Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([F:20])=[C:12]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)[CH:13]=2)OC1.Br[C:23]1[N:27]2[CH:28]=[CH:29][C:30]([C:32]([OH:35])([CH3:34])[CH3:33])=[N:31][C:26]2=[N:25][CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].CN(C)C=O>[F:20][C:11]1[CH:10]=[CH:9][C:8]([C:23]2[N:27]3[CH:28]=[CH:29][C:30]([C:32]([OH:35])([CH3:33])[CH3:34])=[N:31][C:26]3=[N:25][CH:24]=2)=[CH:13][C:12]=1[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3cnccn3)c2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cnccn4)c3)cnc2n1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To 2-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]pyrazine prepared above was added 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (0.266 g, 1.04 mmol) followed by dry potassium phosphate (0.065 g), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.06 g) and dry N,N-dimethylformamide (5 ml). The mixture was degassed with nitrogen then stirred for 16 h at 65° C. under an atmosphere of dry nitrogen. The reaction was cooled to ambient temperature, silica gel added, and the solvent stripped at reduced pressure. The residue was subjected to chromatography on silica gel eluting with dichloromethane on a gradient of methanol (3.5-5%). The appropriate fractions were combined, concentrated in vacuo and the residue crystallised from toluene to afford 2-[3-(4-fluoro-3-(pyrazin-2-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol: δH (400 MHz, DMSO) 1.51 (6H, s), 5.51 (1H, s), 7.41 (1H, d, J 7), 7.62 (1H, dd, J 11 and 9), 7.88 (1H, m), 7.95 (1H, s), 8.18 (1H, dd, J 7 and 2), 8.72 (1H, d, J 2), 8.84 (1H, dd, J 1 and 2), 8.99 (1H, d, J 7), 9.14 (1H, dd, J 2 and 2); m/z (ES+) 350 (MH+).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:21])([CH3:20])[O:6][C@@H:7]([C@@H:16]([CH3:19])[CH:17]=[O:18])[C@@H:8]([CH3:15])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])[CH3:3].[CH3:22][Mg]Br>CCOCC>[CH3:1][C:2]([Si:5]([CH3:20])([CH3:21])[O:6][C@@H:7]([C@@H:16]([CH3:19])[CH:17]([OH:18])[CH3:22])[C@@H:8]([CH3:15])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:3])[CH3:4]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=O
Solvent: CCOCC
Product: CON(C)C(=O)[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(C)O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of 6.9 g (21.8 mmol) of (2R,3S,4R)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-N-methoxy-N,2,4-trimethyl-5-oxo-pentanamide in 50 mL of ether is added 10.2 mL (30.5 mmol) of a 3M solution of methylmagnesium bromide in ether, dropwise, at −40° C., after which the mixture is stirred at −20° C. for 1 hour. The reaction mixture is then dilluted with 200 mL of ether and the reaction is quenched by adding the reaction mixture to 20 g of crushed ice at 0° C. The mixture is then washed with 100 mL of 1 M sodium hydrogen sulfate solution and partitioned with two 150 mL portions of ether. The organic layers are then combined and dried over sodium sulfate. The crude product mixture is then chromatographed employing an eluent mixture of 20% ethyl acetate in hexane initially and then an eluent mixture of 40% ethyl acetate in hexane to yield two diastereomers as light yellow oils which are used in the next step without further purification.
