Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[NH:20][C:19]=2[CH3:28])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2].C(=O)([O-])[O-].[K+].[K+].[C:35]([O:38][CH2:39][CH2:40]Br)(=[O:37])[CH3:36].CN(C)C=O>O>[C:35]([O:38][CH2:39][CH2:40][N:20]1[C:21]2[C:26](=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:18]([C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:17])=[C:19]1[CH3:28])(=[O:37])[CH3:36]
Reactant: CC(=O)OCCBr
Reactant: Cc1[nH]c2ccc(F)cc2c1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCn1c(C)c(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)c2cc(F)ccc21
Temperature: 40 °C
Reaction time: 3 h
Yield: 30.6 %

Procedure:
N-(3-Cyano-4-neopentyloxyphenyl)-5-fluoro-2-methyl-1H-indole-3-carboxamide ¼ hydrate (0.8 g) obtained in Example 9,. potassium carbonate (0.2 g) and 2-bromoethyl acetate (0.4 g) were added to dimethylformamide (5 ml) and the mixture was stirred at 40° C. for 3 hr. Then the reaction mixture was treated with water and the oganic layer was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was separated and purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (0.3 g). melting point: 124-125° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([NH2:13])[C:9]=1[C:10]([OH:12])=[O:11].[C:14](Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)(Cl)=O>ClCCCl.CN(C)C=O.O>[Cl:3][C:4]1[C:9]2[C:10](=[O:12])[O:11][C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=c1oc(-c2ccccc2)nc2cccc(Cl)c12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 111.6 %

Procedure:
40 g of 50% strength aqueous sodium hydroxide solution are added to a stirred suspension of 85.8 g of 6-chloroanthranilic acid in 1,250 g of 1,2-dichloroethane in the course of 10 minutes at from 20° to 30° C. The salt suspension is freed from water by refluxing it for 1 hour in a water separator. Thereafter, 56.2 g of benzoyl chloride are added in the course of 40 minutes at from 25° to 35° C., and stirring is continued for a further 30 minutes. Under the same conditions, a further 14.1 g of benzoyl chloride are added in the course of 5 minutes, and stirring is continued for 55 minutes at 25° C. 0.2 g of dimethylformamide are added, after which 64 g of gaseous phosgene are passed into the stirred, refluxed mixture in the course of 11/2 hours, and excess phosgene is then expelled by blowing in nitrogen. The reaction mixture is cooled to 40° C., and extracted three times with water and once with a little concentrated sodium chloride solution. Evaporating down the organic phase, in the final stage at 140° C. and under 20 mbar, gives 115 g (89%) of 5-chloro-2-phenyl-4H-3,1-benzoxazin-4-one of melting point 148°-152° C. According to HPLC and comparison with an analytical standard, the purity is 86%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:15]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]2)=[C:16]=[O:17]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:16]([NH:15][C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][N:22]=[CH:23]4)=[O:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=Nc1cccc2cnccc12
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Solvent: CCOCC
Product: O=C(Nc1cccc2cnccc12)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 80 %

Procedure:
1-(3,4-Dichlorophenyl)piperazine (1280 mg, 5.55 mmol) in diethyl ether (30 mL) was treated with the product from Example 61A (˜40 mL). The mixture was filtered, the filter cake washed with diethyl ether, and dried under reduced pressure to provide the title compound as a white solid (1.78 g, 80%). 1H NMR (300 MHz, DMSO-d6) δ 9.29 (d, J=1.0 Hz, 1H), 8.84 (s, 1H), 8.49 (d, J=5.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.78 (m, 1H), 7.61-7.71 (m, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.22 (d, J=3.1 Hz, 1H), 7.01 (dd, J=9.1, 2.7 Hz, 1H), 3.68 (M, 4H), 3.30 (m, 4H); MS (EST+) m/z 401/403 (M+H)+, 35Cl/37Cl).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5].C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:30]=1[C:31](Cl)=[O:32]>CN(C=O)C>[CH2:17]([NH:16][C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([C:4](=[O:5])[CH2:3][CH2:2][NH:1][C:31](=[O:32])[C:30]3[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:29]=3[F:28])[CH:20]=[CH:19][C:9]=2[N:10]=1)=[O:15])[CH3:18]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)CCN)cc2s1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(C(=O)CCNC(=O)c3cc(F)ccc3F)cc2s1
Yield: 22 %

