Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[CH:8]=[N:7]1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2Cc2cccc(F)c2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Yield: 99.5 %

Procedure:
A suspension of compound 16.1 (2.71 g, 10 mmol) and palladium 10% on carbon (1.0 g, wet) in methanol (40 mL) was hydrogenated under a hydrogen balloon for 14 hours. The reaction mixture was then filtered through Celite (20 g), rinsed with dichloromethane/methanol (3/1), and concentrated to give the title compound as a white crystalline solid (2.40 g, 100%). The product is used without further purification. LCMS ESI(+) m/z: 242 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)(O)[O-].[K+].O>C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:16][CH3:17])[C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNCC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1[N+](=O)[O-]

Procedure:
1-Benzyl-4-[(N-ethylamino)methyl]piperidine (EXAMPLE 261, 5.68 g) and 2-chloro-3-nitropyridine (3.87 g) are dissolved in 96 ml of acetonitrile and 4.05 g of solid potassium bicarbonate is added. The reaction is refluxed for 20 hr, cooled to 20°-25°, poured into water and extracted with ethyl acetate. The organic extracts are dried (sodium sulfate), and concentrated under reduced pressure. Purification by flash column chromatography (15% ethyl acetate/hexane to 80% ethyl acetate/hexane) gives the title compound, HRMS calcd. for C20H26N4O2 =354.2056, found=354.2045.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[N:3]1.[OH-].[NH4+:12]>C1COCC1>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:7]([NH2:12])(=[O:9])=[O:8])=[N:3]1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ccc(S(N)(=O)=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-methyl-1H-pyrazole-3-sulfonyl chloride (3 g, 16.61 mmol) in THF (100 mL) was cooled to 0° C. and to it was added dropwise ammonium hydroxide (6.47 mL, 166 mmol). The reaction mixture was allowed to warm to RT and left to stir for 3 hours. The reaction mixture was concentrated in vacuo. The solid formed was filtered and washed with water (2×20 mL) to give the title compound. The filtrate was extracted with ethyl acetate (3×50 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated to give another batch of the title compound. Both batches were combined to give the title compound (3.27 g). LCMS (A): m/z (M+H)+ 162, C4H7N3O2S requires 161 (acidic).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[Br:8][C:11]1[CH:10]=[CH:9][C:21]2[NH:20][C:19]3[C:14]([C:13]=2[CH:12]=1)=[CH:15][CH:16]=[CH:17][CH:18]=3
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Brc1ccc2[nH]c3ccccc3c2c1
Reaction time: 2 h
Yield: 76 %

Procedure:
NBS (12.77 g, 71.8 mmol) in DMF was added to 9H-carbazole (12 g, 71.8 mmol) in 200 mL at 0° C. dropwise. The reaction was monitored by HPLC. After 2 h, HPLC indicated 76% of desired product and 6% of dibrominated compound. The reaction was quenched by adding 500 mL of ice water. The internal temperature was controlled to be lower than 10° C. The precipitate formed was collected by filtration. The solid was stirred in 400 mL of warm methanol. (˜40° C.). The solid was collected by filtration. The solid was dissolved in 150 mL of DCM. 200 mL of methanol was added. The DCM was boiled off. The solvent level was down to 150 mL. The slurry was stirred at room temperature overnight. The solid was collected by filtration. 9 g (51% yield) of solid was collected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[C:7]([C:15]#[N:16])[C:6]2=O.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][C:7]=1[C:15]#[N:16]
Reactant: COc1cc2[nH]cc(C#N)c(=O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Temperature: 0 °C