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[CH3:15].[F:16][C:17]1[CH:18]=[CH:19][C:20](B2OC(C)(C)C(C)(C)O2)=[C:21]2[C:25]=1[C@H:24]([O:26][C:27]1[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=1)[CH2:23][CH2:22]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:15][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:20]1[CH:19]=[CH:18][C:17]([F:16])=[C:25]2[C:21]=1[CH2:22][CH2:23][C@H:24]2[O:26][C:27]1[CH:40]=[CH:39][C:30]2[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=2[CH:28]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2ccncn2)cc(C)c1I
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccncn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 4-(4-iodo-3,5-dimethylphenyl)pyrimidine and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 15): tR=1.26 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[O:21][C:20]([P:22]([OH:25])([OH:24])=[O:23])=[C:19]([CH2:26][CH3:27])[C:18]=3[CH2:28][CH3:29])[CH:14]=[C:13]([C:30]([OH:32])=[O:31])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:33][CH2:34]N=C=NCCCN(C)C.C(O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[O:21][C:20]([P:22]([OH:25])([OH:24])=[O:23])=[C:19]([CH2:26][CH3:27])[C:18]=3[CH2:28][CH3:29])[CH:14]=[C:13]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(-c2cc(C(=O)O)cc(C(=O)Nc3cccc(Br)c3)c2)oc(P(=O)(O)O)c1CC
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(C(=O)Nc2cccc(Br)c2)cc(-c2oc(P(=O)(O)O)c(CC)c2CC)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 1-(3-bromophenylcarbamoyl)-3-carboxy-5-(diethyl 2-phosphonofuran-5-yl)benzene (1 mmol), EDCI (2 mmol), DMAP (0.1 mmol) and ethanol (1.5 mmol) in 70 mL of CH2Cl2 were stirred at rt for 14 h. After evaporation the mixture was redissolved in MeOH and slurried with 5 g of DOWEX 50WX8-400 free acid and 5 g of DOWEX 1X8-400 bicarbonate resin for 4 h and then filtered. The filtrate was evaporated to provide 1-(3-bromophenylcarbamoyl)-3-carboethoxy-5-(diethyl 2-phosphonofuran-5-yl)benzene.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:13]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)=[CH:5][CH:4]=2)=[O:15])=[CH:19][CH:18]=1
Reactant: Cc1ccc2ccc(C(=O)O)c(O)c2n1
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2ccc(C(=O)NCc3ccc(Cl)cc3)c(O)c2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a solution of 8-hydroxy-2-methylquinoline-7-carboxylic acid (0.305 g) of Preparation 5 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxy-benzotriazole monohydrate (0.217 g). The mixture is stirred overnight. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried to yield 0.337 g of the title product as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CO[CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25].CN(C)C=O>O>[CH2:15]([CH:14]([CH2:17][CH3:18])[C:13]([NH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25])=[O:19])[CH3:16]
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: CCC(CC)C(=O)Nc1ccc2ncnc(N)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)C(=O)Nc1ccc2ncnc(NC=C(C(=O)OC)C(=O)OC)c2c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 56.1 %