Procedure:
Similar to the synthesis of Example 249, a mixture of 1-(6-(3-aminopropanoyl)-2-benzothiazolyl)-3-ethylurea, triethylamine and 2,5-difluorobenzoyl chloride in DMF was reacted to give the desired compound 0.019 g (22%). LC/MS 433.0 (M+1); LC retention time 2.94 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[O:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:14])[NH:5][C:4](=[O:15])[CH:3]=1.[N:16]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[NH2:16][C:3]1[C:4](=[O:15])[NH:5][C:6](=[O:14])[N:7]([CH2:8][C:9]2[O:13][CH:12]=[CH:11][CH:10]=2)[C:2]=1[NH2:1]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=O)n1Cc1ccco1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(N)n(Cc2ccco2)c(=O)[nH]c1=O
Temperature: 70 °C
Yield: 53.4 %

Procedure:
6-Amino-1-furfuryluracil (3.0 g, 14.5-mmol) was dissolved with heating in 30% aqueous acetic acid (30 ml) and then a solution of sodium nitrite (1.7 g, 24.6 mmol) in water (5 ml) was added dropwise. The reaction was heated to 70° C. for 30 min and then cooled to 0° C. The solids were collected by filtration and rinsed with cold water (20 ml). The solids were dissolved into concentrated aqueous ammonium hydroxide solution (10 ml) and then a solution of sodium hydrosulfite (9.8 g, 47.8 mmol) in water (30 ml) was added in one portion. After heating at 80° C. for 1 hour, the slurry was cooled to ambient temperature. The solids were collected by filtration, rinsed with water (4×50 ml) and vacuum dried over phosphorus pentoxide to give 5,6-diamino-1-furfuryluracil (1.72 g, 53% yield) as a brown solid.
Reaction SMILES: O/[N:2]=[C:3](\[C:9](=O)[CH3:10])/[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[O:13]([C:15]#[N:16])[K]>CCO.O.[Pd]>[CH3:10][C:9]1[NH:16][C:15](=[O:13])[NH:2][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C(=N/O)C(C)=O
Reactant: N#CO[K]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 18.7 %

