Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[O:17]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1>C(Cl)Cl>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][C:18]([OH:17])([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: FC(F)(F)c1ccnc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C(F)(F)F)ccn2)CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 58.9 %

Procedure:
To a slightly cloudy solution of 2-bromo-4-(trifluoromethyl)pyridine (4.0 g, 14.2 mmol) in dry methylene chloride (52.7 mL) cooled at −78° C. was added a 1.6 M solution of n-butyllithium in hexanes (9.65 mL). After being stirred for 40 min at −78° C., a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (2.59 g, 12.9 mmol) in dry methylene chloride (10.0 mL) was added dropwise. The reaction was stirred at −78° C. for 1 h and quenched with aqueous NH4Cl. THF was removed by rotary evaporation. The aqueous layer was extracted with methylene chloride three times. The combined organic layers were dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (30:70 EtOAc/hexanes) to give 2.63 g (59%) of desired product as a brown oil. LC-MS calculated for C16H21F3N2O3: (M+H) 347; found 247.0 (M-Boc+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:16]=3[N:15]=2)[C:7]=1[CH3:24].[CH2:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[ClH:1].[ClH:1].[CH2:25]([N:32]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:16]=4[N:15]=3)[C:7]=2[CH3:24])[CH2:34][CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1c(SCCCCl)ccnc1CSc1nc2cc(F)ccc2[nH]1
Reactant: c1ccc(CN2CCNCC2)cc1
Product: Cc1c(SCCCN2CCN(Cc3ccccc3)CC2)ccnc1CSc1nc2cc(F)ccc2[nH]1
Product: Cl
Yield: 80 %

Procedure:
According to the procedure indicated in Example 1), reaction of 2-{[[4-(3-chloropropylthio)-3-methyl-2-pyridinyl]methyl]thio}-5-fluoro-1H-benzimidazole with N-benzylpiperazine gives the title compound as a beige powder. Yield 80%, m.p. 130-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[NH2:20][CH2:21][C:22]([OH:24])=[O:23].C(=O)([O-])[O-].[Na+].[Na+].Cl>O.C(O)C>[C:22]([CH2:21][NH:20][C:10]1[CH2:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]=1)([OH:24])=[O:23]
Reactant: NCC(=O)O
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)CNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Yield: 77.5 %

Procedure:
A suspension of 3.5 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione, 5.5 g of glycine, 5.5 g of sodium carbonate, 100 ml of ethanol and 30 ml of water was refluxed with stirring for an hour and the mixture was poured into water. The pH of the solution was adjusted to 4 by addition of 2N hydrochloric acid and was extracted with chloroform. The mixture was filtered and the filtrate was dried over magnesium sulfate and evaporated to dryness. The gummy residue was crystallized by trituration with methanol and the mixture was filtered. The recovered solid was crystallized from ethanol to obtain 3.1 g (77% yield) of 2-carboxymethylamino-7-chloro-5-phenyl-3H-1,4-benzodiazepine melting at 215°-220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[N:19]1([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=3[CH:9]([N:22]3[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:20][CH2:21]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCN1CCNCC1
Reactant: Cc1ccc2c(c1)Sc1ccc(Cl)cc1CC2Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)Sc1ccc(Cl)cc1CC2N1CCN(CCN2CCOC2=O)CC1

