Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[CH2:13]O.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][CH2:13][C:4]1[C:5]([O:11][CH3:12])=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(OC)c(CO)c(OC)c1
Reactant: Sc1ccccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC)c(CSc2ccccc2Br)c(OC)c1
Yield: 8.9 %

Procedure:
To a solution of 30.8 g (2,4,6-trimethoxyphenyl)methanol (155.4 mmol) and 29.2 g 2-bromobenzenethiol (155.4 mmol) in 150 ml DCM at 0° C. was added dropwise 1.3 eq TFA. The reaction was stirred 15 minutes at room temperature before saturated NaHCO3 was added until neutral. The organic volatiles were removed under reduced pressure and the aqueous residue was extracted with ethyl acetate (3×150 ml). The organic layer was collected, washed with brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure afforded a yellowish solid. The solid was washed with ethyl acetate to yield 51.3 g white solid (2-bromophenyl)(2,4,6-trimethoxybenzyl)sulfane (13.9 mmol, 89% yield).
Reaction SMILES: [N+](=[CH2:3])=[N-].[Br:4][CH2:5][C:6]([C:8](=[N:34][OH:35])[C:9]([NH:11][CH:12]1[C:32](=[O:33])[N:14]2[C:15]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])=[CH:16][CH2:17][S:18][C@H:13]12)=[O:10])=[O:7]>C(OCC)C.O1CCCC1>[Br:4][CH2:5][C:6]([C:8](=[N:34][O:35][CH3:3])[C:9]([NH:11][CH:12]1[C:32](=[O:33])[N:14]2[C:15]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])=[CH:16][CH2:17][S:18][C@H:13]12)=[O:10])=[O:7]
Reactant: C=[N+]=[N-]
Reactant: O=C(CBr)C(=NO)C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Solvent: C1CCOC1
Solvent: CCOCC
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12

Procedure:
A solution of diazomethane in diethyl ether was added little by little to a solution of 4-nitrobenzyl 7-[2-(2-bromoacetyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (0.9 g.) in tetrahydrofuran (30 ml.) under ice-cooling until the reaction terminated, and then acetic acid was added to the resultant solution to decompose excess diazomethane. The resultant solution was concentrated under reduced pressure to give the foamy product of 4-nitrobenzyl 7-[2-(2-bromoacetyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 0.9 g.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.[Br:14]Br>CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]([Br:14])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1
Reactant: BrBr
Reactant: O=C1CCCCc2cc(Br)ccc21
Solvent: CCOCC
Product: O=C1c2ccc(Br)cc2CCCC1Br
Temperature: 0 °C
Yield: 37.3 %

Procedure:
Example 3, 2-Bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.5 g, 5.9 mmol) was dissolved Et2O (25 mL), cooled to 0° C. and bromine (0.35 mL, 6.6 mmol) was added dropwise. The solution was stirred at 24° C. until TLC indicated reaction complete (2-18 h; scale dependent). The solvent was removed by rotory evaporation and the crude product applied to a 25 (M) Biotage® silica gel column. Gradient elution from 50-100% B (A=Hexanes; B=10% EtOAc/hex) over 500 mL and gave 2,6-dibromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one 700 mg, and 1.5 g of a second fraction containing dibromide (1:1). RT=2.2 minutes (condition 1).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24]>>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:29][O:28][CH2:27][CH2:26][O:25][CH:23]=[CH2:24])=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22]
Reactant: O=C(O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Product: C=COCCONC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F

Procedure:
4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylic acid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in the presence of coupling reagent in appropriate solvent. The reaction is generally carried out at ambient temperature and normally complete within several hours (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide is obtained after conventional workup.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4](=[O:14])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.P(=O)(O)(O)O>COCCO.O>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]2[CH2:5][C:4](=[O:14])[C:3]3[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:1]2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(C=CC(=O)c2ccccc2O)cc1
Agent: O=P(O)(O)O
Solvent: COCCO
Solvent: O
Product: Cc1ccc(C2CC(=O)c3ccccc3O2)cc1