Procedure:
A mixture of ethyl (2E)-2-(hydroxyimino)-3-oxobutanoate (8.50 g, 53.41 mmol) and 10% Pd/C (0.42 g) in EtOH (25 mL) and a 1.5 M solution of HCl (40 mL) were stirred under hydrogen (50 psig) for 4 h. The vessel was carefully vented then the mixture was filtered through Celite which was subsequently washed with EtOH. The filtrate was concentrated slightly to remove some of the EtOH but the water bath was kept below 40° C. A 5M solution of aqueous HCl (5 mL) was added to the yellow solution and this was added dropwise to a solution of KOCN (6.50 g, 80.12 mmol) in water (25 mL) at RT. The reaction mixture was stirred at RT for 3 days then cooled to 0° C. After 2 h, the precipitate was filtered and washed with a cold 1:1 mixture of MeOH/water (20 mL) and dried under vacuum to afford 1.70 g (19%) of the title compound as a grey powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.61 (br. s., 1H), 10.14 (br. s., 1H), 4.16 (d, 2H), 2.20 (br. s., 3H), 1.23 (t, 3H). LCMS m/z 171.3 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH:36]([NH2:39])([CH3:38])[CH3:37].O>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:39][CH:36]([CH3:38])[CH3:37])[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CC(C)N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Nc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.011 ml (0.13 mmol) of isopropylamine were stirred in 1.5 ml of THF for 60 min. Another 11 μl (0.13 mmol) of isopropylamine were then added, and the mixture was stirred at RT for another 60 min. About 10 ml of water were added to the reaction mixture, and the precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 35 mg (56% of theory) of the desired target compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][NH:5][S:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:19])[CH:15]=2)[CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C.O1CCCC1>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:20][CH3:21])[S:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:19])[CH:15]=2)[CH:10]=1)(=[O:8])=[O:7])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: COC(CNS(=O)(=O)c1ccc2cc(Cl)ccc2c1)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CN(CC(OC)OC)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
N-(2,2-Dimethoxyethyl)-6-chloro-2-naphthalenesulfonamide was dissolved in DMF (100 ml) and combined with sodium hydride (1.16 g, in oil), cooled to 0° C., treated dropwise with a solution of ethyl bromoacetate (4.843 g) in tetrahydrofuran (15 ml) and then stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, aqueous sodium bicarbonate and brine, dried and concentrated to obtain N-(2,2-dimethoxyethyl)-N-(6-chloro-2-naphthalenesulfonyl)glycine ethyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[N:13]O)[CH:6]=[CH:5]2.[H][H]>CO.O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][NH2:13])[CH:6]=[CH:5]2
Reactant: [H][H]
Reactant: ON=Cc1ccc2cc(Cl)ccc2n1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc2cc(Cl)ccc2n1

Procedure:
A solution of 0.78 g (3.79 mmol) of 6-chloroquinoline-2-carbaldehydeoxime in 30 mL of saturated ammoniacal methanol and 10 mL of tetrahydrofuran is hydrogenated with Raney nickel for 48 hours at 3 bar hydrogen pressure. The catalyst is filtered off and the solution is concentrated. The residue is chromatographed on silica gel, eluting with a gradient of dichloromethane/methanol (90:10) to dichloromethane/methanol/25% aqueous ammonia (90:10:1). The corresponding fractions are combined and concentrated by evaporation. Yield: 0.33 g (45% of theory); Rf value: 0.43 (silica gel; dichloromethane/methanol=9:1); C10H9ClN2 (192.65); mass spectrum: (M+H)+=193/195 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>C1COCC1>[CH3:5][C:2]1([CH3:6])[CH2:3][O:4][C:20]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:24])[F:25])=[CH:23][CH:22]=2)=[N:1]1
Reactant: CC(C)(N)CO
Reactant: FC(F)(F)c1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)COC(c2ccc(C(F)(F)F)cc2)=N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To an ice-cold solution of 2-amino-2-methyl-1-propanol (21.4 g, 240 mmol) and triethylamine (16.8 mL, 120 mmol) in THF was added dropwise 4-trifluoromethyl benzyl chloride (25.0 g, 120 mmol). After the addition, the reaction mixture was stirred at 0° C. for 30 mins and then stirred at ambient temperature for 8 hrs. The precipitate was removed by filtration and the filtrate was concentrated by evaporating the solvent under reduced pressure. The resulting residue was treated dropwise with thionyl chloride with vigorous stirring at 0° C. After complete addition, the reaction mixture was further stirred at ambient temperature for 1 hr. Ether was poured into the reaction mixture and the precipitate was collected by filtration. The precipitate was dissolved in water and the aqueous solution was hydrolyzed with 10% (w/v) NaOH. The aqueous phase was extracted three times with ether, and the combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex/EtOAc=5/1) to yield the title compound (25.4 g, 87%).
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C>[Br:20][CH:1]([C:3]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: BrBr
Reactant: CCc1nc2ccccc2c(=O)n1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(Br)c1nc2ccccc2c(=O)n1C
Temperature: 25 °C
Yield: 79.1 %