Procedure:
20 G. of 2,10-dichloro-10,11-dihydro-7-methyl-dibenzo[b,f]thiepin are stirred with 41 g. of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone and 400 ml. of chloroform at the boiling temperature for 20 hours. The solution is cooled and washed successively with 2N sodium hydroxide and with water. The organic phase is decanted and extracted with dilute methanesulfonic acid. The acid solution is made alkaline with sodium hydroxide and the oil which separates out is shaken out with ether. The ether solution is washed with water, dried over magnesium sulfate and evaporated under reduced pressure, whereby there is obtained 3-{2-[4-(2-chloro-10,11-dihydro-7-methyl-dibenzo[b,f]-thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone (melting point 161°-163°C.) which is converted into the corresponding dimethanesulfonate (melting point 187°-189°C.) by reaction with methanesulfonic acid.
Reaction SMILES: [CH2:1]([C:4]1([CH3:19])[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7][N:6]([CH3:18])[CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].[CH3:22][C:23]1([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:25][O:24]1>CN(C=O)C>[CH2:1]([C:4]1([CH3:19])[C:9]2[N:10]([CH2:22][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)([OH:24])[CH3:25])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7][N:6]([CH3:18])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C)CN(C)Cc2c1[nH]c1ccc(C)cc21
Reactant: CC1(c2ccncc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(C)CN(C)Cc2c1n(CC(C)(O)c1ccncc1)c1ccc(C)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
4-Allyl-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 3.9 mmol) was dissolved in DMF (10 mL) and stirred for 10 min at RT. Sodium hydride (475 mg, 11.7 mmol) was added portionwise and stirring was continued for 15 min at RT. 4-(2-Methyl-oxiranyl)-pyridine (690 mg, 5.1 mmol) diluted in DMF was added dropwise at RT and the reaction mixture was further stirred for 16 h after which it was quenched with ice water and extracted with EtOAc (3×70 mL). The combined organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized in ether to obtain 700 mg of 1-(4-allyl-2,4,8-trimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-4-yl-propan-2-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17](O)[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([O:29][Si](C)(C)C)=[C:26]([CH3:28])[CH3:27]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:26]([CH3:28])([CH3:27])[C:25]([O:24][CH3:23])=[O:29])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: CC(C)CC(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(CC(C)C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-ol (0.41 mmol) in 20 mL of CH2Cl2 at 0° C. was added 1M TiCl4 in CH2Cl2 (0.5 mmol) all at once. After 30 min, (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (0.24 mL, 1.2 mmol) was added and the reaction was warmed to rt and stirred overnight. The reaction was quenched with water and extracted with CH2Cl2. The CH2Cl2 extracts were dried over MgSO4, filtered, and concentrated by rotary evaporator to give methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoate. MS found: (M+H)+=383.
Reaction SMILES: P(CCCC)(CCCC)CCCC.CCN(CC)CC.[OH:21][CH:22]([CH:27]=[CH2:28])[C:23]([O:25][CH3:26])=[O:24].I[C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:38]1([CH2:28][CH2:27][C:22](=[O:21])[C:23]([O:25][CH3:26])=[O:24])[C:39]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: C=CC(O)C(=O)OC
Reactant: Ic1cccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(=O)CCc1cccc2ccccc12
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 6.9 %

Procedure:
To a stirred solution of Pd(OAc)2 (340 mg), nBu3P (613 mg), and Et3N (1.99 g) in DMF (30 ml) was added methyl 2-hydroxy-3-butenoate (1.76 g) followed by 1-iodonaphthalene (5.0 g), and the reaction mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was poured into water (300 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel (130 g) column chromatography eluting with hexane/ethyl acetate (50:1) to give methyl 4-(1-naphthyl)-2-oxobutyrate (254 mg) as a red oil.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=1)[C:11]([CH3:20])([CH3:19])[CH2:10][CH2:9]2.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1)#[N:23]>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:21])[C@@:3]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:30](=[O:31])[C:27]4[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=4)[CH:16]=3)[C:11]([CH3:19])([CH3:20])[CH2:10][CH2:9]2)[N:4]=1
Reactant: CC1(C)CC[C@@]2(N=C(N)OCC2(F)F)c2cc(N)ccc21
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: CC1(C)CC[C@@]2(N=C(N)OCC2(F)F)c2cc(NC(=O)c3ccc(C#N)cn3)ccc21
Yield: 65 %

Procedure:
The condensation of (R)-5′,5′-difluoro-4,4-dimethyl-3,4,5′,6′-tetrahydro-2H-spiro[naphthalene-1,4′-[1,3]oxazine]-2′,7-diamine (intermediate A7.2) and 5-cyanopicolinic acid yielded the title compound (65% yield) as a pale yellow solid. MS (ISP): m/z=426.0 [M+H]+.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11]C(O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1([N:21]=[C:22]=[N:23][CH:24]2CCCCC2)CCCCC1.NN.[NH:32]=C(CCC)C(OCC)=O>C(Cl)Cl>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][CH2:11][N:32]1[CH:24]=[N:23][CH:22]=[N:21]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCC(=N)C(=O)OCC
Agent: NN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCn1cncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen, 60.0 g (0.30 mol) of N-BOC-γ-aminobutyric acid (BACHEM) is dissolved in 1200 mL of methylene chloride and treated with 30.5 g (0.15 mol) of dicyclohexylcarbodiimide (DCC). The reaction is allowed to stir for 2 hours and filtered under nitrogen. The anhydride solution is then added to a solution of 1.58 g (98.5 mmol) of anhydrous hydrazine in 100 mL of methylene chloride at 0° C. The reaction is allowed to warm to ambient temperature and stirred overnight. Concentration in vacuo gives the crude hydrazide which is purified either by recrystallization or by silica gel chromatography (Waters Prep-500A). A 21.7 g (100 mmol) sample of hydrazide is dissolved in 100 mL of methanol and treated with 12.9 g (100 mmol) of ethyl iminovalerate under nitrogen. The reaction is stirred at reflux overnight and concentrated in invacuo. Purification by silica gel chromatography (Waters Prep-500A) gives 5-butyl-3-(3-tertbutoxycarbonylaminopropyl-1H-1,2,4-triazole.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[C:18]([C:23]([O:25]CC)=[O:24])=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1)=[O:11].[OH-].[Na+]>CO.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[C:18]([C:23]([OH:25])=[O:24])=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:28][CH:29]=1)=[O:11]
Reactant: CCOC(=O)c1nccnc1Oc1ccc(C(=O)c2nc3ccccc3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(c1ccc(Oc2nccnc2C(=O)O)cc1)c1nc2ccccc2[nH]1

