-amino-2-hydroxyhexanoate and 100 ml of methylene chloride which has been cooled to 0° to 5° C is added 0.1 moles of N-methylmorpholine followed by 0.055 moles of carbobenzoxy chloride. The reaction mixture is stirred for 1 hour then washed with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and concentrated in vacuo. Chromatography of the residue on silica gel and elution with methanol/chloroform gives ethyl 6-(benzyloxycarbonylamino)-2-hydroxyhexanoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([CH3:33])([CH3:32])[CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)[N:14]=[CH:13][C:12]=1[N+:29]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pt].C(#N)C>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([CH3:33])([CH3:32])[CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)[N:14]=[CH:13][C:12]=1[NH2:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(CNc1c([N+](=O)[O-])cnc2ccc(OCc3ccccc3)cc12)NC(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(CNc1c(N)cnc2ccc(OCc3ccccc3)cc12)NC(=O)OC(C)(C)C
Yield: 103.7 %

Procedure:
tert-Butyl[2-(6-benzyloxy-3-nitroquinolin-4-ylamino)-1,1-dimethylethyl]carbamate (13.75 g), 5% platinum on carbon (1.03 g), and acetonitrile (250 mL) were combined. The mixture was shaken overnight under 50 psi (3.4×105 Pa) of hydrogen. The reaction was filtered through CELITE filter agent, and the filter pad was rinsed with acetonitrile. The filtrate was concentrated under reduced pressure. Residual water was removed by an azeotrope with toluene. Removal of all volatiles under reduced pressure provided 13.34 g of crude tert-butyl[2-(3-amino-6-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]carbamate as a brown foam.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.C([Sn](CCCC)(CCCC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)CCC>C1(C)C=CC=CC=1.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>[Br:7][C:5]1[CH:6]=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Brc1csc(-c2ccccn2)c1
Yield: 73.7 %

Procedure:
2,4-Dibromothiophene (695 mg, 2.87 mmol), 2-(tri-n-butylstannyl)pyridine (830 mg, 1.92 mmol), and tetrakis(triphenylphosphine)palladium (0) (220 mg, 0.19 mmol) were refluxed in 3 mL of toluene at 120° C. overnight. After filtrated out of solid residue, the reaction mixture was purified by flash chromatography using a gradient of ethyl acetate in hexane to give a beige solid as the title compound (340 mg), m/z 240, 242 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCCCCl)cc1

Procedure:
A suspension of 4-hydroxybenzaldehyde (40 g), 1-bromo-3-chloropropane (63 mL), and potassium carbonate (136 g) in acetone (920 mL) was heated to reflux for 16 h. The resulting mixture was filtered, and the filtrate was evaporated. Distillation of the residue (0.5 mm Hg, 220° C.) gave the title compound as a pale yellow oil that crystallized on standing (46 g).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)cc1
Yield: 72 %

Procedure:
Using a procedure similar to that described in example except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 4-bromoanisole, the hydrochloride salt of the title compound was formed in 72% yield as a white solid, mp 228°-231° C. elemental Analysis for C28H29 NO2.HCl: Calculated: C, 75.07; H, 6.75; N, 3.13 Found: C, 74.93; H, 6.74; N, 3.14
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([F:16])[CH:3]=1.Br[CH:18]([CH3:27])[C:19]([O:25][CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:18]([CH3:27])[C:19]([O:25][CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:12]=2)=[C:4]([F:16])[CH:3]=1
Reactant: Oc1ccc(Oc2ccc(Br)cc2F)cc1
Reactant: COC(=O)C=C(OC)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Yield: 58.2 %

Procedure:
A mixture of 12.0 g (42.4 mmol) 4-(4-bromo-2-fluorophenoxy)phenol, 9.5 g (42.4 mmol) methyl 4-bromo-3-methoxy-2-pentenoate, 6.45 g (46.6 mmol) potassium carbonate and 180 ml acetonitrile was heated at reflux for 16 hours. The mixture was poured into water and extracted with ether. The combined ether extracts were washed with dilute aqueous NaOH, washed with water, dried over MgSO4 and the solvent was removed by rotary evaporation. The residue was purified by HPLC eluting with 95:5 hexane:acetone, to give 10.5 g (58 percent) of the product as a clear colorless oil. Calc: C, 53.66; H, 4.27. Found: C, 53.28, H, 4.40. Structure was established on the basis of IR and NMR analysis.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO>N1C=CC=CC=1>[C:9]([NH:6][C:5]1[CH:7]=[CH:8][NH:1][C:2](=[O:3])[N:4]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Reaction time: 0.08 h