Procedure:
To a solution of 2-ethyl-3-methyl-3H-quinazolin-4-one (11.28 g, 60 mmol) and sodium acetate (4.92 g, 60 mmol) in glacial acetic acid (130 mL) heated to 50° C. was added dropwise a solution of bromine (3.70 mL, 72 mmol) in glacial acetic acid (50 mL). After addition was complete the reaction was heated to reflux for 2 hours. The reaction was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 10% sodium bisulfite solution, water and dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (0-25% ethyl acetate-hexanes) to yield the product as a white solid (12.68 g, 79%). 1H NMR (400 MHz, CDCl3) δ 2.19 (d, 3H, J=6.6 Hz), 3.77 (s, 3H), 5.08 (q, 1H, J=6.6 Hz), 7.50 (t, 1H, J=8.1 Hz), 7.74 (m, 2H), 8.29 (d, 1H, J=8.9 Hz); ESI-MS m/z 267.0 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH:10]([CH2:16][CH2:17][CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:10]([CH2:16][CH2:17][CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCCC(Br)C(=O)OCC
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(Oc1ccccc1Br)C(=O)OCC
Temperature: 45 °C
Yield: 79.1 %

Procedure:
13.8 ml (119.6 mmol) of 2-bromophenol, 25 g (119.6 mmol) of ethyl 2-bromopentanoate, 19.8 g (143.3 mmol) of potassium carbonate, 19.8 g (119.6mmol) of potassium iodide and 210 ml of N,N-dimethylformamide are introduced into a 1 l three-necked flask equipped with a reflux condenser. The mixture is heated at 45° C. for 16 hours. 600 ml of water are added and extraction is carried out with ethyl acetate (3×300 ml). The combined organic phases are washed with 200 ml of a molar sodium hydroxide solution, 2×200 ml of water and 300 ml of brine. They are then dried over sodium sulphate, filtered and concentrated under vacuum and the residue is purified by silica flash chromatography (cyclohexane elution) to give 28.5 g (79%) of ethyl 2-(2-bromophenoxy)pentanoate in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:26]([NH:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:28])[CH3:27].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.O.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>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([C:8](=[C:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:5]2[CH:4]=[CH:3][C:2]([C:33]3[CH:34]=[CH:35][C:30]([NH:29][C:26](=[O:28])[CH3:27])=[CH:31][CH:32]=3)=[CH:7][CH:6]=2)=[CH:14][CH:13]=1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(=O)Nc1ccc(-c2ccc(C(=C3CC(C)(C)CC(C)(C)C3)c3ccc(O)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a solution of 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.1 g, 0.250 mmol) and (4-acetylaminophenyl)boronic acid (0.148, 0.826 mmol) in ethylene glycol dimethyl ether (8 mL) was added tetrakis(triphenylphosphine)palladium (0) (0.026 g, 0.023 mmol) followed by 2 M Na2CO3 (3 mL). The reaction mixture was refluxed for 4 h, cooled to room temperature then diluted with water followed by EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried (MgSO4) filtered and concentrated to an oil. The crude oil was dissolved in DCM, loaded onto silica gel and purified with a gradient of 100% hexanes to 40% hexanes:EtOAc over 60 mins. Pure fractions were combined and concentrated to give 0.05 g (41%) of the title compound 99 as an off white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.89 (s, 12 H), 1.25 (s, 2 H), 1.93 (s, 4 H), 2.03 (s, 3 H), 6.66 (d, J=8.5 Hz, 2 H), 6.94 (d, J=8.4 Hz, 2 H), 7.16 (d, J=8.3 Hz, 2 H) 7.52-7.64 (m, 6 H), 9.27 (s, 1 H), 9.99 (s, 1 H). HRMS (ESI) Calcd for C31H36NO2: 454.2746 (M+H)+. Found 454.2757.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][N:13]=[N:12][CH:11]=1)=[O:8].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[F:26][C:21]1[CH:20]=[C:19]([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[N:12][CH:11]=2)=[O:8])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccnnc1)c1cc(-c2ccncc2)ccc1OCc1ccc(F)c(F)c1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-([(3,4-difluorophenyl)methyl]oxy)-N-4-pyridazinylbenzamide (may be prepared as described in Example 78; 200 mg, 0.48 mmol), 4-pyridinylboronic acid (88 mg, 0.74 mmol), tetrakis(triphenylphosphine)palladium(0) (33.0 mg, 0.03 mmol), sodium carbonate (0.95 ml, 0.95 mmol) and 1,2-dimethoxyethane (3 ml). The mixture was sealed and heated to 120° C. for 1 hour under microwave conditions. The 1,2-dimethoxyethane was evaporated under reduced pressure and the residue was purified using MDAP to yield the title compound. 35 mg.
Reaction SMILES: C(=O)(O[CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)N.Cl>[OH-].[Na+]>[OH:21][CH2:20][C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([OH:22])[CH:8]=1)[C:5](=[CH2:4])[C:17]1([OH:19])[O:18][N:12]2[CH2:13][CH:14]2[CH:16]1[NH:15]2
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=C1c2c(O)cc(CO)cc2N2CC3NC3C1(O)O2
Reaction time: 72 h
Yield: 25.7 %