Procedure:
To the solution of ethyl 3-(4-(1H-benzo[d]imidazole-2 carbonyl)phenoxy)pyrazine-2-carboxylate (30 g, 77 mmol) in methanol (250 mL) was added aqueous NaOH solution (4.62 g, 115 mmol) in 50 mL of water. The reaction mixture was heated to reflux for 1 h. The reaction mixture was concentrated then diluted with water. The aqueous layer was washed with ethyl acetate and then acidified by addition of 2N HCl to pH 6. The precipitate was collected by filtration, dried to give the title compound as a light brown solid. MS [M+H]=351.2.
Reaction SMILES: [Cl:1][Si](C)(C)C.[CH3:6][CH:7]([CH3:14])[C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11].CS(C)=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][CH:9]([C:8](=[O:13])[CH:7]([CH3:14])[CH3:6])[C:10](=[O:12])[CH3:11]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)CC(=O)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: O
Solvent: CC#N
Solvent: CS(C)=O
Product: CC(=O)C(Cl)C(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
Chlorotrimethylsilane (13.4 ml, 105 mmol) was added dropwise to a stirred pale yellow solution of tetrabutylammonium iodide (566 mg, 1.53 mmol) in dry acetonitrile (100 ml) at room temperature under nitrogen. The resulting solution was cooled in ice and 5-methylhexane-2,4-dione (4.50 g, 35.1 mmol) and then dry dimethylsulphoxide (7.47 ml, 105 mmol) were added dropwise over 5 minutes producing a yellow solution which was allowed to warm slowly to room temperature with stirring over 1 hour. Tetrabutylammonium bromide (566 mg, 1.75 mmol) was then added in one portion and the reaction was stirred at room temperature for 2 hours. The mixture was diluted with water (200 ml), stirred for 10 min and then extracted with ether (3×100 ml). The combined ether layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a yellow oil. The crude product was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (98:2, by volume) to provide the title compound (2.00 g) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[S:8]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CCC>O>[S:8]1[CH:12]=[CH:11][C:10]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:9]1
Reactant: OB(O)c1ccsc1
Reactant: Brc1cccnc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: c1cncc(-c2ccsc2)c1
Temperature: 100 °C
Yield: 92 %

Procedure:
Into a glass reaction vessel equipped with a cooling apparatus were added 0.015 mmol of bis(dicyclopentyl(2-methoxyphenyl)phosphine)dichloropalladium(II), 1.5 mmol of 3-bromopyridine, 2.25 mmol of 3-thiopheneboronic acid, 3.0 mmol of potassium phosphate and 4 mL of n-butanol. The resultant mixture was stirred with heating at 100° C. for 4 hours. The resultant reaction mixture was cooled down to room temperature, 20 mL of water was added, and the mixture was extracted with 20 mL of diethyl ether twice. The resultant organic layers were mixed, and dried over anhydrous magnesium sulfate, then, filtrated, to obtain a solution. This solution was concentrated, and purified by silica gel column chromatography, to obtain 3-(3-thienyl)-pyridine with a yield of 92%.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([O:14][C:15](=[O:22])[CH2:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH3:13].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>O1CCCC1.O>[CH2:12]([O:14][C:15](=[O:22])[CH:16]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=1)[C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH3:13]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)C(C)C
Temperature: 70 °C

Procedure:
A suspension of potassium tert-butoxide (0.54 g) in anhydrous tetrahydrofuran (200 mL) at 0° C. was treated with a mixture of tert-butanol (0.1 mL) and 4-methyl-3-oxopentanoic acid ethyl ester (0.65 mL). After stirring at room temperature for 45 minutes a solution of 1-bromomethyl-4-methanesulfonylbenzene (1.0 g) in tetrahydrofuran (50 mL) was added and the resulting mixture heated at 70° C. for 24 hours. The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran removed under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts dried over magnesium sulfate and then the solvent removed under reduced pressure to afford title compound, 1.4 g.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1)=O.[CH:13]1([CH2:16][NH:17][C:18]([NH2:20])=[S:19])[CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>C(O)C>[CH:13]1([CH2:16][NH:17][C:18]2[S:19][CH:2]=[C:3]([C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=3)[N:20]=2)[CH2:15][CH2:14]1
Reactant: NC(=S)NCC1CC1
Reactant: N#Cc1ccc(C(=O)CBr)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(-c2csc(NCC3CC3)n2)nc1
Temperature: 25 °C
Yield: 90 %