Procedure:
A stirred mixture of 20 g of 1,4-dihydro-6,7-dimethoxy-4-oxo-quinoline-3-carbonitrile and 87 ml of phosphorous oxychloride was refluxed for 2 h, cooled, and evaporated free of volatile matter. The residue was stirred at 0° C. with dichloromethane-water as solid sodium carbonate was added until the aqueous layer was pH 8. The organic layer was separated, washed with water, dried and concentrated. Recrystallization from dichloromethane gave a solid, mp 220-223° C.
Reaction SMILES: C1COCC1.C([Li])CCC.[CH3:11][C:12]#[N:13].C([O:16][C:17]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=O)C>O>[O:16]=[C:17]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:11][C:12]#[N:13]
Reactant: CC#N
Reactant: CCOC(=O)c1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: N#CCC(=O)c1cccs1
Temperature: -50 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a flask charged with THF (250 ml) was added dropwise n-butyl lithium (18.4 mL, 46 mmol) at −78° C. under a N2 atmosphere. After addition the resulting solution warmed to −50° C. and dry MeCN (1.86 g, 45 mmol) was added slowly. After 1 h, the reaction was cooled to −78° C. and was treated with thiophene-2-carboxylic acid ethyl ester (6.93 g, 44.5 mmol). After stirring for 1 h the resulting mixture was warmed to RT and stirred for 1 h. Water was added dropwise at 0° C. to quench the reaction and the solution was extracted with ethyl acetate (3×200 mL). The organic layers were combined, washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure to give a solid residue, which was re-crystallized from CH2Cl2. After the solid was collected by filtration, they were redissolved in ethyl acetate (100 mL), and acidified with dilute hydrochloride (2N). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to yield 3-oxo-3-thiophen-2-yl-propionitrile (4.7 g, yield=70%) as a yellow solid, which was used directly in the next step without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][S:13]([O-:15])=[O:14].[Na+]>CN(C)C=O.O>[CH3:12][S:13]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:15])=[O:14]
Reactant: CS(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of 4-nitrobenzyl bromide (10.0 g, 46.4 mmol) in dimethylformamide (25 mL) was added sodium methanesulfinate (7.10 g, 69.6 mmol). The reaction mixture was stirred at 65° C. for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with water, stirred for 10 minutes and filtered to give the title compound (9.27 g, 93%).
Reaction SMILES: [CH2:1]1[C:6](=O)[N:5](Br)[C:3](=[O:4])[CH2:2]1.[NH2:9][C:10](N)=[S:11]>O>[NH2:9][C:10]1[S:11][C:1]([CH2:2][CH2:3][OH:4])=[CH:6][N:5]=1
Reactant: NC(N)=S
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Product: Nc1ncc(CCO)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 117.5 %

Procedure:
To an ice cold suspension of NBS (1.182 g, 6.72 mmol) in water (8 mL) was added 2,3-dihyofuran (0.75 mL, 9.92 mmol) slowly. The resulting solution was stirred at 0° C. for 1 h, followed by addition of thiourea (0.505 g, 6.63 mmol). The mixture was heated under reflux under nitrogen atmosphere overnight to form a yellow clear solution. The mixture was extracted with EtOAc (3×5 mL) and the aqueous solution was treated with ammonium hydroxide to pH 12. The solution was extracted with CH2Cl2 (2×5 mL), followed by extraction with EtOAc (8×10 mL). The CH2Cl2 layer contains small amount of product and large amount of impurities, which was discarded. The EtOAc layers were combined, dried, and concentrated to give 1.123 g 2-(2-amino-thiazol-5-yl)-ethanol
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:11][CH:12]=C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14]=[O+][O-]>CO.ClCCl>[C:1]([O:5][C:6]([C:8]1([CH2:11][CH:12]=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC1(C(=O)OC(C)(C)C)CC1
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(CC=O)CC1

Procedure:
A solution of 5.7 g (31.3 mmol) of 1-allyl-cyclopropanecarboxylic acid tert-butyl ester in 50 mL methanol and 50 mL dichloromethane under nitrogen was taken to −78° C. where ozone was bubbled in for 1 hour. Nitrogen was bubbled in until the familiar blue color dissipated. Three drops of pyridine followed by 2 mL of dimethyl sulfide were added and the cooling bath removed. After 2 hours the reaction was poured into aqueous saturated ammonium chloride solution, extracted with dichloromethane, dried and concentrated to deliver a quantitative yield of the desired aldehyde as an oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:16]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=3[N:14]3[C:10](=[N:11][N:12]=[CH:13]3)[CH2:9][N:8]=2)=[CH:5][CH:6]=1.[CH2:22]=[O:23]>C1(C)C(C)=CC=CC=1>[OH:23][CH2:22][C:13]1[N:14]2[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[C:7]([C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[N:8][CH2:9][C:10]2=[N:11][N:12]=1
Reactant: C=O
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Solvent: Cc1ccccc1C
Product: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A process according to claim 2 wherein estazolam is reacted with paraformaldehyde in xylene at 120° C. to 140° C. for a time sufficient to form 1-(hydroxymethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.C1(C)C=CC(C(OC)=O)=CC=1>CCO>[O:4]1[CH2:5][CH2:6][N:1]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: C1COCCN1
Agent: COC(=O)c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1ccc(CN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 66.6 g of morpholine and 269 mL of triethylamine in 1.5 L of abs. EtOH under N2 at 0° C. was added dropwise over 30 min a solution of methyl 4-bromomethylbenzoate (from the previous reaction) in 450 mL of abs. EtOH. The resulting solution was stirred at 0° C. for 2 hours at which point the reaction was slowly warmed up to r.t over 4 hours and stirred at r.t overnight. The HPLC showed no unreacted methyl 4-bromomethylbenzoate but the remaining methyl p-toluate from the previous reaction. The solvent was removed under reduced pressure and the residue was taken up in 2 L of 1.5 N HCl. The acidic phase was washed with 3×350 mL diethyl ether and then with 1×350 mL EtOAc then neutralized to pH 7 with NaOH and then to pH 7.5 with 10% NaHCO3 in water. The product was then extracted with 3×700 mL of EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduce pressure, affording an orange oil. The excess EtOAc was removed by toluene distillation. The title compound was used in the next step without ether purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Si:9](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(CC)CC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](Oc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-bromophenol (16.4 g, 0.1 mole) in CH2Cl2 (300 mL) was added t-butyldiphenylsilyl chloride (29 g, 0.1 mole), Et3N (20 g, 0.2 mole) and 4-dimethylaminopyridine (DMAP) (1 g). The solution was stirred at RT for 2 days, quenched with H2O (1L) and extracted with ether (2L). The ether extracts were dried and evaporated. Flash chromatography of the residue using 5% ethyl acetate in hexane afforded the title compound which was used as such for the next step.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=3)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.CN(C=O)C.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[F:34].C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[F:27][C:28]1[CH:29]=[C:30]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:9]3[C:10]4[CH2:11][CH:2]([OH:1])[CH2:3][CH2:4][C:5]=4[CH:6]=[CH:7][CH:8]=3)=[O:21])=[CH:15][CH:16]=2)[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C(Nc1cccc2c1CC(O)CC2)c1ccc(I)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc2c1CC(O)CC2)c1ccc(-c2ccc(F)c(F)c2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 54.7 %

