Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1([CH2:14][N:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[O:17][C:16]2=[O:31])[CH2:13][O:12]1.C(=O)([O-])O.[Na+].O>C(O)C>[Cl:1][C:2]1[N:3]([CH2:13][C:11]([OH:12])([CH3:10])[CH2:14][N:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=3)[O:17][C:16]2=[O:31])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC1(Cn2nc(-c3ccc(OC(F)(F)F)cc3)oc2=O)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)(Cn1cc([N+](=O)[O-])nc1Cl)Cn1nc(-c2ccc(OC(F)(F)F)cc2)oc1=O
Yield: 94.1 %

Procedure:
To a suspension of 2-chloro-4-nitro-1H-imidazole (2.21 g, 14.98 mmol) and 3-(2-methyloxiran-2-ylmethyl)-5-(4-trifluoromethoxyphenyl)-3H-[1,3,4]oxadiazol-2-one (2.37 g, 7.49 mmol) in ethanol (25 ml), sodium hydrogencarbonate (1.32 g, 15.73 mmol) was added followed by stirring under reflux for 8 hours. To the reaction mixture, water was added, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate, and concentrated under reduced pressure to afford 3-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-5-(4-trifluoromethoxyphenyl)-3H-[1,3,4]oxadiazol-2-one (3.27 g, yield 94%) as a light yellow amorphous form.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[O:27][CH:28]=2)[N:3]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.O>C1COCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[O:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=4)[C:7]([C:8]#[N:9])=[C:2]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[N:3]=3)[N:25]=2)=[CH:30][CH:31]=1
Reactant: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: C1CCNC1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(SCc2coc(-c3ccc(Cl)cc3)n2)nc(N2CCCC2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
80 mg (0.15 mmol) of the compound from Example 123A are initially charged in 2 ml of dry THF, and 22 mg (0.31 mmol) of pyrrolidine are added. The reaction mixture is stirred at RT for 10 h. About 2 ml of water are then added, and the mixture is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). After removal of the solvent on a rotary evaporator, the product was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.CCN(CC)CC.[F:17][C:18]1([F:33])[O:22][C:21]2[CH:23]=[CH:24][C:25]([C:27]3([C:30](Cl)=[O:31])[CH2:29][CH2:28]3)=[CH:26][C:20]=2[O:19]1>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:30]([C:27]2([C:25]3[CH:24]=[CH:23][C:21]4[O:22][C:18]([F:33])([F:17])[O:19][C:20]=4[CH:26]=3)[CH2:29][CH2:28]2)=[O:31])[CH:5]=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(N)nc(Cl)c1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
To a solution of 6-chloro-4-methylpyridin-2-amine (300 mg, 2.1 mmol) and Et3N (1.8 mL, 13 mmol) in dichloromethane (5 mL) was added a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (1.6 g, 6.3 mmol) in dichloromethane (5 mL). The resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (10 mL) and was washed with 1N aqueous HCl (1×20 mL) and saturated aqueous NaHCO3 (1×20 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-70% ethyl acetate in hexane to yield N-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (700 mg, 91%). ESI-MS m/z calc. 366.1. found 366.9 (M+1)+. Retention time 2.15 minutes.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[C:8]([F:12])[C:9]=1[CH2:10][OH:11].[CH:14]1([CH2:17]Br)[CH2:16][CH2:15]1>CN(C)C=O>[CH:14]1([CH2:17][O:13][C:6]2[CH:5]=[C:4]([F:3])[C:9]([CH2:10][OH:11])=[C:8]([F:12])[CH:7]=2)[CH2:16][CH2:15]1
Reactant: OCc1c(F)cc(O)cc1F
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCc1c(F)cc(OCC2CC2)cc1F
Reaction time: 24 h
Yield: 134 %

Procedure:
Sodium hydride (82 mg, 55%, 1.87 mM) was added to a solution of 3,5-difluoro-4-hydroxymethyl-phenol (300 mg, 1.87 mM) in dimethylformamide (4 mL). After 1 h stirring at room temperature cyclopropylmethylbromide (135 mg, 1.87 mM) was added and stirring continued for 24 h. The mixture was partitioned between water and diethylether. Organic phases were pooled, washed with brine and dried with MgSO4 to yield after evaporation a yellow oil (673 mg). This residue was purified by column chromatography (silica gel; n-hexane/ethylacetate gradient) to yield 287 mg (71%) of the product as a yellowish oil. MS (EI): 214.1 (M)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5].[C:14](OCC)(=[O:20])[C:15](OCC)=[O:16]>>[CH2:12]([O:11][C:9]([C:8]1[S:7][C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[C:14]([OH:20])[C:15]=1[OH:16])=[O:10])[CH3:13]
Reactant: CCOC(=O)CSCC(=O)OCC
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1sc(C(=O)OCC)c(O)c1O

