Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:18][C:17]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=1
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)Nc1cc(O)ccc1F
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc(F)c(NC(=O)Cc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.6 %

Procedure:
To a solution of methyl 2-fluoro-5-nitrobenzoate (1.65 g, 8.29 mmol) and N-(2-fluoro-5-hydroxyphenyl)-2-[3-(trifluoromethyl)phenyl]acetamide (2.60 g, 8.30 mmol) produced in Example 53(i) in N,N-dimethylformamide (17 mL) was added potassium carbonate (1.72 g, 12.5 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (90 mL), washed successively with water (2×90 mL) and saturated brine (90 ml), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off. The obtained organic layer was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (3.78 g, 93%) as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[S:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15]([C:16]([OH:18])=O)=[C:4]2[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.Cl.[CH3:35][O:36][C:37](=[O:42])[C@H:38]([CH2:40][OH:41])[NH2:39].C(N(CC)CC)C>CN(C)C=O>[OH:41][CH2:40][C@H:38]([NH:39][C:16]([C:15]1[N:14]=[CH:13][N:5]2[C:6]3[CH:12]=[CH:11][S:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12)=[O:18])[C:37]([O:36][CH3:35])=[O:42]
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccsc2C1=O
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(=O)c1ncn2c1CN(C)C(=O)c1sccc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
A suspension of 15.5 g (0.0493 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid in 200 ml of dimethylformamide was treated portionwise with 8.07 g (0.0498 mol) of carbonyidiimidazole while gassing with argon. After completion of the CO2 evolution the mixture was stirred at 65° for 1 hr. After cooling to 0-5° the clear solution obtained was treated with 8.62 g (0.0554 mol) of L-serine methyl ester hydrochloride and with 12.3 ml (0.0554 mol) of triethylamine and stirred at room temperature for 16 hrs. The suspension was completely freed from the solvents. The residue was partitioned between water and ethyl acetate and extracted. The yellow oily residue was chromatographed over silica gel with ethyl acetate as the eluent. There were obtained 17.09 g (95%) of methyl (S)-3-hydroxy-2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-3-ylcarbonylamino)-propionate as a yellowish oil. An analytical sample was recrystallized from ethyl acetate and gave white crystals; m.p. 158-160°. [α]D20 =+3.9° (CHCl3, c=1%).
Reaction SMILES: CN(C)C=O.[C:6](Cl)(=O)[C:7]([Cl:9])=[O:8].[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:26]=[CH:25]C(C(O)=O)=[CH:20][N:19]=2)[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:26]=[CH:25][C:6]([C:7]([Cl:9])=[O:8])=[CH:20][N:19]=2)[CH2:14][CH2:13]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(N2CCOCC2)nc1
Reaction time: 0.25 h

Procedure:
N,N-Dimethylformamide (1 mL) was slowly added to a solution of oxalyl chloride (0.13 g, 1 mmol) in chloroform (5 mL). 6-Morpholinonicotinic acid (0.21 g, 1 mmol) was added and the reaction mixture was stirred for 15 minutes. The reaction mixture was concentrated under vacuum, diluted with toluene and then concentrated under vacuum to provide 6-morpholinonicotinoyl chloride. This material was kept under vacuum at ambient temperature overnight and then used in the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19](=[O:20])[C:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]3[N:39]=[CH:40][N:41]=[C:15]23)[CH2:10][CH2:9]1)[C:2]1C=CC=CC=1.O1CCCC1>[C].[Pd].C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19](=[O:20])[C:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]3[N:39]=[CH:40][N:41]=[C:15]23)[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(Cc3ccccc3)CC2)c2ncnn12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(CC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-{[4-(1-benzylpiperidin-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (4.82 g), 10% palladium-carbon (2.39 g), tetrahydrofuran (30 mL) and ethanol (60 mL) was stirred at room temperature for 2 days under a hydrogen atmosphere. The reaction mixture was filtered, and the solvent was evaporated. The residue was purified by basic silica gel chromatography [eluent: methanol/ethyl acetate=0/100→5/95 (volume ratio)] to give the title compound as a colorless amorphous compound (146 mg, 3%).
Reaction SMILES: [NH2:1][N:2]1[C:6]([C:7]#[N:8])=[CH:5][CH:4]=[C:3]1[CH:9]1[CH2:12][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:10]1.C(O)(=O)C.[CH:27](N)=[NH:28]>C(O)CCC>[NH2:8][C:7]1[C:6]2=[CH:5][CH:4]=[C:3]([CH:9]3[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:14])[CH2:12]3)[N:2]2[N:1]=[CH:27][N:28]=1
Reactant: N=CN
Reactant: N#Cc1ccc(C2CN(C(=O)OCc3ccccc3)C2)n1N
Solvent: CC(=O)O
Solvent: CCCCO
Product: Nc1ncnn2c(C3CN(C(=O)OCc4ccccc4)C3)ccc12
Temperature: 25 °C
Yield: 39.8 %