Procedure:
4-Formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (100 mg) was dissolved in 1N aqueous sodium hydroxide (10 ml), and the pale yellow solution was allowed to stand at room temperature for 72 hours. The reaction mixture was neutralized with 1N hydrochloric acid and then lyophilized. The residue was subjected to a silica gel column chromatography and elution was carried out with a mixture of methanol and chloroform (1:9, v/v). The desired fractions were combined and then evaporated to dryness in vacuo to give 4-hydroxymethyl-8-methylene-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-6,9-diol (21 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@@H:15]([CH3:17])[C@H:13]([OH:14])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:28]([O-])([N+]([O-])=O)=[O:29]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:28]=[O:29])[C:5]([N:7]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@@H:15]([CH3:17])[C@H:13]([OH:14])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O
Yield: 100.4 %

Procedure:
3.2 g of 1-(2-chloroethyl)-3-n-butyl-3-L-rhamnopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 3.5 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-L-rhamnopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:10][CH:11]2[CH2:15][CH2:14][CH2:13]C2)=[N:5][C:6](C)=[CH:7][CH:8]=1.C([O:18][C:19]([CH:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[C:28]([F:30])[C:27]([OH:31])=[C:26]([F:32])[CH:25]=1)=[O:20])C>>[CH:11]1([S:10][C:4]2[C:3]([CH2:2][O:31][C:27]3[C:26]([F:32])=[CH:25][C:24]([CH:22]4[CH2:23][CH:21]4[C:19]([OH:20])=[O:18])=[CH:29][C:28]=3[F:30])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: Cc1ccc(CCl)c(SC2CCCC2)n1
Reactant: CCOC(=O)C1CC1c1cc(F)c(O)c(F)c1
Product: O=C(O)C1CC1c1cc(F)c(OCc2cccnc2SC2CCC2)c(F)c1
Yield: 81.4 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.024 g, 0.113 mmol) obtained in Step C of Preparation Example 23 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.026 g, 0.113 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.036 g, 81%).
Reaction SMILES: C(N(CC)CC)C.O[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1.C(Cl)[Cl:19]>>[Cl:19][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(O)nc1
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(Cl)nc1
Yield: 58.1 %

Procedure:
This example proceeded as in Example 1, but with use of 500 g of CH2Cl2 and 0.3 mole of triethylamine. The yield of 13.9 g of product mixture (content of nicotinic derivatives was 98.5 percent; the ratio of ClNS/HNS was 64/36) corresponded to a yield of 58.1 percent of 6-chloronicotinic acid and 32.7 percent of 6-hydroxynicotinic acid, related to the amount of isocinchomeronic acid-N-oxide used.