Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][CH:8]2[CH2:10][CH2:9]2)=[C:4]([CH3:13])[CH:3]=1.[CH2:14](I)[CH3:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][N:7]([CH:8]2[CH2:9][CH2:10]2)[CH2:14][CH3:15])=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CNC1CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCN(Cc1ccc(Br)cc1C)C1CC1
Temperature: 60 °C

Procedure:
A mixture of (4-bromo-2-methyl-benzyl)-cyclopropyl-amine (Intermediate 158, 600.0 mg, 2.49 mmols), ethyl iodide (1.56 g, 10.0 mmols), and K2CO3 (690.0 mg, 5.00 mmols) in 10 mL acetone was heated at 60° C. for 18 hours. The mixture was cooled to room temperature, diluted with H2O, and extracted with EtOAc. The combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound was isolated by column chromatography (2.5% EtOAc-hexanes).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[C:18](=[O:20])[CH3:19].O>C(OCC)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: COc1nc(Br)ccc1I
Reactant: CC(=O)N(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: COc1nc(Br)ccc1C(C)=O
Temperature: -40 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of 6-bromo-3-iodo-2-methoxypyridine (500 mg) in diethyl ether (15 mL) was cooled to −80° C. in a nitrogen atmosphere, and n-butyllithium (2.6 M, 0.735 mL) were added dropwise. After stirring at the same temperature for one hour, N,N-dimethylacetamide (0.37 mL) was added dropwise. The mixture was warmed to −40° C. over 1.5 hours to complete the reaction. Water and ethyl acetate was added to the reaction system. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give the title compound as a colorless powder (284 mg, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.OC1C=CC(CC(O)=O)=CC=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:64][C:65]([O:68][C:69]([NH:71][C@H:72]([C:76]1[CH:81]=[CH:80][C:79]([OH:82])=[CH:78][CH:77]=1)[C:73](O)=[O:74])=[O:70])([CH3:67])[CH3:66]>C(Cl)Cl.CN(C)C=O>[OH:82][C:79]1[CH:80]=[CH:81][C:76]([C@@H:72]([NH:71][C:69](=[O:70])[O:68][C:65]([CH3:66])([CH3:64])[CH3:67])[C:73](=[O:74])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)=[CH:77][CH:78]=1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1ccc(O)cc1
Yield: 91 %

Procedure:
Preparation of example 153 from the title compound of Example 7 (hydrochloride) (42 mg, 0.134 mmol), (2R)-({[(1,1-dimethylethyl)oxy]carbonyl)}amino)(4-hydroxyphenyl)ethanoic acid (54 mg, 0.202 mmol), triethylamine (0.056 mL, 0.402 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (77 mg, 0.202 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Additional (2R)-({[(1,1-dimethylethyl)oxy]carbonyl}amino)(4-hydroxyphenyl)ethanoic acid (27 mg, 0.10 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39 mg, 0.10 mmol) were added after 24 hours to drive the reaction to completion. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (48 mg, 0.091 mmol) as a yellow powder in 68% yield.
Reaction SMILES: [CH3:1][O:2][Si:3]([O:10][CH3:11])([O:8][CH3:9])[CH2:4][CH2:5][CH2:6]Cl.[N-:12]=[N+:13]=[N-:14].[Na+].[N-]=[N+]=[N-]>CO>[CH3:1][O:2][Si:3]([O:10][CH3:11])([O:8][CH3:9])[CH2:4][CH2:5][CH2:6][N:12]=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CO[Si](CCCCl)(OC)OC
Agent: [Na+]
Solvent: CO
Product: CO[Si](CCCN=[N+]=[N-])(OC)OC

Procedure:
To a 2 liter, 3-necked round bottom glass flask fitted with a stirrer, heating mantle, reflux condenser, and nitrogen inlet source was charged 99 grams (0.5 mole) of a 3-trimethoxysilylpropylchloride, 112 grams (1.72 moles) sodium azide and 1 liter of methanol. The mixture was stirred at reflux temperature for 11 days, cooled to about 10 C. in a wet-ice bath and filtered. The filtrate was concentrated under vacuum on a steam bath. The semi-solid sludge was treated with 0.2 liter n-heptane, filtered and again concentrated under vacuum on a warm water bath. Continued distillation gave a 62 mole % yield of product (74 C./63 mm) comprised of 92 wt.% azide product and 8 wt.% 3-trimethoxysilylpropylchloride.
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5]C(C)(C)C)=O.[H-].[Na+].[C:18]([C:20]1([N:25]([C:31]2[CH:32]=[N:33][N:34]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH:35]=2)[C:26](=[O:30])[CH:27]=[C:28]=[CH2:29])[CH2:24][CH2:23][O:22][CH2:21]1)#[N:19]>C1COCC1>[CH3:29][C:28]1[C:27]2[C:26](=[O:30])[N:25]([C:31]3[CH:32]=[N:33][N:34]([CH2:36][C:37]([F:40])([F:38])[F:39])[CH:35]=3)[C:20]3([CH2:24][CH2:23][O:22][CH2:21]3)[C:18]=2[NH:19][C:3](=[O:5])[C:2]=1[C:1]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: C=C=CC(=O)N(c1cnn(CC(F)(F)F)c1)C1(C#N)CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c2c([nH]c(=O)c1C(=O)OC(C)(C)C)C1(CCOC1)N(c1cnn(CC(F)(F)F)c1)C2=O
Reaction time: 0.33 h
Yield: 52.4 %