Procedure:
A mixture of 4-amino-6-(2-ethylbutyramido)quinazoline (5.58 g), dimethyl methoxymethylenepropanedioate (5.62 g) and N,N-dimethylformamide (22 ml) was stirred at 100° C. for 1.5 hours. After cooling to ambient temperature, water (90 ml) was added to the reaction mixture. The resulting solid was separated by filtration, washed with water and dried to give dimethyl [[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]propanedioate (4.85 g).
Reaction SMILES: C(NC(C)C)(C)C.[Si:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[O:29]=[C:30]([CH2:36][CH3:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32].CCCCCC.C(OCC)(=O)C>O1CCCC1>[Si:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:30]([CH2:36][CH3:37])([OH:29])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:20][CH:21]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CCOC(=O)C(=O)CC
Reactant: CCOC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(O)(CC)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 25 %

Procedure:
Under the atmosphere of argon, to a solution of diisopropylamine (572 mg, 5.65 mmol) in anhydrous tetrahydrofuran (7 mL) was added a 1.54 M n-butyl lithium-hexane solution (3.5 mL, 5.4 mmol) with stirring under ice cooling, and the mixture was stirred at 0° C. for 10 min and then at −78° C. for 5 min. To the mixture, a solution of ethyl 3-(4-t-butyldimethylsilyloxyphenyl)propionate (1.47 g, 4.78 mmol) in anhydrous tetrahydrofuran (7 mL) was added dropwise at the same temperature over 6 min, and the reaction mixture was further stirred for 20 min. The cold solution of the enolate thus prepared above was added dropwise via a cannula into a solution of ethyl 2-ketobutyrate (518 mg, 3.98 mmol) in anhydrous tetrahydrofuran (5 mL) having been cooled to −78° C. After stirring at −78° C. for 1 h, the reaction mixture was quenched and adjusted to pH 4 with acetic acid, and the temperature was raised to room temperature. The reaction solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and water to separate the phases. The organic layer having been washed with brine was concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 10:1→5:1) to give diethyl 3-(4-t-butyldimethylsilyloxybenzyl)-2-ethyl-2-hydroxysuccinate as oil in amounts of 433 mg (low polar diastereomer, yield: 25%) and 290 mg (high polar diastereomer, yield: 17%), respectively.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]([CH3:15])([CH3:14])[CH2:8][C:9](OCC)=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][OH:10]
Reactant: CCOC(=O)CC(C)(C)CC1OCCO1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(CCO)CC1OCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 117.3 %

Procedure:
86.7 g of ethyl 4-(dioxolan-2-yl)-3,3-dimethylbutanoate, prepared above, are dissolved in 720 ml of ether. This solution is added dropwise at 10° C. to a suspension of 9 g of lithium aluminum hydride in 700 ml of ether. When the addition is complete, the mixture is stirred for 3 hours at room temperature and then cooled to 10° C. A saturated solution of sodium sulfate is added dropwise at this temperature until a granular precipitate is obtained, which is filtered off. The ether filtrate is evaporated to dryness at a temperature below 30° C. to give 81.9 g of 4-(dioxolan-2-yl)-3,3-dimethylbutanol in the form of an oil, which is used as such for the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH:8]C(OC(C)(C)C)=O.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:17])[CH3:18])[NH2:8]
Reactant: COC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNC(=O)[C@@H](N)C(C)C
Reaction time: 1 h

Procedure:
t-butyloxycarbonyl-L-valyl-glycine methyl ester (1.44 g, 5 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was left at room temperature for 1 hour. The solution was evaporated to dryness in vacuo and the residue triturated with dry ether.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(OCCCCCCBr)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-4-(4-hydroxyphenyl)piperazine (5.00 g) in N,N-dimethylformamide (50 ml) was treated with 1,6-dibromohexane (10.5 ml) and potassium carbonate (4.71 g), and the mixture was stirred for 18 hours at ambient temperature. To the reaction mixture was added water (200 ml), and the resulting precipitate was collected by filtration, washed with water and n-hexane successively and dried under reduced pressure to give crude 1-acetyl-4-[4-(6-bromohexyloxy)phenyl]piperazine (10.52 g), that was used in the next reaction directly.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccc(Cl)cc2C#N)cn1
Yield: 63 %

Procedure:
As described for example 84a, 5-chloro-2-fluoro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 20 h at 90° C. After aqueous workup and crystallization from ethyl acetate the title compound was obtained as a white solid (yield: 63%). MS: m/e=218.2 [M+H]+.
Reaction SMILES: Cl.[CH:2]1([CH2:7][CH2:8][N:9]2[C@@H:17]3[C@@H:12]([C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+]>Br>[CH:2]1([CH2:7][CH2:8][N:9]2[C@@H:17]3[C@@H:12]([C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCC1
Agent: Br
Agent: Cl
Agent: [Na+]
Product: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCC1
Temperature: 0 °C
Yield: 85.1 %

Procedure:
5.80 g (0.0173 mol) of rac-cis-3-(2-cyclopentyl-ethyl)-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride were dissolved in 0.18 l of 48% aqueous HBr and boiled under reflux for 5 hours. The mixture was poured on to ~200 g of ice and treated with 200 ml of 28% aqueous NaOH solution. The mixture was extracted three times with ethyl acetate, whereupon the organic phase was washed with saturated sodium chloride solution, dried with MgSO4, filtered and concentrated. By chromatography of the residue over silica gel with ethyl acetate there were obtained 4.20 g (85%) of oily rac-cis-3-(2-cyclopentyl-ethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:9]([O:8][C:7]1[C:2]([Br:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccnc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ncccc1OCc1ccccc1
Temperature: 110 °C
Yield: 94.1 %