Procedure:
The 2'-Hydroxy-4-methylchalcone of Example 13 (7.3 g.) was boiled under reflux with a solution of 85% phosphoric acid (22 ml.) in 2-methoxyethanol (219 ml.) for 8 hrs. The reaction mixture was diluted with water (1 liter) and the oily precipitate extracted into dichloromethane (300 ml.). The organic extract was separated and washed with water and saturated sodium bicarbonate solution. Filtration and evaporation gave a residue of 4'-methylflavanone contaminated with the starting chalcone.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>O1CCOCC1.CN(C)C=O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:13](=[O:14])[C:12]4[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:10]3=[O:15])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1c1cc(C2CC2)[nH]n1
Temperature: 120 °C

Procedure:
5-Cyclopropyl-1H-pyrazol-3-amine (5 g) was slurried in dioxane (80 mL) and N,N-dimethylformamide (80 mL), then phthalic anhydride (6 g) was added and the reaction was heated at 120° C. for 4 days. The reaction was cooled and concentrated. The crude material was triturated with isopropyl ether/ethanol 1/1 (30 mL) to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:24]=2[CH:32]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:24]=4[CH:32]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)cc1Cl
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(OC)c(Cl)c4)n3)ccc2o1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and 5-amino-2-(methoxycarbonyl)benzofuran were reacted to produce N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.34 (bs, 2H), 8.10-8.07 (m, 2H), 7.78 (t, 1H, J=2.7 Hz), 7.66-7.53 (m, 4H), 7.12 (d, 1H, J=9.3 Hz), 3.87 (s, 3H), 3.85 (s, 3H); LCMS: purity: 99%; MS (m/e): 443 (MH+).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Br[C:17]1[CH:18]=[C:19]([S:23]([C:26]2[CH:27]=[N:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][C:30]=3I)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>>[C:12]([O:11][C:9]([N:2]1[CH2:3][CH:4]2[CH2:8][N:7]([C:17]3[CH:18]=[C:19]([S:23]([C:26]4[CH:27]=[N:28][C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][C:30]=5[N:7]4[CH2:6][CH:5]5[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH:4]5[CH2:8]4)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=3)[CH2:6][CH:5]2[CH2:1]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=S(=O)(c1cccc(Br)c1)c1cnc2c(I)cccc2c1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Product: CC(C)(C)OC(=O)N1CC2CN(c3cccc(S(=O)(=O)c4cnc5c(N6CC7CN(C(=O)OC(C)(C)C)CC7C6)cccc5c4)c3)CC2C1
Yield: 12 %

Procedure:
The title compound was prepared by analogy to the procedure of 1.3, except using tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and 3-(3-bromophenylsulfonyl)-8-iodoquinoline. 18 mg (12%) of the title compound were obtained as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][N:3]=1.CN(C=O)C.[N-:18]=[N+:19]=[N-:20].[Na+]>O>[N:18]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][N:3]=1)=[N+:19]=[N-:20]
Reactant: CN(C)C(=O)c1ccc(Cl)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccc(N=[N+]=[N-])nc1
Temperature: 120 °C
Reaction time: 60 h
Yield: 26.4 %

