Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:17])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.C[C:19]([CH3:22])([O-])[CH3:20].[K+].Br[CH2:25][CH2:26][CH3:27].Cl>CO.O.CS(C)=O>[Br:1][C:2]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:17])=[CH:9][CH:10]=3)[C:5]([CH2:25][CH2:26][CH3:27])([CH2:20][CH2:19][CH3:22])[C:4]=2[CH:3]=1
Reactant: CCCBr
Reactant: COc1cc2c(cc1Br)Cc1cc(Br)ccc1-2
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: CCCC1(CCC)c2cc(Br)ccc2-c2cc(OC)c(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a stirred mixture of 2,7-dibromo-3-methoxyfluorene (87.7 g, 0.244 mol), potassium t-butoxide (28 g, 0.25 mol) and dry methyl sulfoxide (500 mL) was added 1-bromopropane (22.6 mL, 0.25 mol) at such a rate as to keep the reaction exotherm temperature below 45° C. A further quantity of potassium t-butoxide (39.0 g; 0.35 mol) and 1-bromopropane (31.6 mL; 0.35 mol) were added. The resulting mixture was stirred at room temperature for 1 hour and treated with 50% methanol/water (500 mL). The purple color was discharged by addition of 6.0M hydrochloric acid (2.0 mL) and the mixture cooled at 0° C. for 1 hour. The crude product was collected and washed with 50% methanol/water (250 mL) and dried to yield crude product (106 g). Purification by extraction from neutral alumina (5 cm3) with hexane on an Ace-Kauffman column with hexane afforded 2,7-dibromo-9,9-dipropyl-3-methoxyfluorene (95 g; m. pt. 127-131.5° C.). Further purification by re-crystallization (2-propanol) gave pure product (84 g, yield 78%).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH3:11])[CH:7]=[CH:6][C:5]=2[CH3:12].[Li]CCCC.CCCCCC.[Si:24]([CH3:28])([CH3:27])(Cl)[Cl:25]>CCOCC.C1COCC1>[Cl:25][Si:24]([CH:3]1[C:4]2[C:9](=[C:8]([CH3:11])[CH:7]=[CH:6][C:5]=2[CH3:12])[CH:10]=[C:2]1[CH3:1])([CH3:28])[CH3:27]
Reactant: CC1=Cc2c(C)ccc(C)c2C1
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1=Cc2c(C)ccc(C)c2C1[Si](C)(C)Cl
Temperature: 0 °C
Yield: 102.7 %

Procedure:
7.24 g of 2,4,7 trimethylindene (45.8 mmol) were suspended in 70 ml of Et2O, cooled to 0° C., and to it were added 19.2 ml of a 2.5 M BuLi solution in hexane (48.0 mmol) with stirring. A slightly yellow cream is obtained. After allowing the reaction mixture to reach ambient temperature, additional 10 ml of Et2O were added, to improve stirring. After about 1 h the mixture was cooled again to 0° C. and 7.20 g of Me2SiCl2 (55.2 mmol, 1.2 eq) in 30 ml di THF, previously cooled to 0° C., were added to it. At the end of the addition, the reaction mixture was allowed to reach ambient temperature. At this point the reaction mixture, which appeared as a white suspension, was filtered to remove LiCl, and then all solvents and excess Me2SiCl2 were removed under reduced pressure to leave 11.8 g of pale yellow oil (98% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.Cl.[CH3:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1)[CH3:31].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](=[O:19])[NH:41][CH2:40][CH2:39][C:36]3[CH:37]=[CH:38][C:33]([CH2:32][N:30]([CH3:31])[CH3:29])=[CH:34][CH:35]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: CN(C)Cc1ccc(CCN)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(CN(C)C)cc4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a stirred suspension of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (0.10 g, 0.28 mmol), 2-(4-((dimethylamino)methyl)phenyl)ethanamine dihydrochloride (0.056 g, 0.31 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′-tetramethyluronium hexafluorophosphate (0.13 g, 0.34 mmol) in N,N-dimethylformamide (1.4 mL) at ambient temperature was added N,N-diisopropylethylamine (0.25 mL, 1.4 mmol). The resulting solution was stirred at ambient temperature for 60 minutes, then partitioned between water (15 mL) and ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 90/10 chloroform/(90/10 methanol/concentrated ammonium hydroxide), to afford methyl 6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate as a colorless film (0.083 g, 57% yield).
Reaction SMILES: [C:1]1([Mg]Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]1([C:19]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22](=[O:32])[C:21]=3[CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:1]1([C:22]2([OH:32])[C:21]3[CH:20]=[C:19]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Mg]c1cccc2ccccc12
Reactant: O=C1c2ccccc2-c2ccc(-c3ccccc3)cc21
Product: OC1(c2cccc3ccccc23)c2ccccc2-c2ccc(-c3ccccc3)cc21