Procedure:
A mixture of 2-bromo-pyridine-3-ol (50.4 g, 0.29 mol), benzyl bromide (45.5 g, 0.28 mol) and potassium carbonate (52 g, 0.38 mol) in dry N,N-dimethylformamide (DMF; 300 mL) was heated at 110° C. for 30 minutes. The mixture was filtered through a pad of Celite®, the solvent was removed under reduced pressure and the black residue was taken up between ice cold 0.5 M aqueous NaOH and EtOAc. The organic phase was washed twice with brine, dried (MgSO4), and concentrated under reduced pressure to yield 69.6 g (93%) of the title compound as a brown oil. HRMS m/z calcd for C12H10BrNO (M)+ 263.9946. found 263.9939. *Previously described in J. Med. Chem. 1996, 39, 5267–5275.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:26][CH3:27])=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][C:13](=[O:16])[CH:12]=[C:11]2[NH:17][C:18]1[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=1[Cl:25].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[Cl:25][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:24])[C:18]=1[NH:17][C:11]1[C:10]2[C:15](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:7]([O:26][CH3:27])=[CH:8][CH:9]=2)[NH:14][C:13](=[O:16])[CH:12]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCBr
Reactant: C1COCCN1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCN1CCOCC1

Procedure:
The title compound was prepared from 8-(3-bromopropoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one and morpholine following the procedure outlined in Example 18, Step 2. 1H NMR (400 MHz, DMSO-d6, HCl salt): δ 10.58 (br, 1H), 10.44 (s, 1H), 8.94 (s, 1H), 8.77 (s, 2H), 7.93 (d, 1H), 7.09 (d, 1H), 4.82 (s, 1H), 4.02 (t, 2H), 3.98 (m, 2H), 3.93 (s, 3H), 3.76 (t, 2H), 3.46 (d, 2H), 3.33 (m, 2H), 3.10 (m, 2H), 2.22 (m, 2H); MS (ESI): 479.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:16][C:17]#[N:18]>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:16][C:17]#[N:18])[CH:5]=[N:4][CH:3]=1
Reactant: N#CCCl
Reactant: Oc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#CCOc1cncc(Br)c1
Temperature: 0 °C
Yield: 57.7 %

Procedure:
A dry, 250 mL one neck round bottom flask was charged with 3-bromo-5-hydroxypyridine 3 (4.9470 g, 28.4 mmol), 40 mL dry ACN, cesium carbonate (CS2CO3) (3.41 ml, 42.6 mmol) and a stirbar. The flask was fitted with an Ar inlet, and cooled to 0° C. To the solution was added 2-chloroacetonitrile (2.34 ml, 37.0 mmol) dissolved in 10 mL dry ACN over 15 minutes via an addition funnel. The reaction warmed to room temperature overnight. The slurry was filtered through a 0.22 μm PTFE filter membrane, and concentrated under a stream of nitrogen. The residue was loaded onto 100 g of SiO2 wet-packed with ACN, and eluted with 500 mL ACN. The eluent was concentrated in vacuo, and the residue was sublimed at 0.5 mm Hg in a 90° C. oil bath to afford 2-(5-bromopyridin-3-yloxy)acetonitrile (3.49 g, 57.6% yield). 1H NMR (300 MHz, MeOH) δ ppm 5.12 (s, 2H) 7.81 (dd, J=2.63, 1.83 Hz, 1H) 8.35 (d, J=2.63 Hz, 1H) 8.38 (dd, J=1.83, 0.29 Hz, 1H). 13C NMR (75 MHz, MeOH) δ ppm 55.24 (s, 1 C) 116.18 (s, 1 C) 121.90 (s, 1 C) 126.59 (s, 1 C) 137.86 (s, 1 C) 145.61 (s, 1 C) 155.29 (s, 1 C). HPLC-MS: retention time=1.42 min (99.0%@215 nm; 98.9% @254 nm; m/z=212.8, calculated for C7H579Br2N2O+H+=213.0, m/z=214.8, calculated for C7H581Br2N2O+H+=215.0).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[S:14](Cl)(=[O:16])=[O:15])=[O:2].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>N1C=CC=CC=1>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[NH:18][S:14]([C:9]1[C:10]2[C:5](=[C:4]([NH:3][CH:1]=[O:2])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:16])=[O:15]
Reactant: O=CNc1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: O=CNc1cccc2c(S(=O)(=O)Nc3nccs3)cccc12
Yield: 48.4 %