Procedure:
Next, to a solution of N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-4-iodobenzamide (100 mg, 0.25 mmol) in a 3 to 1 mixture of DMF and H2O was added 3,4-di-fluorophenylboronic acid (80.3 mg, 0.51 mmol), tetrakis(triphenylphosphine)-palladium(0) (8.82 mg, 0.01 mmol), and sodium carbonate (80.9 mg, 0.76 mmol). The mixture was stirred at 80° C. for 2.5 hours, and after cooled to room temperature, the product was extracted with diethyl ether. The organic layer was washed with water then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. After triturated with ethylacetate and hexane, the solid was filtered to afford 3′,4′-difluoro-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)biphenyl-4-carboxamide (51.9 mg, 54%).
Reaction SMILES: C[O-].C[O-].[Mg+2:5].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCCCCCC>[C:6]1([O-:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Mg+2:5].[C:6]1([O-:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1ccccc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CCCCCCC
Product: [O-]c1ccccc1
Yield: 93.7 %

Procedure:
A mixture of 48.5 g of this magnesium methylate and 105 g of phenol was suspended in 150 ml of n-heptane. The suspension was heated to reflux n-heptane at 98° C. for 10 hours, then cooled, and evaporated in a rotary evaporator to remove n-heptane and methanol, thereby giving 110 g of magnesium phenolate.
Reaction SMILES: COC(=O)[O-].[CH3:6][N+:7]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8]1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([O-:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:6][N+:7]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Oc1ccccc1
Agent: COC(=O)[O-]
Agent: C[N+]1(C)CCCC1
Product: [O-]c1ccccc1

Procedure:
By following the same procedure as Example 7 except that 10.0 g of N,N-dimethylpyrrolidinium methyl carbonate and 5.4 g of phenol were used, 10.7 g (yield of 94.7% to N-methylpyrrolidine) of dimethylpyrrolidinium phenolate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=1.FC(F)(F)S(O)(=O)=O.ClCCCl.[N+](=[CH:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[N-]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc[nH]c3=O)c(Cl)cc2F)c1=O
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCCCCC
Product: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h

Procedure:
Into a mixture of 1.0 g of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-1H-pyridin-2-one, 70 mg of trifluoromethanesulfonic acid and 40 ml of 1,2-dichloroethane, 0.4 ml of ethyl diazoacetate (purity: 90%) is dropped at room temperature over 2 hours. After dropping, the reaction mixture is further stirred for 2 hours, and subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=2/1) to give 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-2-(ethoxycarbonylmethoxy)pyridine.
Reaction SMILES: CN(C=O)C.S(Cl)([Cl:8])=O.[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14](O)=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1>C1C=CC=CC=1>[Cl:8][C:14]1[C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:11]([F:10])=[CH:12][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
DMF (10 ml) and thionyl chloride (14 ml) are added successively to 4-fluoro-2,6-dinitrophenol (26.00 g) in benzene (50 ml). The resulting solution is stirred at room temperature for 5 min (an intermediate precipitates) and then heated under reflux for 1.5 h (or until the starting material has reacted completely). The reaction mixture is cooled to room temperature, concentrated and the residue is poured onto ice/water. The precipitate is collected by filtration, washed three times with water and dried. After recrystallization from ethanol 23.50 g (83% of theory) of product are obtained in crystalline form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][N+:3]=1[O-].C(Cl)Cl.CCOC(C)=O>[Ni].C(O)C>[NH2:8][C:6]1[C:5]([F:11])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)[n+]([O-])cc1F
Agent: [Ni]
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)ncc1F
Reaction time: 3 h
Yield: 90.3 %