Procedure:
from 1-naphthylmagnesium chloride and 2-phenyl-9-fluorenone;
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH3:13].[OH:14][CH2:15][C:16]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[H-].[Na+]>CN(C)C=O.O>[CH3:13][O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][O:14][CH2:15][C:16]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1COCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(Bromomethyl)-1-methoxy-4-nitrobenzene (100.0 mg, 0.34 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (93.0 mg, 0.38 mmol) were combined in dimethylformamide (4 mL) and cooled to 0° C. The reaction was treated with sodium hydride (9.0 mg, 0.38 mmol), stirred at 0° C. for 1 hr and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (15% ethyl acetate/hexanes) gave 110 mg (71%). 1H-NMR (CDCl3, 500 MHz) δ 8.11 (dd, J=6.1, 3.1 Hz, 1H), 8.08 (d, J=2.8 Hz, 1H), 7.34 (m, 4H), 7.21-7.24 (m, 1H), 6.80 (d, J=8.9 Hz, 1H), 4.37 (s, 2H), 3.85 (s, 3H), 3.74-3.75 (m, 2H), 3.48 (s, 2H), 3.02-3.07 (m, 2H), 2.21-2.24 (m, 2H), 1.87-1.93 (m, 2H), 1.43 (s, 9H). Mass spec.: 479.16 (MNa)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C1(C)C=CC(S(O[CH2:26][C@H:27]2[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:32][C:29]1([CH3:33])[O:28][C@@H:27]([CH2:26][O:1][C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:31][O:30]1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC[C@H]2COC(C)(C)O2)cc(C(=O)OC)c1
Temperature: 0 °C

Procedure:
2.1 g of dimethyl 5-hydroxy-isophthalate and 2.9 g of (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl toluene-4-sulfonate were stirred at reflux for 3 hours in 120 ml of dimethylformamide with the addition of 6.9 g of potassium carbonate. The reaction mixture was poured on to ice-water, extracted with methylene chloride, the combined methylene chloride phases were washed with water, dried over magnesium sulfate, filtered and evaporated. There was obtained dimethyl (S)-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isophthalate, MS: m/z 324 ([M]+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([NH2:14])=[NH:13])[CH2:2][CH3:3].C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>O1CCOCC1>[O:17]=[C:18]1[NH:14][C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])=[N:13][CH:25]=[C:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCCOc1ccccc1NC(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: C1COCCO1
Product: CCCOc1ccccc1Nc1ncc(C(=O)OCC)c(=O)[nH]1
Reaction time: 5 h
Yield: 78.3 %

Procedure:
To a solution of N-(2-propoxyphenyl)guanidine (9.1 g) in dioxane (30 ml) is added dropwise diethyl ethoxymethylenemalonate (10.2 g), and the mixture is refluxed with stirring for 5 hours. After cooling, the precipitate is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-6-oxo-2-(2-propoxyanilino)-5-pyrimidinecarboxylate (11.7 g). M.p. 198°-200° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@H:27]1[C:32]([OH:34])=[O:33]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:12][C:13]([CH2:19][N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@H:27]2[C:32]([OH:34])=[O:33])=[C:14]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)[C@@H]1COCCN1
Product: COC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 83.1 %