Procedure:
As shown in step 24-iii of Scheme 24, to a solution of ditert-butyl propanedioate (3.579 g, 3.705 mL, 16.55 mmol) in THF (50 mL) at 23° C. was added NaH (496.4 mg, 12.41 mmol). After stirring for 20 minutes, a solution of Compound 2076 (2.70 g, 8.275 mmol) in THF (50 mL) was added. After 1 hour, the reaction was quenched with saturated aqueous ammonium chloride (100 mL) and partitioned between water and EtOAc (150 mL each). The organics were separated, washed with brine (200 mL) containing 1 N HCl (10 mL aq), washed with brine (150 mL), dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by medium pressure silica gel chromatography (0-100% EtOAc in hexanes) to provide intermediate tert-butyl 4′-methyl-2′,5′-dioxo-6′-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1′,2′,4,5,5′,6′-hexahydro-2H-spiro[furan-3,7′-pyrrolo[3,4-b]pyridine]-3′-carboxylate (2.03 g, 4.334 mmol) as a pale yellow solid: ESMS (M+H) 469.31; 1H NMR (DMSO-d6, 300 MHz) δ 12.80 (br s, 1H), 8.16 (s, 1H), 7.80 (s, 1H), 5.17 (q, J=9, 2 H), 4.18 (d, J=12, 1 H), 3.90 (m, 2H), 3.75 (m, 1H), 2.45 (m, 1H), 2.44 (s, 3H), 2.33 (m, 1H), 1.52 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:31][CH2:32][N:33]([C:12]([C:3]3[C:2]([OH:1])=[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=[N:10]4)=[CH:5][CH:4]=3)=[O:14])[CH2:34][CH2:35]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: O=C(c1ccc2cccnc2c1O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In a similar manner to Example 4 except for the use of 8-hydroxyquinoline-7-carboxylic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:7]1=[O:36].[S:40]1[CH:44]=[CH:43][CH:42]=[C:41]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:7](=[O:36])[N:6]2[CH2:5][C:4]2[CH:37]=[CH:38][CH:39]=[C:2]([C:41]3[S:40][CH:44]=[CH:43][CH:42]=3)[CH:3]=2)=[CH:17][CH:16]=1)#[N:19]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(Cc2cccc(Br)c2)C1c1ccc(C#N)cc1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(Cc2cccc(-c3cccs3)c2)C1c1ccc(C#N)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A solution of ethyl 3-(3-bromobenzyl)-4-(4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-5-carboxylate (Example 35) (40 mg, 0.07 mmol), 2-thiophen-boronic acid (10.69 mg, 0.08 mmol), 2 M aqueous sodium carbonate (100 μl, 0.2 mmol) and bis(triphenylphosphine)palladium(II)chloride (4.7 mg, 0.01 mmol) in dimethylformamide (2.0 ml) is stirred at 90° C. overnight (16 h). Additional bis(triphenylphosphine)palladium(II) chloride (4.7 mg, 0.01 mmol) is added, and the reaction is stirred at 90° C. for another 24 h, after which time additional bis(triphenylphosphine)palladium(II) chloride (4.7 mg, 0.01 mmol) is added and the reaction stirred 3 h longer at 90° C. The reaction mixture is diluted with dimethylformamide (5 ml) and purified directly by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10). The product fractions are concentrated and pulled through a thin layer of silica gel 60 with dichloromethane as eluent. Concentration in vacuo gives the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][P:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19](I)[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:16])[CH:7]([P:8]([O:10][CH2:11][CH3:12])([O:13][CH2:14][CH3:15])=[O:9])[CH2:19][CH3:20])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCI
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
Diethylphosphonoacetic acid tert-butyl ester (1.0 g, 4.0 mmol) was dissolved in N,N-dimethylformamide (1.4 and 60% sodium hydride (0.17 g, 4.4 mmol) was added at 0° C. After stirring at room temperature for 30 minutes, the reaction mixture was cooled again to 0° C., ethyl iodide (0.33 mL, 4.1 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with 0.5N hydrochloric acid, water and saturated brine, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=57/43) to give the title compound (0.92 g, 3.3 mmol, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Si](C)(C)C)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23].C(=O)([O-])[O-].[K+].[K+].[Br:30]Br>ClCCCl>[NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Br:30])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23]
Reactant: BrBr
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)cc2)c(C)c(N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(Br)cc2)c(C)c(N)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.5 %