Procedure:
A solution of benzyl 3-(1-amino-5-cyano-1H-pyrrol-2-yl)azetidine-1-carboxylate (575 mg, 1.94 mmoL) and formamidine acetate (2.02 g, 19.4 mmol) in 1-butanol (8 mL) was stirred at 120° C. for 4 hours. The mixture was then cooled to rt and was partitioned between EtOAc (25 mL) and H2O (25 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The crude material was purified by ISCO® chromatography using 3:1 ethyl acetate/hexanes to obtain 250 mg (40%) of the desired product. ES-MS m/z 324.34 [M+H]+, HPLC RT (min) 2.30.
Reaction SMILES: [O:1]=[C:2]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:4]2([CH2:9][CH2:8][CH:7]([NH:10][C:11]([C@H:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[O:12])[CH2:6][CH2:5]2)[O:3]1.[Cl:25][C:26]1[C:27]([CH3:36])=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C>C(#N)C>[Cl:25][C:26]1[C:27]([CH3:36])=[C:28]([S:32]([N:15]2[CH2:16][CH2:17][CH2:18][C@H:13]([C:11]([NH:10][CH:7]3[CH2:8][CH2:9][C:4]4([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:2](=[O:1])[O:3]4)[CH2:5][CH2:6]3)=[O:12])[CH2:14]2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: O=C1OC2(CCC(NC(=O)[C@H]3CCCNC3)CC2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](C(=O)NC2CCC3(CC2)OC(=O)c2ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A mixture of (3S)-N-(3-oxo-3H-spiro[2-benzofuran-1,1′-cyclohexan]-4′-yl)piperidine-3carboxamide (11 mg, 0.03 mmol), 3-chloro-2-methylbenzenesulfonyl chloride (6.8 mg, 0.03 mmol), and triethylamine (10.5 μL, 0.075 mmol) in acetonitrile (0.2 mL) was stirred at r.t. for 2 hours. The mixture was purified by flash column to yield 10.2 mg of final product was obtained. Yield: 65%. LCMS: 517.0 (M+H)+; 539.1 (M+Na)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[NH2:25])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.O>ClCCl>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([C:21]([F:22])([F:23])[F:24])=[CH:16][C:15]=2[NH:25][C:35](=[O:36])[CH2:34][CH2:33][CH2:32][C:29]2[CH:28]=[CH:27][N:26]=[CH:31][CH:30]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2N)cc1
Reactant: O=C(O)CCCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2NC(=O)CCCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (step 2, 250 mg, 0.67 mmol), 4-(4-pyridinyl)butanoic acid (200 mg, 1 mmol), and WSC (191 mg, 1 mmol) in dichloromethane (7 ml) was stirred at room temperature for 1.5 h. The mixture was added water (5 ml) and extracted with dichloromethane(30 ml). The organic layer was washed with brine (5 ml), then dried (Na2SO4). The solvent was removed under reduced pressure to afford the title compound as pale brown amorphous. MS (EI) m/z: 519 (M+)
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=C)[C:13]([OH:15])=[O:14].CSC>ClCCl>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:1])[C:13]([OH:15])=[O:14]
Reactant: O=[O+][O-]
Reactant: C=C(C(=O)O)c1ccccc1OC
Solvent: CSC
Solvent: ClCCl
Product: COc1ccccc1C(=O)C(=O)O
Yield: 69 %