Procedure:
Methyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.65 g, 3.37 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.44 g, 3.37 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (1.51 g, 83%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][OH:11])=[CH:4][CH:3]=1.COCCO[AlH2-]OCCOC.[Na+].C1(C)C=CC=CC=1.C(OCC)(=O)C.[I:37]I>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[I:37])=[CH:9]/[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: II
Reactant: OCC#Cc1ccc(Br)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC/C=C(\I)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(4-bromophenyl)-1-propyne-3-ol B (6.58 g, 31.2 mmol) in anhydrous tetrahydrofuran (THF, 66 mL) was chilled in an ice bath. A 65% w/w solution of Red-Al in toluene (PhMe, 18.7 mL, 19.4 g, 62.4 mmol) was added dropwise over 15 minutes. After 1 hour ethyl acetate (EtOAc, 3.0 mL, 2.75 g, 31.2 mmol) was added. The reaction mixture was chilled in a dry-ice/acetone bath. A solution of I2 (12.7 g, 49.9 mmol) in anhydrous THF (66 mL) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction was quenched with saturated Na2SO3 and filtered through Celite. The filter cake was washed well with EtOAc. The filtrate was washed with water and brine, dried (MgSO4), filtered, and concentrated. Column chromatography (20% EtOAc/hexanes) provided (Z)-1-(4-bromophenyl)-1-iodopropene-3-ol C (8.82 g, 83%) as a yellow solid. 1H NMR (300 MHz, CDCl3) 1.82 (t, 1H), 4.37 (collapsed dd, 2H), 6.25 (t, 1H), 7.34 (d, 2H), 7.44 (d, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[C:5]=1[F:12])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:22][CH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH3:37])=[C:31]([F:38])[C:30]=2[F:39])[CH2:25][CH2:24]1>CN(C=O)C>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:29]([CH:26]2[CH2:27][CH2:28][CH:23]([CH2:22][O:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([F:12])[C:6]=3[F:11])[CH2:24][CH2:25]2)=[C:30]([F:39])[C:31]=1[F:38])[CH3:37]
Reactant: CCOc1ccc(C2CCC(CCl)CC2)c(F)c1F
Reactant: CCOc1ccc(O)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(OCC2CCC(c3ccc(OCC)c(F)c3F)CC2)c(F)c1F
Temperature: 30 °C
Reaction time: 7 h
Yield: 49.7 %

Procedure:
4-Ethoxy-2,3-difluorophenol (6) (2.2 g) and tripotassium phosphate (K3PO4) (11.0 g) were added to DMF (100 ml) under a nitrogen atmosphere, and the stirring was continued at 70° C. The compound (20) (3.0 g) was added thereto, and the stirring was continued at 70° C. for 7 hours. After the reaction mixture obtained had been cooled to 30° C. and separated from the solid by filtration, toluene (100 ml) and water (100 ml) were added thereto and mixed. The mixture was then allowed to separate into organic and aqueous phases. The extraction into an organic phase was carried out. The organic phase obtained was washed with brine and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off, and the residue obtained was purified by means of column chromatography (silica gel/toluene=1/2 by volume). The product was further purified by means of recrystallization (Solmix A-11: heptane=1:2 by volume), giving 2.2 g of 1-(4-ethoxy-2,3-difluorophenyl)-4-(4-ethoxy-2,3-difluorophenoxymethyl)-cyclohexane (No. 828). The yield based on the compound (20) was 74.0%.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]([CH3:11])([CH3:10])[C:8]#[N:9])[CH2:2]2.[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C(OCCCC)CCC.C1COCC1.CO>[CH:5]12[CH2:6][CH:1]1[CH2:2][N:3]([C:7]([CH3:11])([CH3:10])[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:9])[CH2:4]2
Reactant: [Li]c1ccccc1
Reactant: CC(C)(C#N)N1CC2CC2C1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: CC(C)(C(N)c1ccccc1)N1CC2CC2C1
Yield: 44 %