Procedure:
The diethyl thioglycolate and diethyl oxalate are mixed, and then added to a first solution containing a first electron donor in the microwave reactor. The microwave reactor is heated by the 2.45 GHz microwave at a power of 100-500 W to perform a condensation reaction for 20-60 minutes to obtain 2,5-diethoxycarbonyl-3,4-dihydroxythiophene. The reaction is shown in the chemical formula (B).
Reaction SMILES: Cl.[CH2:2]([NH:6][C:7](=[O:15])[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH3:5].[H][H]>C(O)C.O.[Rh]>[CH2:2]([NH:6][C:7](=[O:15])[NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCNC(=O)Nc1ccncc1
Agent: [Rh]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCNC(=O)NC1CCNCC1
Yield: 19.4 %

Procedure:
A solution of 3-n-butyl-1-(4-pyridyl)urea hydrochloride (37.4 g) in ethanol-water (1:1, 400 ml) containing 5% rhodium/alumina catalyst (10 g) was hydrogenated (50°, 750 psi) until no further uptake of hydrogen occurred. The catalyst was then removed by filtration and the solvent evaporated to leave an oil which partially solidified on storage at 0°. The solid was separated, treated with base, extracted with chloroform/n-butanol, the extracts evaporated and the residue recrystallized twice from ethyl acetate to give 3-n-butyl-1-(4-piperidyl)urea, (6.3 g), m.p. 132°-134°.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=1.O>C(O)CCC>[N:23]1[CH:3]=[C:2]([CH2:5][C:6]2[CH:16]=[CH:15][C:9]3[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=3[CH:7]=2)[N:18]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:17]2
Reactant: Nc1cccnn1
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Solvent: CCCCO
Solvent: O
Product: CSc1nc2ccc(Cc3cnc4cccnn34)cc2s1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A stirred mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal (500 mg, 1.8 mmol) from Step 4 of Example 117 and pyridazin-3-amine (350 mg, 3.6 mmol) in 1-butanol (20 mL) was heated at reflux for 15 h. The mixture was cooled to rt and water (40 mL) was added. The mixture was extracted with EtOAc (20 mL×3) and the combined organic layers were washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2 to 5% MeOH in DCM to afford 6-(imidazo[1,2-b]pyridazin-3-ylmethyl)-2-(methylthio)benzo[d]thiazole (460 mg, 80%) as a light brown solid. 1H NMR (300 MHz, CDCl3) δ 8.32 (dd, J=4.5, 1.5 Hz, 1H), 7.94 (dd, J=9.3, 1.5 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 7.02 (m, 1H), 4.45 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 313 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[CH3:17].[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O.CS(C)=O>[CH3:17][C:3]1[CH:4]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:18]=[O:19])[CH:25]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
2-Bromo-1,3-dimethyl-5-[3-(methylsulfonyl)propoxy]benzene (1.0 g), 3-formylphenylboronic acid (0.49 g, 1.05 eq), tripotassium phosphate (1.32 g, 2.0 eq), 10% Pd—C(PE) (0.1 g, 1.38 mol %), rac-BINAP (26.8 mg, 1.38 mol %), dimethyl sulfoxide (10 mL) and water (5 mL) were added. After nitrogen substitution, the mixture was stirred at 80° C. for 3 hr. The obtained reaction mixture was analyzed by high performance liquid chromatography to find the title compound (91.2% peak area).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:24])[CH2:13][CH:12]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:21](=O)[NH2:22])[CH:10]=2)[O:5]1.O=P(Cl)(Cl)Cl>ClCCCl>[CH3:1][O:2][CH2:3][C:4]1([CH3:24])[CH2:13][CH:12]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:21]#[N:22])[CH:10]=2)[O:5]1
Reactant: COCC1(C)CC(n2ccccc2=O)c2cc(C(N)=O)ccc2O1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COCC1(C)CC(n2ccccc2=O)c2cc(C#N)ccc2O1
Reaction time: 0.75 h