Procedure:
In a 500 mL round-bottomed flask, 6-chloro-N,N-dimethylnicotinamide (8.15 g, 44.1 mmol) was combined with DMF (50.0 ml) to give a brown solution. Sodium azide (3.44 g, 53.0 mmol) was added and the reaction mixture was heated to 120° C. and stirred for 60 h. The reaction mixture was diluted with 100 mL H2O and extracted with EtOAc (2×200 mL). The organic layers were combined, washed with H2O (1×50 mL), sat NaCl (1×100 mL), dried over Na2SO4 and concentrated in vacuo to a yellow oil. MeOH was added and the entire mixture solidified upon concentration. The crude product was dried under vacuum overnight. The pasty solid was recrystallized from EtOAc/Hex. The solid was filtered and washed with a minimal amount of hexane. The white powder was dried under vacuum at 45° C. for 3 hrs to give 2.23 g (26%) of the title compound. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.95 (s, 1H), 8.09 (d, J=9.1 Hz, 1H), 7.75 (dd, J=9.1, 1.5 Hz, 1H), 3.15 (br. s., 6H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:18]([NH2:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>>[CH2:18]([NH:21][C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:19]=[CH2:20]
Reactant: C=CCN
Reactant: CCCCCNc1nc(Cl)nc2c(C)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCCCCC)c2scc(C)c2n1
Yield: 52.8 %

Procedure:
In a sealed tube were heated 391 mg (1.2 mmol) of 2-chloro-7-methyl-4-pentylaminothieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 184 mg (yield: 52.9%) of the title compound.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH2:4][C:3]1([CH3:14])[CH3:13].C1C=CC(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:29]([CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH2:4][C:3]1([CH3:14])[CH3:13])=[N+:30]=[N-:31]
Reactant: CC1(C)Cc2ccc(C#N)cc2C1O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC1(C)Cc2ccc(C#N)cc2C1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of Step B. 3-hydroxy-2,2-dimethyl-2,3-dihydro-1H-indene-5-carbonitrile (4.98 g, 0.027 mol) in toluene (60 mL) at 0° C. was added DPPA (8.6 mL, 0.040 mol) via syringe dropwise followed by DBU (6.0 mL, 0.040 mol) via syringe dropwise. After stirring at 0° C. for 10 min and rt for 30 min, the mixture was heated at 80° C. for 60 h, then cooled to rt and partitioned between EtOAc (400 mL)/water (100 mL). Resulting layers were separated and the organic layer was washed with water (100 mL), aq HCl (1N, 60 mL×2), water (100 mL), sat. aq. NaHCO3 (80 mL), brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give yellow oil as the crude product. Purification by flash chromatography on silica gel (120 g) eluting with EtOAc/hexane mixtures provided the title compound as a colorless oil (4.12 g, 73% yield). HPLC Ret. time: 3.37 min. LCMS MH+ (m/z) 213.3. 1H NMR: (DMSO-d6, 400 MHz): δ 7.86 (s, 1H), 7.76 (d, 1H), 7.49 (d, 1H), 4.74 (s, 1H), 2.80 (m, 2H), 1.13 (s, 3H), 1.06 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)[CH3:2].[Br:14]Br>CCOCC>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]([Br:14])[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCC(=O)CC1
Reactant: BrBr
Solvent: CCOCC
Product: CCOC(=O)CC1CCC(=O)C(Br)C1