Procedure:
The title compound (393 mg, 44%) was prepared from 2-(3-azabicyclo[3.1.0]hex-3-yl)-2-methylpropanenitrile D15 (583 mg, 3.9 mmol), and phenyllithium in dibutylether (2.15 ml of a 2.0M solution; 4.3 mmol) in THF (7 ml), followed by reaction with sodium borohydride (445 mg, 11.7 mmol) in methanol (10 ml) in a similar manner to that described in D2. 1H NMR (CDCl3) δ: 0.38 (1H, m), 0.66 (1H, m), 0.74 (3H, s), 0.93 (3H, s), 1.30-1.40 (2H, m), 1.74 (2H, bs), 2.67 (2H, m), 2.91 (2H, t, J=8 Hz), 4.03 (1H, s), 7.20-7.30 (3H, m), 7.38 (2H, m).
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[C:11]([NH2:13])=[NH:12].[Cl:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.[C:24]([O:30][CH3:31])(=[O:29])[CH2:25][C:26]([CH3:28])=O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[C:11]1[NH:13][C:26]([CH3:28])=[C:25]([C:24]([O:30][CH3:31])=[O:29])[CH:17]([C:16]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:15]=2[Cl:14])[N:12]=1
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: COC(=O)CC(C)=O
Reactant: Cc1ncsc1C(=N)N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(c2scnc2C)=NC1c1ccc(F)cc1Cl
Yield: 31.6 %

Procedure:
2 mmol 4-methyl-5-thiazolformamidine acetate, 2 mmol 2-chloro-4-fluorobenzaldehyde, 2 mmol methyl acetoacetate and 2.2 mmol sodium acetate were reacted under reflux in 10 ml anhydrous ethanol for 20 hr, concentrated, and then ethyl acetate and water were added to separate the layers. The ethyl acetate layer was dried over anhydrous sodium sulfate, and separated by a column chromatography to obtain 0.24 g of a colorless crystal with mp 145-147° C.; 1H-NMR (400 MHz, DMSO-d6) δ 2.34 (3H, s); 2.38 (3H, s); 3.50 (3H, s); 5.95 (1H, s); 7.12-7.49 (3H, m); 9.08 (1H, s); 9.61 (1H, s); MS (EI) 379.0 (M+).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[C:2]=[O:3].[CH3:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]1[N:31]=[CH:32][N:33]=[CH:34][C:25]2=1.CCN(C(C)C)C(C)C>C1COCC1.CO>[CH3:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=2)=[O:3])=[CH:17][C:16]=1[C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]1[N:31]=[CH:32][N:33]=[CH:34][C:25]2=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-c1ccc2[nH]c3ncncc3c2c1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc2[nH]c3ncncc3c2c1
Temperature: 25 °C

Procedure:
To 1-isocyanato-3-(trifluoromethyl)benzene (9.8 μl, 0.070 mmol) was added a solution of 4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)aniline (17.5 mg, 0.064 mmol) and DIPEA (16 μL, 0.089 mmol) in THF (0.4 mL). The reaction was stirred at ambient temperature until LCMS indicated complete reaction, typically 16 hours. The reaction mixture was diluted to a total of 2 mL with THF and MeOH and purified by preparative LCMS to recover the product as a TFA salt (17.1 mg, 46.6%). 1H NMR (300 MHz, DMSO): δ 13.1 (bs, 1H), 9.66 (s, 1H), 9.15 (s, 2H), 8.92 (s, 1H), 8.33 (s, 1H), 8.01 (s, 1H), 7.72 (d, 1H), 7.62 (dd, 1H), 7.4-7.6 (m, 3H), 7.2-7.4 (m, 3H), 2.21 (s, 3H). MS (EI) m/z=462 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[NH:5]2.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[N:5]2[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1
Reactant: CC1Nc2cc(Br)ccc2-n2cccc21
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)N2c3cc(Br)ccc3-n3cccc3C2C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
A solution of 7-bromo-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (225 mg, 0.86 mmol) in methylene chloride (4 mL), under nitrogen, was treated with m-anisoyl chloride (219 mg, 1.28 mmol) followed by triethyl amine (0.24 mL, 1.72 mmol). The reaction was stirred at 25° C. for 15 h, after which time the reaction was washed with a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was concentrated in vacuo. The product was purified via Biotage Horizon® (25S, silica, gradient from 5% EtOAc/hexane to 40% EtOAc/hexane) to yield 287 mg (84%) of 7-bromo-5-(3-methoxybenzoyl)-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline as a white foam. MS (ESI) m/z 397/399 ([M+H]+); HRMS: calcd for C20H17BrN2O2, 396.0473; found (ESI+), 397.05389.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C:18]3=[O:23])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:26](C)=O.[Na+].C=O.C(O)(=O)C.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:26])[CH2:19][C:18]3=[O:23])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3=O)cn2)c1=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C(=O)C1
Reaction time: 4 h
Yield: 60.3 %