Procedure:
To methyl 4-amino-3-chloro-5-methyl-6-(4-(trimethylsilyl)phenyl)picolinate (150 mg, 0.43 mmol) and potassium carbonate (215 mg, 1.56 mmol) in 1,2-dichloroethane (DCE, 2.9 mL) was added bromine (0.03 mL, 0.58 mmol) and stirred at room temperature for 18 h. The DCE was concentrated off under vacuum and the crude material was partitioned between ethyl acetate and aqueous potassium carbonate. The aqueous layer was extracted with ethyl acetate (3×), washed with water, dried over anhydrous magnesium sulfate, filtered, and adsorbed onto silica gel. Purification by flash chromatography (0-40% ethyl acetate/hexanes) afforded the title compound as a yellow solid (68 mg, 45%).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[O:7])[CH2:4][CH2:5][CH3:6].[N+:8]([CH3:11])([O-:10])=[O:9]>>[N+:8]([CH2:11][CH2:1][CH2:2][C:3](=[O:7])[CH2:4][CH2:5][CH3:6])([O-:10])=[O:9]
Reactant: C=CC(=O)CCC
Reactant: C[N+](=O)[O-]
Product: CCCC(=O)CCC[N+](=O)[O-]

Procedure:
To 53.4 g (544 mmol) of 1-hexen-3-one in 250 mL of methanol and 294 mL (5440 mmol) of nitromethane was added as a slow, steady stream 30 mL (136 mmol) of 25% NaOMe in methanol. The resultant yellow solution was warmed to −5° C. over 1 h, and kept between −5° C. and −10° C. for an additional 3 h. The solution was warmed to 0° C. for 1 h and was then quenched with 250 mL of saturated NH4Cl. The mixture was diluted with 200 mL brine to aid in layer separation, and extracted with ether (2×250 mL). The combined ether extracts were washed with Brine, dried with MgSO4, filtered and concentrated to give 75.7 g (88%) of a yellow liquid. 1H NMR revealed the presence of ca. 10% of 7-nitro-trideca-4,10-dione arising from the combination of one molar equivallent of nitromethane with two molar equivallents of 1-hexen-3-one. The products are insepararable by silica gel chromatography (EtOAc/hexanes), so the material was generally used in the next step without purification. Title compound: mass spectrum m/e=144 (M−1).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[CH3:17])=[C:6]([NH:18][C:19](=O)[CH2:20][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=1.Cl.O>O1CCOCC1>[CH3:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[N:10]1[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:27])=[CH:5][C:6]=2[N:18]=[C:19]1[CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(NC2CCCCC2C)c(NC(=O)Cc2cccs2)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CCCC[C@H]1n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Temperature: 135 °C
Yield: 92 %

Procedure:
0.77 g 4-(2-Methyl-cyclohexylamino)-3-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester were reacted with 5 ml of 4M hydrochloric acid in dioxane at 100° C. in a microwave reactor for 5 min. 1 ml water was added and the mixture was heated to 135° C. for 15 min. The reaction was concentrated and the residue purified by chromatography (silica, ethyl acetate/heptane) to yield 0.65 g (91%) of 1-((1R,2R)-2-Methyl-cyclohexyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:19][CH:7]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][N:6]2[C:5]1=[O:20].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]1[CH2:19][CH:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[C:5]1=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)N(CCO)CC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N(CCO)CC2CNCCN12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(2-hydroxyethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate (Compound 67-D) (1 mmol) was dissolved in CH2Cl2 (3 mL) followed by the slow addition of TFA (1 mL) at 0° C. The reaction mixture was stirred at rt for 1 hour and then the solvent was removed in vacuum to give the crude product 70-A, which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][CH:18]=1>>[N:17]1([C:2]2[N:7]=[C:6]([NH:8][C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C[C@@H](Nc1cncc(Cl)n1)c1ccccc1
Product: C[C@@H](Nc1cncc(-n2cnc3ccccc32)n1)c1ccccc1
Yield: 57.6 %