Procedure:
74.0 G. of 4-oxocyclohexaneacetic acid ethyl ester and 1200 ml. of anhydrous ether were placed in a 3 l. three-necked flask, provided with a thermometer, nitrogen inlet, dropping funnel, condenser and stirrer. The solution was cooled to -10° by means of a dry ice-acetone bath, and 64.0 g. of bromine was added dropwise over a period of 30-40 minutes. The resulting colorless solution was washed three times with 100 ml. of water, then two times with 125 ml. of cold saturated sodium bicarbonate solution followed by 100 ml. of water. The combined aqueous solutions were extracted twice with 150 ml. of ether. The combined ether extracts were dried over anhydrous magnesium sulfate, and the ether was removed by distillation from a steam bath at atmospheric pressure to give a residue of crude 3-bromo-4-oxocyclohexaneacetic acid ethyl ester, weighing 105 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[CH3:23][N:24]([CH2:26][C:27]1[N:28]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([F:39])[CH:33]=2)[CH:29]=[CH:30][N:31]=1)[CH3:25].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:25][N:24]([CH2:26][C:27]1[N:28]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:9](=[O:11])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:14])=[C:34]([F:39])[CH:33]=2)[CH:29]=[CH:30][N:31]=1)[CH3:23]
Reactant: O=C(Nc1ccc(Cl)cc1)NC(C(=O)O)c1ccccc1F
Reactant: CN(C)Cc1nccn1-c1ccc(N)c(F)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)Cc1nccn1-c1ccc(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (from EXAMPLE 55, 62 mg, 0.19 mmol) and 4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluorophenylamine (45 mg, 0.19 mmol) in pyridine (3 mL) cooled in an ice-bath, POCl3 (0.035 mL, 0.38 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (19 mg). MS 539.1 and 541.1 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][Li].[OH:3][C@@H:4]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C:14](=[O:17])[CH:15]=[CH2:16])[CH2:5]1.[Cl-].[NH4+]>CCOCC>[CH2:16]([CH2:15][C:14](=[O:17])[C@@H:13]1[C@:18]2([CH3:27])[C@H:10]([C@H:9]3[C@H:21]([C:20](=[O:26])[CH2:19]2)[C@:22]2([CH3:25])[C@H:6]([CH2:5][C@H:4]([OH:3])[CH2:24][CH2:23]2)[CH2:7][CH2:8]3)[CH2:11][CH2:12]1)[CH3:1]
Reactant: [Li]C
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
Methyl lithium in ether (≈1.3M: 7.5 ml) was added slowly to a slurry of cuprous iodide (950 mg) in dry ether (40 ml) under nitrogen at -20°, the initial yellow precipitate just redissolving. 3α-Hydroxy-21-methylene-5α-pregnane-11,20-dione (500 mg) in dry ether (10 ml) was added rapidly to the solution forming a yellow precipitate. After 3/4 hr. at ≈0° the mixture was poured into saturated ammonium chloride solution and the oily precipitate extracted with ether. The extracts were washed with saturated ammonium chloride solution, then water, and dried over anhydrous sodium sulphate. The dried solution was evaporated to an off white foam (430 mg) which was purified by preparative t.l.c. in ethyl acetate/petrol (1:1). The main band (Rf ≈ 0.4) gave a white foam which on trituration with petrol, containing a small quantity of ether, gave title compound (320 mg.) as a white solid, m.p. 112°-113°, [α]D + 105° (c = 1.01).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:32]#[N:33])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:34][N:35]1[CH2:39][CH2:38][CH2:37][C:36]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:15]4[CH2:16][CH2:17][CH:34]([N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[CH2:3][CH2:4]4)=[C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:32]#[N:33])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CN1CCCC1=O
Reactant: COCCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Product: COCCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1
Temperature: 105 °C