Procedure:
To a solution of 1-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)piperazin-2-one (332e) (500 mg, 1.32 mmol) in methanol (20 mL) was added Na(OAc)3BH (2.0 g, 13.2 mmol), formaldehyde (30% aq., 8 mL), and acetic acid (2.7 mL, 45 mmol). The mixture was stirred for 4 h. The pH of the reaction mixture was adjust to 11˜13 by adding NaOH (1M). It was then extracted with methylene chloride three times. The combined organic exact was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The residue was purified by silica-gel column eluting with 50:1 methylene chloride/methanol to afford 332f as a gray solid (312 mg, 60%). MS: [M+H]+ 393. 1H NMR (500 MHz, CDCl3) δ 8.61 (d, J=2.5 Hz, 1H), 8.17 (d, J=2.5 Hz, 1H), 7.88 (s, 1H), 7.45 (dd, J=9 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 6.74 (d, J=9 Hz, 1H), 3.64 (m, 2H), 3.53 (s, 3H), 3.22 (s, 2H), 2.74 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([NH:18][NH:19][C:20](=O)[CH:21]([CH3:23])[CH3:22])=[N:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Na+]>P(Cl)(Cl)(Cl)=O>[CH:21]([C:20]1[N:16]2[CH:17]=[C:12]([C:11]3[O:10][CH:9]=[N:8][C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:13]=[CH:14][C:15]2=[N:18][N:19]=1)([CH3:23])[CH3:22]
Reactant: CC(C)C(=O)NNc1ccc(-c2ocnc2-c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1nnc2ccc(-c3ocnc3-c3ccccc3)cn12
Temperature: 75 °C
Yield: 42.7 %

Procedure:
Isobutyric acid N′-[5-(4-phenyl-oxazol-5-yl)-pyridin-2-yl]-hydrazide (730 mg, 2.26 mmol) was taken up in phosphorous oxychloride (10 mL) and heated at 75° C. for 18 hours. The reaction was cooled with an ice bath, added to a beaker of water (50 mL), and the mixture was made basic by dropwise addition with 3 N sodium hydroxide. The basic mixture was extracted with ethyl acetate (3×); the combined organic layers were washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to a yellow oil. The residue was recrystallized from ethyl acetate/methanol (95/5) affording the title compound as yellow crystals (294 mg, 43%). The filtrate was purified by flash chromatography (eluting with ethyl acetate/methanol 97:3) to give more of the title compound (220 mg, 32%). LCMS (m/z) 305 M+1. 1H NMR (400 MHz, CDCl3) δ8.22 (s 1 H), 8.05 (s, 1 H), 7.84 (d, 1 H, J=9.8 Hz), 7.64-7.66 (m, 2 H), 7.44 7.49 (m, 4 H), 3.29-3.34 (m, 1 H), 1.51 (d, 6 H, J=7.2 Hz).
Reaction SMILES: C([Li])CCC.C([Mg]Cl)CCC.Br[C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([Br:19])[CH:18]=1.CN([CH:24]=[O:25])C>CCOCC.CCCCCC.C1(C)C=CC=CC=1>[Br:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([OH:20])[CH:16]=1)[CH:24]=[O:25]
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=Cc1cc(O)cc(Br)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a toluene solution (1.6 M) of n-butyl lithium (2.5 M hexane solution, 2.1 eq.) was added at −10° C. n-butyl magnesium chloride (2.0 M THF solution, 0.6 eq.). The reaction mixture was stirred at −10° C. for 30 min before a toluene solution (0.7 M) of 3,5-dibromophenol (1 eq.) was added dropwise at −10° C. over a period of 35 min. After stirring at −10° C. for a further 30 min, the reaction mixture was cooled to −40° C. before DMF (20 eq.) was added dropwise over 20 min. The reaction mixture was then slowly warmed to rt and allowed to stir at rt for 1 h. The reaction was carefully quenched at 0° C. with 10% aqueous HCl and extracted with ether. The combined organic extracts were washed with water and brine and dried over MgSO4. Concentration of the filtrate in vacuo afforded a yellow solid. Recystallization of the crude product in ether/hexane afforded the title compound as a beige powder.