Procedure:
A stream of ozone is sparged at -75° C. for 3 hours 30 minutes into a solution of 1 g (5.62 mmol) of 2-(2-methoxyphenyl)acrylic acid, obtained under the conditions described in Example 38, in dichloromethane. 1.66 cm3 (22.5 mmol) of dimethyl sulphide are added and stirring is continued, the temperature being allowed to rise to the region of 20° C. After concentrating the reaction mixture to dryness, 0.7 g (69%) of (2-methoxyphenyl)oxoacetic acid is obtained in the form of crystals, the characteristics of which are as follows: mass spectrum (E.I.) M/Z=180 (M+)
Reaction SMILES: Cl[Ge:2]([CH3:17])([Ge:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12])[Ge:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:4][CH3:5].[OH-:18].[Na+]>O>[O:18]([Ge:2]([CH3:17])([Ge:10]([CH2:13][CH3:14])([CH2:15][CH3:16])[CH2:11][CH3:12])[Ge:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:8][CH3:9])[Ge:2]([CH3:17])([Ge:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12])[Ge:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:4][CH3:5]
Reactant: [OH-]
Reactant: CC[Ge](CC)(CC)[Ge](C)(Cl)[Ge](CC)(CC)CC
Agent: [Na+]
Solvent: O
Product: CC[Ge](CC)(CC)[Ge](C)(O[Ge](C)([Ge](CC)(CC)CC)[Ge](CC)(CC)CC)[Ge](CC)(CC)CC

Procedure:
This compound was prepared according to the process described in Example I, starting from 3.0 g of 2-chloro-2-methylhexaethyltrigermane, 0.6 g of sodium hydroxide and 3 ml of water. 3.1 g (55%) of colorless, liquid oxybis(1,1,1,3,3,3-hexaethylmethyltrigermane) were obtained; nD20 =1.5410.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH2:13][O:14][CH3:15])([CH3:12])[CH2:10][CH2:9][CH2:8][S:7][C:6]=2[CH:16]=1.C[O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1>N1CCCCC1.[Cu]I.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:14][CH2:13][C:11]1([CH3:12])[CH2:10][CH2:9][CH2:8][S:7][C:6]2[CH:16]=[C:2]([C:27]#[C:26][C:23]3[CH:24]=[CH:25][C:20]([C:19]([OH:28])=[O:18])=[CH:21][CH:22]=3)[CH:3]=[CH:4][C:5]1=2
Reactant: COCC1(C)CCCSc2cc(Br)ccc21
Reactant: C#Cc1ccc(C(=O)OC)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: COCC1(C)CCCSc2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 80 °C
Yield: 46.3 %

Procedure:
To 478 mg (1.59 mmol) of 8-bromo-5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepine, dissolved in 2.9 ml of piperidine, was added successively 4.8 mg (0.02 eq.) of CuI, 7.0 mg (0.02 eq.) of Ph3P, and 24.1 mg (0.01 eq.) of (Ph3P)4Pd. After heating to 80° C., a solution of 508 mg (2 eq.) of 4-ethynyl-benzoic acid methyl ester in 2.8 ml of piperidine was added within 2 h via dropping funnel and then kept at this temperature for 3 additional h. After cooling, the reaction mixture was poured onto crushed ice/ HCl diluted, extracted with diethylether, the organic phase was washed with water, dried over magnesium sulfate, filtrated and evaporated to dryness. Flash chromatography (SiO2, hexane/ethylacetate 95/5) yielded 270 mg of the title compound as colorless oil.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].NCC[CH2:9][CH2:10][CH2:11][CH2:12]N>C(O)CCCCO>[CH3:9][CH2:10][CH2:11][CH2:12][NH:4][C:3]([NH2:5])=[N:2][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: NCCCCCCN
Reactant: N=C(N)N
Agent: Cl
Agent: OCCCCCO
Product: CCCCN=C(N)NCCCC
Temperature: 80 °C