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.31 mmol) of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]phenyl}amino)-7-fluoro-6-(2-methoxyethoxy)-3-quinolinecarbonitrile and 287 mg (1.86 mmol) of 4-(1-pyrrolidinylpiperidine) in 1 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 17 hours to yield the crude product. Purification by silica gel chromatography (gradient 98:2 methylene chloride/methanol to 4:1 methylene chloride/methanol) gives 120 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-(2-methoxyethoxy)-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 238-241° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7](S(C)(=O)=O)[N:6]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH2:24][C:25]#[N:26])[CH:21]=[CH:22][CH:23]=1.O>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]([C:7]2[N:6]=[C:5]([O:4][CH3:3])[CH:10]=[C:9]([O:11][CH3:12])[N:8]=2)[C:25]#[N:26])[CH:21]=[CH:22][CH:23]=1
Reactant: N#CCc1cccc(Cl)c1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(C(C#N)c2cccc(Cl)c2)n1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
Sodium hydride (6.0 g of 80% in oil) was added portionwise to a stirred solution of 4,6-dimethoxy-2-(methylsulphonyl)pyrimidine (21.8 g) and (3-chlorophenyl)acetonitrile (15.1 g) in dry dimethylformamide (150 ml) at 5° C. The mixture was stirred at 10° C. for 30 minutes, and then at room temperature for 3 hours. The resulting suspension was poured into water (1.2 l) and the oil was extracted into ether. The combined extracts were washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated to give an orange oil, which was purified by chromatography to give 26.3 g of the desired product as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14](OCC)=[O:15].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N+:8]([C:7]1[C:2]2[NH:1][C:14](=[O:15])[CH2:13][O:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)CBr
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2cccc([N+](=O)[O-])c2N1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2-amino-3-nitrophenol (1.54 g, 10 mmol), ethyl bromoacetate (1.67 g, 10 mmol), potassium carbonate (1.54 g, 11 mmol) and DMF (5.0 mL) was stirred at room temperature for 20 h. Reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). Combined ethyl acetate layers were washed with water (50 mL×2), dried (brine, sodium sulphate), concentrated and dried on high vacuum to give 5-Nitro-4H-benzo[1,4]oxazin-3-one, K-64 (1.6 g).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:15]Br>CC(O)=O>[C:1]([C:5]1[NH:6][C:7]2[C:13]([Br:15])=[C:12]([NH2:14])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)c1nc2ccc(N)cc2[nH]1
Solvent: CC(=O)O
Product: CC(C)(C)c1nc2ccc(N)c(Br)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 0.53 g (2.8 mmol) of 2-tert-butyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.05 ml (1.0 mmol) of Br2 dropwise and resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo and purified on silica gel column chromatography (CHCl3, neat) to yield 0.18 g (0.67 mmol, 67%) of the desired product.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=NOC(C4C(C(F)(F)F)=C(C5C=CC=CC=5)ON=4)=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[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.[C:51]1([C:57]2[C:61]([C:62]([F:65])([F:64])[F:63])=[C:60]([C:66]3[S:67]C4C5C(=CC(C=C)=CC=5)CCC=4[N:70]=3)[O:59][N:58]=2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[C:8]1([C:7](=[N:14][CH:15]([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2[S:67][C:66]([C:60]4[O:59][N:58]=[C:57]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)[C:61]=4[C:62]([F:65])([F:64])[F:63])=[N:70][C:28]=2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Reactant: CCOC(=O)C(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Product: CCOC(=O)C(CCc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2)N=C(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 91A employing 3-phenyl-4-(trifluoromethyl)-5-(7-vinyl-4,5-dihydronaphtho[2,1-d]thiazol-2-yl)isoxazole (Preparation 82E) as a starting material. The reaction was heated at 70° C. for 7 hr. The compound had an LC/MS M+1=692.4.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[S:33][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:30]=1>CN(C)C1C=CN=CC=1.CC(C)=O>[CH:12]1([C:10]([NH:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([O:1][S:34]([C:32]4[S:33][C:29]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=5)=[CH:30][CH:31]=4)(=[O:35])=[O:36])[CH:16]=[CH:15][C:5]=3[N:6]=2)=[O:11])[CH2:13][CH2:14]1
Reactant: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(-c4ccccn4)s3)cc2s1)C1CC1
Yield: 8.5 %

Procedure:
A solution of cyclopropanecarboxylic acid (6-hydroxybenzothiazol-2-yl)amide (intermediate 6) (60 mg, 0.256 mmol), pyridine (80 μl, 0.991 mmol), 4-dimethylaminopyridine (3 mg, 0.025 mmol) and 5-(2-pyridyl)thiophene-2-sulfonyl chloride (99 mg, 0.384 mmol) in 2 ml of acetone is stirred for 24 hours at 40° C. The reaction medium is concentrated to dryness, taken up in 2 ml of DMSO and purified 4 times by preparative LC/MS (method B) to give 10 mg of 5-pyridin-2-ylthiophene-2-sulfonic acid 2-(cyclopropanecarbonyl-amino)benzothiazol-6-yl ester.