Procedure:
Slurry crude 6-(2-bromo-acetyl)-nicotinonitrile (5.2 g), cyclopropylmethyl-thiourea (2.7 g, 20.8 mmol) and sodium bicarbonate (1.95 g, 23.1 mmol) in ethanol (135 mL) at room temperature. Stir the mixture at reflux for 1 h under a nitrogen atmosphere. Cool the mixture to room temperature and concentrate in vacuo to a solid. Recrystallize from ethanol (20 mL) and water (100 mL) at 5° C. to obtain the desired intermediate as a tan solid (4.8 g, 81%). MS (ES+) m/z: 257 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:50]([O:52][C:53]1[CH:61]=[CH:60][CH:59]=[CH:58][C:54]=1[CH:55]([OH:57])[CH3:56])[CH3:51]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:39](=[O:41])[O:57][CH:55]([C:54]1[CH:58]=[CH:59][CH:60]=[CH:61][C:53]=1[O:52][CH2:50][CH3:51])[CH3:56]
Reactant: CCOc1ccccc1C(C)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccccc1C(C)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Yield: 45.9 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (80 mg) was added to toluene/triethylamine=10/1 (9 ml) and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (109 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-ethoxy-α-methylbenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (58 mg, yield 43%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]([CH3:16])[C:4](=[O:17])[C:3]1=[O:18].[O:19]1[CH2:24][CH2:23][O:22][C:21]2[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:20]1=2.C(N(CC)CC)C>ClCCl>[O:19]1[CH2:24][CH2:23][O:22][C:21]2[CH:25]=[C:26]([NH:29][S:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[N:2]([CH3:1])[C:3](=[O:18])[C:4](=[O:17])[N:5]4[CH3:16])(=[O:14])=[O:13])[CH:27]=[CH:28][C:20]1=2
Reactant: Cn1c(=O)c(=O)n(C)c2cc(S(=O)(=O)Cl)ccc21
Reactant: Nc1ccc2c(c1)OCCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c(=O)n(C)c2cc(S(=O)(=O)Nc3ccc4c(c3)OCCO4)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride (example 6-3a, 450 mg, 1.6 mmol) was added to a stirred solution of the 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (215 mg, 1.4 mmol) and triethylamine (170 mg, 1.7 mmol) in dichloromethane (10 mL). The reaction was stirred at ambient temperature overnight then concentrated. The crude product was purified by silica gel chromatography (0-30% ethyl acetate in hexanes) to provide N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide as a white solid. MS (M+H, 404.10); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.47 (s, 3H), 3.49 (s, 3H), 4.12 (m, 414), 6.55 (m, 1H), 6.61 (d, J=2.4 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 7.53 (m, 1H), 7.59 (d, J=2 Hz, 1H), 10.00 (s, 1H).
Reaction SMILES: [CH2:1]([CH:8]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH2:1]([CH:8]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(CO[Si](C)(C)C(C)(C)C)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC(Cc1ccccc1)C(=O)O
Temperature: 0 °C
Yield: 67.9 %

Procedure:
The methyl 2-benzyl-3-(t-butyldimethylsilyloxy)propionate (3.3 g) was dissolved in 100 ml of methanol, cooled to 0° C. and treated with 50 ml of 30% potassium hydroxide with vigorous stirring. The reaction was then allowed to warm to room temperature over five hours. The reaction was diluted with 200 ml of water, rinsed with diethyl ether, and the aqueous solution was cooled to 0° C. Dichloromethane (100 ml) was added, followed by the slow addition of 260 ml of 1M hydrochloric acid, with stirring. The layers were separated and the aqueous layer was extracted with dichloromethane (3×200 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by radial chromatography (2% to 4% methyl alcohol in chloroform, 4 mm plate) to yield 2.14 g of the 2-benzyl-3-(t-butyldimethylsilyloxy)propionic acid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](O)[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:7]1[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(O)cc(-c2cccc(C(F)(F)F)c2)n1
Product: CSc1nc(Cl)cc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
2-Methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ol (2.11 g) was heated to reflux in phosphorous oxychloride (15 mL) for four hours. Phosphorous oxychloride was evaporated under reduced pressure and the remaining residue dissolved in ethyl acetate (100 mL) and washed with saturated sodium chloride (50 mL). Organics were separated, dried over sodium sulphate and solvent was evaporated under reduced pressure to yield product 4-chloro-2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (2.11 g) as a brown oil.