Procedure:
A mixture of 2.98 g of 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-carbamoylchroman, 2 ml of POCl3 and 200 ml of 1,2-dichloroethane is boiled for 45 min. Cooling and customary working up gives 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyanochroman.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].CCOC(C)=O>C(O)(C)C>[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Reactant: COc1ccccc1N
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccccc1Nc1ncc2c(n1)CCN(C(=O)c1cccnc1)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 2-methoxyaniline (0.012 g, 0.100 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 33.5% yield (0.011 g, 0.030 mmol).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[CH:7]=O.[Br-].[CH2:12]([O:14][C:15]([CH:17]=[C:18]([CH3:44])[CH:19]=[CH:20][CH:21]=[C:22]([CH3:43])[CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:16])[CH3:13].[Na].C(O)C>CN(C)C=O>[CH2:12]([O:14][C:15](=[O:16])[CH:17]=[C:18]([CH3:44])[CH:19]=[CH:20][CH:21]=[C:22]([CH3:43])[CH:23]=[CH:7][C:6]1[C:5]([CH3:9])=[C:4]([CH3:10])[S:3][C:2]=1[CH3:1])[CH3:13]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1sc(C)c(C=O)c1C
Agent: [Br-]
Agent: [Na]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)sc(C)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.9 G. of 2,4,5-trimethyl-3-thiophenecarboxaldehyde and 6.75 g. of (7-ethoxycarbonyl-2,6-dimethyl-2,4,6-heptatrienyl)triphenylphosphonium bromide are dissolved in 50 ml of dry dimethylformamide. The solution is treated at 10° C. dropwise with a solution of 0.29 g. of sodium in 8 ml. of ethanol. The mixture is subsequently stirred for 4 hours at room temperature, then introduced into 100 ml. of methanol/water 60:40 parts by volume and thoroughly extracted with hexane. The hexane extract is washed with methanol/water (60:40 parts by volume, then with water, dried over sodium sulfate and evaporated. There is obtained 3,7-dimethyl-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenoic acid ethyl ester, which melts after recrystallization from hexane at 88°-89° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH:21]=[CH:20]2>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH:21]=[CH:20]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(Nc1ccc2cc(O)ccc2c1)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc4cc(NC(=O)OCc5ccccc5)ccc4c3)c2cc1OC
Temperature: 25 °C

Procedure:
4-Chloro-6,7-dimethoxyquinoline (prepared by the method described in WO 03/33472) (223 mg, 1.0 mmol), N-(6-hydroxy-(2-naphthyl))(benzyloxy)carboxamide (Step a, 293 mg, 1.0 mmol) and DMAP (122 mg, 1.0 mmol, Aldrich) in toluene (5 mL, Aldrich) were microwaved (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. After cooling to RT, the white precipitate was collected and purified by silica gel column chromatography (80% EtOAc/hexane) to give title compound as a white solid. MS (ESI, pos. ion) m/z: 481.3 (M+1). Mass Calc'd for C29H24N2O5: 480.17.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C#N)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(C#N)cc1
Temperature: -78 °C

Procedure:
A stirred solution of 4-(methylthio)benzonitrile (Aldrich Chemical Co.) (36 mmol) in methylene chloride (50 mL) at -78° C. is treated dropwise with a slurry of m-chloroperbenzoic acid (36 mmol) in 50 mL of methylene chloride over a period of 30 minutes. The mixture is stirred an additional hour at -78° C. and then allowed to warm to room temperature. The reaction mixture is washed with 3N sodium hydroxide solution (50 mL), dried (magnesium sulfate) and concentrated at reduced pressure to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:5]=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[OH-].[K+].Cl>C(O)C.O>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH:9][C:8]([C:7]2[C:2]([OH:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COC(=O)COc1cccc(O)c1C(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1cccc(O)c1C(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of 6′-hydroxy-2′-(methoxycarbonylmethoxy)acetophenone (2.24 g) and 4-bromobenzaldehyde (2.78 g) in ethanol (30 mL) were added water (10 mL) and potassium hydroxide (6.73 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (70 mL), and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give 4-bromo-2′-(carboxymethoxy)-6′-hydroxychalcone (3.77 g). To a suspension of the obtained 4-bromo-2′-(carboxymethoxy)-6′-hydroxychalcone (3.7 g) in benzene (150 mL) were added tris(triphenylphosphine)rhodium(I) chloride (1.82 g) and triethylsilane (6.2 mL), and the mixture was stirred at 70° C. overnight. To the reaction mixture were added 2 mol/L aqueous sodium hydroxide solution and diethyl ether, and the aqueous layer was separated. The aqueous layer was washed with diethyl ether and acidified by addition of concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with n-hexane-ethyl acetate. The precipitated crystals were collected by filtration. The crystals were washed with n-hexane and dried under reduced pressure to give 4-bromo-2′-(carboxymethoxy)-6′-hydroxydihydrochalcone (1.1 g). This material was dissolved in acetic acid (4.15 mL). To the solution were added sodium acetate (1.5 g) and acetic anhydride (1.5 mL), and the mixture was stirred at 115° C. overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (10 mL). To the solution was added sodium methoxide (28% methanol solution, 1.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue was added 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give the title compound (0.85 g).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9](=[NH:12])OC)[CH:6]=[CH:7][CH:8]=1.[CH:13]([NH:15][NH2:16])=O.O>N1C=CC=CC=1>[Br:2][C:3]1[CH:4]=[C:5]([C:9]2[N:12]=[CH:13][NH:15][N:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=N)c1cccc(Br)c1
Reactant: NNC=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Brc1cccc(-c2nc[nH]n2)c1
Temperature: 25 °C