Procedure:
Guanidine hydrochloride (200 parts) and hexamethylene diamine (292 parts) were heated to 120° C. for 4 hours under a nitrogen atmosphere. The temperature of the reaction mixture was then raised to 150–170° C. for a further 10 hours. The product was cooled to 80° C. and 1,5-pentanediol (400 parts) was added while the temperature was maintained at 80° C. until dissolution occurred. The mixture was then cooled to give a solution of polyhexamethyleneguanidine (prepolymer 3) in 1,5-pentanediol.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:12]1[N:17]=[C:16]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([C:27]([CH3:37])([O:29][Si:30]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:31][CH3:32])[CH3:28])=[N:26][C:21]3=[N:20][CH:19]=2)[CH:15]=[CH:14][CH:13]=1.[F:38][C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[C:41]([B:47]2[O:51][C:50]([CH3:53])([CH3:52])[C:49]([CH3:55])([CH3:54])[O:48]2)[CH:40]=1>>[F:38][C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[C:41]([B:47]2[O:51][C:50]([CH3:53])([CH3:52])[C:49]([CH3:55])([CH3:54])[O:48]2)[CH:40]=1.[F:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:18]3[N:22]4[CH:23]=[CH:24][C:25]([C:27]([CH3:28])([O:29][Si:30]([CH2:31][CH3:32])([CH2:35][CH3:36])[CH2:33][CH3:34])[CH3:37])=[N:26][C:21]4=[N:20][CH:19]=3)[N:17]=2)[CH:9]=1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3cccc(Br)n3)cnc2n1
Reactant: N#Cc1ccc(F)cc1Br
Agent: CC1(C)OB(c2cc(F)ccc2C#N)OC1(C)C
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3cccc(-c4cc(F)ccc4C#N)n3)cnc2n1

Procedure:
4-Fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl }benzonitrile was synthesised from 2-bromo-4-fluorobenzonitrile following the procedure in Example 22. 3-(6-Bromopyridin-2-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine was coupled to 4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl }benzonitrile following the procedure in Example 2 to give 4-fluoro-2-{6-[7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl }benzonitrile as an orange oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:26][O:27][CH2:28][C:29]1[C:30]([NH2:44])=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[NH2:44][C:30]1[N:31]=[CH:32][C:33]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]5[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:34][C:29]=1[CH2:28][O:27][CH3:26]
Reactant: COCc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COCc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C(C)C)nc2C)c(=O)n4C)cnc1N

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G) and 3-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (Stage 168.1.1) to give the title compound as a white solid. (HPLC: tR 2.19 min (Method A); M+H=458 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.91 (s, 1H), 8.20 (s, 1H), 8.06-8.01 (m, 2H), 7.85-7.80 (m, 1H), 7.53-7.50 (m, 1H), 7.44-7.41 (m, 1H), 5.99 (s, br, 2H), 4.54 (hp, 1H), 4.30 (s, 2H), 3.57 (s, 3H), 3.31 (s, 3H), 1.95 (s, 3H), 1.47 (d, 6H))
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:27])[C:8]([CH:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]2[O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S(S([O-])=O)=O.[Na+].[Na+].O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:27])[C:8]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]2[O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)c1c(C)cc2ccc(Br)cc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)c1c(C)cc2ccc(Br)cc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (˜8.7 mmol) in CH2Cl2 (40 mL) was added Dess-Martin periodinane (4.07 g, 9.6 mmol). After 1.5 h, a saturated solution of Na2S2O4 (20 mL) and water (20 mL) was added. The mixture was stirred vigorously for 30 min. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 3 the titled compound. 1H-NMR: 400 MHz, (CDCl3) δ: 8.22 (s, 1H), 7.70 (m, 3H), 4.41 (q, J=7 Hz, 2H), 2.47 (s, 3H), 1.39 (t, J=7 Hz, 3H). 19F-NMR: 377 MHz, (CDCl3) δ: −73.2.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][CH3:14])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:2][C:3]#[N:4])=[C:8]([CH2:13][CH3:14])[CH:7]=1
Reactant: CCc1cc(Br)ccc1O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1OCC#N
Reaction time: 12 h
Yield: 83.8 %