Procedure:
A mixture of 2-chloro-5-fluoro-4-nitropyridine-1-oxide (11, 1.3 g, 6.8 mmol) and 1.6 g of Raney nickel in 80 mL of anhydrous ethyl alcohol was hydrogenated at 40 psi in a Parr hydrogenation apparatus for 3 h when TLC showed that the starting material had disappeared and a new spot was detected (CH2Cl2/EtOAc, 4:1, v/v, Rf0.78 and 0.71, for the starting material and the product, respectively). The catalyst was removed by filtration and washed carefully with ethyl alcohol. The filtrate and washings were combined and evaporated in vacuo to give 0.9 g (91%) of product as an off-white solid. A small analytical sample was purified by recrystallization from hot water to afford white crystals: mp 110-111° C.; 1H NMR (CDCl3) δ4.50 (br s, 2 H, NH2, D2O exchangeable), 7.15 (d, 1 H, 3-H, J=6 Hz), 7.95 (d, 1H, 6-H, J=2 Hz). Analysis calculated for C5H4ClFN2: C, 40.97; H, 2.75; N, 19.12. Found: C, 41.18; H, 2.39; N, 18.89.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:10]=[C:11]([C:15]#[CH:16])[CH:12]=[CH:13][CH:14]=1>C(O)(=O)C>[C:5]([NH:8][C:9]1[CH:10]=[C:11]([C:15]#[CH:16])[CH:12]=[CH:13][CH:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: C#Cc1cccc(N)c1
Solvent: CC(=O)O
Product: C#Cc1cccc(NC(C)=O)c1
Yield: 79 %

Procedure:
To a 250 ml 3-neck flask fitted with a condenser, nitrogen inlet and outlet, and magnetic stirrer was added 150 ml of acetic acid and 35 ml of acetic anhydride. The mixture was heated to reflux under nitrogen and cooled under nitrogen. To the cooled mixture was added 15 g (0.114 mole) of 3-aminophenylacetylene and the homogeneous solution was refluxed overnight. The cooled reaction mixture was transferred to a 500 ml one-neck flask, and the acetic acid was removed by a rotor-evaporator under high vacuum. Water (200 ml) was added to the residual oil to crystallize the solid product. The material was isolated by filtration and washed with water and then air dried. Recrystallization from carbon tetrachloride with 200 g/10 g solid plus charcoal yielded 14.4 g (79% yield) of a white crystalline product (m.p. 94°-96° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.C(Cl)(=O)C(C)(C)C.FC(F)(F)C(O)=O.[N:46]1([C@H:51]2[CH2:55][CH2:54][NH:53][CH2:52]2)[CH:50]=[N:49][CH:48]=[N:47]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])[C@H:11]([C:27]([N:53]3[CH2:54][CH2:55][C@H:51]([N:46]4[CH:50]=[N:49][CH:48]=[N:47]4)[CH2:52]3)=[O:28])[CH2:10]2)=[CH:30][CH:31]=1
Reactant: c1ncn([C@H]2CCNC2)n1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](n4cncn4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 150.2 %

Procedure:
Following a procedure similar to that described in Preparation 18(a), but using 768 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 218 mg of pivaloyl chloride and 238 mg of (3S)-3-(1,2,4-triazol-1-yl)pyrrolidine trifluoroacetate, 803 mg of the title compound were obtained as a powder.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:25]([CH3:27])[CH3:26])[C:9](/[CH:18]=[CH:19]/[C:20](OCC)=[O:21])=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[H-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:25]([CH3:27])[CH3:26])[C:9](/[CH:18]=[CH:19]/[CH2:20][OH:21])=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1c(C(C)C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)c1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1/C=C/CO
Temperature: -10 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of ethyl(2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propenoate (50 mg) in toluene was added dropwise 1.5 M diisobutylalminum hydride (0.277 mL) in toluene (24 mL) in a dryice-acetone bath. After addition, the mixture was stirred for 2 hours (−10° C.). The reaction mixture was quenched with sodium, potassium-tartarate and was filtered through Celite. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 40 mL) eluted with hexane-ethyl acetate=10-1, 5-1, and 3-1 to give (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propen-1-ol as an yellow solid (30 mg).