Procedure:
To a slurry of methyl 3-bromobenzenecarboximidoate hydrochloride (example IV-21 Step 1; 0.541 g; 2.18 mmol) in pyridine (3 mL) at 0° C. was added a solution of formic hydrazide (0.157 g; 2.62 mmol). The flask was stoppered and gradually warmed to room temperature (overnight) and poured into water (˜20 mL). Precipitated solid was collected by filtration and the filtrate was extracted with EtOAc (×3). Combined extracts were washed (water, brine), dried over Na2SO4, concentrated in vacuo. The residue obtained was combined with the above precipitate, and the whole was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless solid. LC/MS (method A) tR 2.49 min, m/z 224, 226 (M+H, Br isotopes).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[N:11]([CH2:22][C:23](O)=[O:24])[C:10](=[O:26])[C@@H:9]1[CH2:27][CH:28]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=O)(C)(C)C.[NH2:35][C:36]1[CH:37]=[C:38]2[C:51](=[CH:52][CH:53]=1)[CH2:50][C@:40]1([C:48]3[C:43](=[N:44][CH:45]=[CH:46][CH:47]=3)[NH:42][C:41]1=[O:49])[CH2:39]2.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH:28]1([CH2:27][C@@H:9]2[NH:8][CH2:13][CH:12]([C:14]3[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=3)[N:11]([CH2:22][C:23]([NH:35][C:36]3[CH:37]=[C:38]4[C:51](=[CH:52][CH:53]=3)[CH2:50][C@:40]3([C:48]5[C:43](=[N:44][CH:45]=[CH:46][CH:47]=5)[NH:42][C:41]3=[O:49])[CH2:39]4)=[O:24])[C:10]2=[O:26])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)[C@@H]1CC1CCCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)[C@H](CC2CCCCCC2)NCC1c1cc(F)cc(F)c1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
100 mg (0.21 mmol) 2-((3S)-4-(tert-butoxycarbonyl)-3-(cycloheptylmethyl)-6-(3,5-difluorophenyl)-2-oxopiperazin-1-yl)ethanoic acid, 58 mg (0.23 mmol) (R)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrol[2,3-b]pyridin]-2′(1′H)-one, 56 mg (0.29 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-hydrochloride, 39 mg (0.29 mmol) HOBT, 0.03 ml (0.23 mmol) TEA and 1.50 ml DMF were stirred overnight at RT. The mixture was concentrated by rotary evaporation. The residue was combined with 15 ml of a 1.25M methanolic hydrochloric acid and stirred for 2 h at 50° C. The diastereomers were separated by RP-HPLC. The fractions containing the product were lyophilised.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][O:27][C:21]=2[N:20]=[C:19]1[CH:28]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][O:27][C:21]=2[N:20]=[C:19]1[CH:28]([N:31]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:29][CH3:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2occc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(c1nc2occc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (1 equiv) in dichloromethane is added to a solution of 3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}-propyl)furo[2,3-d]pyrimidin-4(3H)-one (1-6, 1 equiv) and N,N-diisopropylethylamine (1 equiv) in dichloromethane, and the resulting mixture is stirred under ambient conditions for 1 h. The reaction mixture is washed with saturated aqueous NaHCO3 solution, and brine, then dried (MgSO4) and concentrated. The residue is purified by flash chromatography. Elution with CH2Cl2 to 5% NH3-EtOH/CH2Cl2 gives N-[1-(3-benzyl-4-oxo-3,4-dihydrofuro[2,3-d]pyrimidin-2-yl)propyl]4-bromo-N-[2-(dimethylamino)ethyl]benzamide (1-7).
Reaction SMILES: [CH3:1][O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:17]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:23])[C:13](=[CH:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:12]=1.CI>CN(C)C=O>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:17]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=2[N:15]([CH3:1])[C:14](=[O:23])[C:13](=[CH:24][N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:12]=1
Reactant: O=C1Nc2ccc(F)cc2C(c2ccccc2Cl)=NC1=CN1CCOCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(=CN2CCOCC2)N=C(c2ccccc2Cl)c2cc(F)ccc21
Temperature: 0 °C

Procedure:
1.6 gm of a methanolic 30% sodium methylate solution were added to a suspension of 2 gm of 5-(2'-chloro-phenyl)-1,3-dihydro-7-fluoro-3-(morpholino-methylene)-2H-1,4-benzodiazepin-2-one in 50 ml of dimethylformamide at room temperature, whereby a reddish-brown solution was immediately formed. The resulting solution was cooled to 0°C, and then 2.1 gm of methyl iodide were added dropwise thereto. After one hour the mixture was poured into ice water, and the precipitate formed thereby was collected by vacuum filtration and dried over phosphorus pentoxide, yielding the compound named in the heading, which had a melting point of 110°-115°C.