Procedure:
5-Formylamino-naphthalene-1-sulfonyl chloride (0.25 g, 0.93 mmol), 2-aminothiazole (0.09 g, 0.93 mmol) and pyridine (1.00 ml) were stirred under N2 at 25° C. for 19 h. The solution was purified via silica gel chromatography using 3% MeOH/97% CH2Cl2 to obtain 5-formylamino-naphthalene-1-sulfonic acid thiazol-2-ylamide as a white solid (150 mg, 49%). LC/MS (10-99% CH3CN), M/Z: M+1 obs=334.20; tR=1.93 min.
Reaction SMILES: ClN1[C:7](=[O:8])[N:6]([Cl:9])[C:5](=O)N(Cl)C1=O.[Br:13][CH2:14][CH:15]1[O:19]C(=O)NC1>C(Cl)Cl>[Cl:9][N:6]1[CH2:5][CH:15]([CH2:14][Br:13])[O:19][C:7]1=[O:8]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: O=C1NCC(CBr)O1
Solvent: ClCCl
Product: O=C1OC(CBr)CN1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.86 grams (0.0166 moles) trichlorocyanuric acid and 1.79 grams (0.0166 moles) 5-bromomethyl-2-oxazolidinone are added to MeCl2 and stirred overnight at room temperature. The reaction mix was dried over magnesium sulfate and rotovaped. Proton NMR Data: δ3.9(m, 4 protons]5.1(m, 1 proton).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([SH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH:15]1[CH2:20][CH2:19][O:18][C:16]1=[O:17].Cl>O.C(OC(=O)C)(=O)C.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:15]3([C:9](=[O:11])[C:8]=2[CH:12]=1)[CH2:20][CH2:19][O:18][C:16]3=[O:17])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1S
Reactant: O=C1OCCC1Br
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1OCCC12Sc1ccc([N+](=O)[O-])cc1C2=O

Procedure:
In 200 ml of water was dissolved 4.45 g of dipotassium salt of 5-nitrothiosalicylic acid, and 3.55 g of α-bromo-γ-butyrolactone was added dropwise to the solution under ice-cooling with stirring. After stirring the solution at room temperature for 3.5 hours, 10 ml of concentrated hydrochloric acid was added to the solution to acidify, and the solution was subjected to extraction with ethyl acetate. The extract was washed with water, dried and evaporated to dryness under reduced pressure, resulting in α-[(2-carboxy-4-nitrophenyl)thio]-γ-butyrolactone. The crude product was dissolved in 50 ml of acetic anhydride and 10 ml of triethylamine, and heated under a stream of nitrogen at 130° C. for 30 minutes. The reaction solution was evaporated to dryness under reduced pressure, and the residue was chromatographed on a column of activated carbon and silica gel. Recrystallization from ethanol of the resultant crude crystals yielded pale yellow needles of 5-nitro-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2' -dione. Melting point: 190.5°-193.5° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[F:21][C:22]([F:33])([F:34])[O:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:32])=[CH:28][CH:29]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)Nc1ccc(OC(F)(F)F)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-(trifluoromethoxy)-phenyl isocyanate, there is obtained ethyl N-{[p-(trifluoromethoxy)-phenyl]carbamoyl}-5,7-dihydro-6H-dibenz[c,e]azepine-6 -carboximidate, m.p. 129°-130° C.