Procedure:
Bromoacetonitrile (1.19 ml, 9.94 mmol) was added to a solution of 4-bromo-2-ethylphenol (2.0 g, 9.94 mmol) and potassium carbonate (1.35 g, 9.94 mmol) in DMF (50 ml). The reaction was stirred for 12 hours and then partitioned between diethyl ether (200 ml) and water (200 ml). The organics were separated, dried over magnesium sulfate, filtered and concentrated in vacuuo to afford the title compound as a yellow oil (2.0 g). 1H NMR (CDCl3): δ 1.13 (t, J=12.07 Hz, 3 H), 2.45 (m, 2H), 4.84 (s, 2H), 7.03–7.10 (m, 2H), 7.21 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][S:7](Cl)(=[O:9])=[O:8])[CH3:2].[CH3:19][NH:20][CH3:21].Cl>C(Cl)Cl.C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][S:7]([N:20]([CH3:21])[CH3:19])(=[O:9])=[O:8])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)N(C)C
Reaction time: 0.25 h

Procedure:
A solution of 359 mg of 2-benzyl-3-chlorosulphonylpropionic acid ethyl ester in 2 ml of methylene chloride is cooled to -10° and 0.464 ml of a 5.6M solution of dimethylamine in ethanol is added thereto. The solution is stirred for 15 minutes at -15°, mixed with 2N HCl and extracted with methylene chloride. The extracts are washed with water, dried with magnesium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel with eluant C. Rf (A)=0.43.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=O)[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:47]([NH:49][CH2:50][CH3:51])[CH3:48]>ClCCl>[CH2:47]([N:49]([CH2:50][CH3:51])[C:23](=[O:25])[C:8]1[CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:9]=1)[CH3:48]
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCNc1cc(C(=O)N(CC)CC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 0.08 h
Yield: 64.1 %

Procedure:
Bumetanide (1.16 g, 3.2 mmol) was dissolved in dichloromethane (10 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 690 mg, 3.6 mmol) was added. After 5 minutes N-hydroxybenzotriazole (HOBt, 498 mg, 3.6 mmol) was added and the solution was stirred for an additional 5 minutes. Diethylamine (332 uL, 3.2 mmol) was added and the reaction was stirred for 2 hours. The reaction was washed with saturated sodium bicarbonate, water and brine, and dried with magnesium sulfate. The dichloromethane was removed under reduced pressure to yield 860 mg (65%) of pure N,N-diethyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzamide.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[C:18]([NH2:19])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1>O1CCCC1>[C:5]([NH:19][C:18]1[C:9]([NH2:8])=[N:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:17]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2ccccc2nc1N
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccccc2nc1N
Reaction time: 20 h

Procedure:
A solution of 20.8 parts of acetic anhydride in 100 parts of tetrahydrofuran was added to a slurry of 24.0 parts of 2,3-diaminoquinoxaline in 900 parts of tetrahydrofuran. The heterogeneous reaction mixture was stirred at 25° for 20 hrs and then concentrated in vacuo to give 25 parts of 2-acetamido-3-aminoquinoxaline, mp 319° (dec.).
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19]CC)=[O:18])C>C(O)C>[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[N:9]=[C:15]([OH:14])[C:16]([C:17]([OH:19])=[O:18])=[CH:22][N:8]=2)=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reaction time: 0.08 h
Yield: 102671.1 %

Procedure:
A solution of 14.8 g (0.642 mmol) of sodium in 750 ml of dry ethanol is stirred at 0° and 44.6 g (0.214 mmol) of 4-aminobenzamidine .2HCl [Shaw and Cooley, J. Am. Chem. Soc., 79, 3561 (1957)] is added. The mixture is stirred 5 minutes under nitrogen and 46.2 g (0.214 mmol) of diethyl ethoxymethylenemalonate is added. After stirring for 30 min, the mixture is refluxed for 4 hrs and allowed to stand overnight at room temperature. The salt is filtered and washed with isopropanol. The salt is suspended in 214 ml of 2 N potassium hydroxide and stirred at 70° C. for 4 hrs. After treating with a small amount of charcoal, the filtrate is added to 325 ml of 2 N HCl with stirring. The acid is filtered, washed with water, ethanol, and ether, and dried to give 50.8 g of the title compound, mp 312°- 314° C. dec. The product is recrystallized from dimethylacetamide-water to give 44.5 g mp 313°-314° C. dec.