Procedure:
Cytosine (5.55 g) is suspended in dry pyridine (100 ml). Using a syringe, benzoyl chloride (6.4 ml) is then added dropwise. A virtually clear solution is formed from which a precipitate separates out after approximately 5 minutes. Stirring is continued for approximately 2 hours at room temperature, methanol (100 ml) is then added, and the mixture is concentrated in vacuo. The residue is stirred with isopropanol, filtered, washed with a small amount of methanol and diethyl ether, and dried in vacuo.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][CH:8]1[N:16](CC2C=CC=CC=2Cl)[CH:15]=[CH:14][CH:13]=[C:9]1[C:10]([OH:12])=O)(=[O:3])[NH2:2].[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C>CN(C)C=O.O>[C:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:32][CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=1[Cl:28])=[O:12])(=[O:3])[NH2:2]
Reactant: NCc1ccccc1Cl
Reactant: NC(=O)c1cccc(OC2C(C(=O)O)=CC=CN2Cc2ccccc2Cl)c1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccccc2Cl)c1
Yield: 50.1 %

Procedure:
To a stirred solution of 2-(3-Carbamoyl-phenoxy)-N-(2-chloro-benzyl)-nicotinic acid (0.300 grams, 1.25 mmole), o-chlorobenzylamine (0.195 grams, 1.375 mmole), and 1-hydroxybenzotriazole hydrate (0.203 grams, 1.50 mmole) in dry dimethylformamide (3 ml) was added 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (0.311 grams, 1.63 mmole) and stirred over night. The mixture poured into 100 ml water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over Na2SO4, filtered and concentrated to give a white solid that was purified by chromatography on silica gel eluting with 7% methanollmethylene chloride. Recrystalization from ethyl acetate/hexane gave a white solid (0.239 g). M.P. 153-155° C.; Anal. calcd. for C20H16N3O3Cl: C, 62.91; H, 4.22; N, 11.01. Found: C, 62.92; H, 4.30; N, 11.09.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([NH2:45])[CH:42]=[CH:41][N:40]=1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:45][C:43]1[CH:42]=[CH:41][N:40]=[C:39]([O:38][CH3:37])[CH:44]=1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: COc1cc(N)ccn1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)ccn1
Temperature: 50 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (38.9 mg, 0.141 mmol) in dry dichloromethane (2 mL) was added triethylamine (0.049 mL, 0.352 mmol), 2-chloro-1-methylpyridinium iodide (53.3 mg, 0.209 mmol), and 2-methoxy-4-aminopyridine (20.2 mg, 0.163 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 50° C. for 1.5 hours. LC/MS showed reaction complete. The reaction mixture was concentrated and purified by HPLC on a 30×100 mm Waters Sunfire column to afford the title compound as an orange solid after lyophilization.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C1(OCC)C=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOc1ccccc1
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a mixture of 306 mg (purity: 98.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 821 mg (5.49 mmol) of 2-cyclopropyl-6-methylphenol were added ethyl phenyl ether (2.76 g) and 324 mg (5.50 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 384 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 77%) and 2.0 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[F-].[Cs+].[CH3:23][N:24]1[C:28]2[CH:29]=[C:30]([Sn](CCCC)(CCCC)CCCC)[S:31][C:27]=2[CH:26]=[N:25]1.[SnH4]>O1CCOCC1>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:30]3[S:31][C:27]4[CH:26]=[N:25][N:24]([CH3:23])[C:28]=4[CH:29]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(cnn2C)s1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Agent: [Cs+]
Agent: [F-]
Agent: [SnH4]
Solvent: C1COCCO1
Product: C[C@@H](Oc1nc(-c2cc3c(cnn3C)s2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Temperature: 67.5 °C
Reaction time: 2 h

Procedure:
Intermediate 2.06 (29 mg, 0.098 mmol), Pd-PEPPSI-IPent precatalyst (4 mg, 0.005 mmol), cesium fluoride (32 mg, 0.21 mmol) and powdered 4 Å molecular sieves (25 mg) were taken up in dioxane (1 mL) under Ar. 1-methyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (46 μL, 0.13 mmol) was added and the resulting mixture was heated to 65-70° C. After 2 h, the reaction temperature was increased to 80° C. After 18 additional hours, additional Pd-PEPPSI-IPent precatalyst (3 mg, 0.004 mmol), CsF (35 mg, 0.23 mmol) and stannane (23 μL, 0.065 mmol) were added and the reaction was heated to 80° C. After an additional 3 h, additional Pd-PEPPSI-IPent precatalyst (5 mg, 0.006 mmol) was added and the reaction was stirred at 80° C. overnight. After 16 additional hours, the reaction mixture was partitioned between EtOAc and water. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography (MeOH in DCM) to provide (R)-4-((R)-1-(3-methyl-6-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.23. LCMS-ESI+ (m/z): [M+H]+ calcd for C19H21N6O2S: 397.1; found: 397.2. 1H NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.70 (s, 1H), 7.63 (d, J=0.7 Hz, 1H), 7.35 (d, J=0.7 Hz, 1H), 5.74-5.65 (m, 1H), 5.53 (s, 1H), 4.06 (s, 3H), 4.02 (d, J=0.4 Hz, 3H), 3.66-3.58 (m, 1H), 3.45-3.39 (m, 1H), 3.02-2.88 (m, 1H), 2.63-2.48 (m, 2H), 1.52 (d, J=6.3 Hz, 3H).