Procedure:
In a procedure analogous to example 12, reaction of 6-chloro-N-[(1R)-1-phenylethyl]pyrazin-2-amine (240 mg, 1.03 mmol) and benzimidazole (130 mg; 1.10 mmol) furnished the product (187 mg, 59%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[C:4]([F:10])[C:3]=1[N+:11]([O-])=O.CCOC(C)=O>C(O)C.Cl.[Fe]>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[C:4]([F:10])[C:3]=1[NH2:11]
Reactant: O=[N+]([O-])c1c(F)c(Br)cc(F)c1Br
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1c(F)c(Br)cc(F)c1Br
Temperature: 80 °C

Procedure:
2,5-Dibromo-3,6-difluoronitrobenzene (120 g, 0.37 mol) is dissolved in a mixture of ethanol (300 mL) and concentrated HCl (500 mL). The mixture is heated to 80° C. and treated with iron powder (100 g, 1.78 mol) by portion-wise addition over 2 hours. After stirring for an additional hour, the mixture is cooled to room temperature and EtOAc (800 mL) is added. The solids are removed by filtration and then the solution concentrated by rotary evaporator to remove most of the solvent. The residue is partitioned between EtOAc (1000 mL) and water (500 mL). The organic layer is washed with brine (2×250 mL), dried (MgSO4) and concentrated by rotary evaporator to give a brown oil. The crude product is then purified using flash chromatography (9:1 hexanes/EtOAc) to give 2,5-dibromo-3,6-difluoroaniline.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[CH3:22].[F-].[Cs+].[CH2:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1B(O)O)[CH2:26][CH2:27][CH3:28]>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.COCCOC>[CH2:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][C:35]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[CH3:22])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCOc1ccc(OC)cc1B(O)O
Reactant: COC(=O)CCc1cccc(OCc2ccc(Br)c(C)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CCCCOc1ccc(OC)cc1-c1ccc(COc2cccc(CCC(=O)OC)c2)cc1C
Temperature: 85 °C
Yield: 94.6 %

Procedure:
To a 2 dram vial charged with 1.3 (0.0200 g, 0.0551 mmol), tetrakis(triphenylphosphine)palladium (0) (0.0127 g, 0.0110 mmol), cesium fluoride (0.0102 mL, 0.275 mmol), and 2-butoxy-5-methoxyphenylboronic acid 4.2 (0.0247 g, 0.110 mmol), was added DME (1 mL). The resulting mixture was then heated at 85° C. overnight. The reaction was allowed to cool and then filtered and concentrated. The crude was purified by combiflash (0 to 20% EtOAc/hexanes) yielding 4.3 (0.0241 g, 95% yield).
Reaction SMILES: [OH:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:11](Cl)(=[O:20])[C:12]1[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([O:1][CH2:2][P:3]([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])=[O:10])=[O:20]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCOP(=O)(CO)OCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(COC(=O)c1ccccc1OC)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of diethyl (hydroxymethyl)phosphonate (1.2 mmol), 2-anisoyl chloride (1 mmol) and pyridine (2 mmol) in 5 mL CH2Cl2 were stirred at rt for 4 h. Extraction and chromatography provided diethylphosphonomethyl 2-methoxybenzoate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:15])[C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[O:14].[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:11]1[CH:10]=[C:9]([CH:13]=[O:14])[N:8]([C:7]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[Cl:15])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccn1-c1c(Cl)cncc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)cn1-c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
To a solution of 2.14 g of 1-(3,5-dichloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde in 10 ml of N,N-dimethylformamide was added 1.7 g of N-bromosuccinimide. The mixture was stirred at room temperature for 2 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 2.9 g of 4-bromo-1-(3,5-dichloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=2)[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[CH:20][CH:19]=1>>[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]2[NH:16][C:11]3[CH:10]=[C:9]([C:1]4[CH:2]=[C:3]([NH2:8])[C:4]([NH2:7])=[CH:5][CH:6]=4)[CH:14]=[CH:13][C:12]=3[N:15]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Reactant: Nc1ccc(C(=O)O)cc1
Product: Nc1ccc(-c2nc3ccc(-c4ccc(N)c(N)c4)cc3[nH]2)cc1

Procedure:
Prepared by Method 1, using a 1:1 ratio of biphenyl-3,3′,4,4′-tetramine to 4-aminobenzoic acid and a reaction time of 2 h.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([NH:20][C:21]2[C:22](=[CH:40]N(C)C)[O:23][C:24]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)=[CH:27][C:25]=3[N:26]=2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C>[C:1]([O:5][C:6](=[O:44])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[CH:40]=[C:22]3[C:21]([NH:26][C:25]4[C:24]([O:23]3)=[CH:30][CH:29]=[C:28]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[CH:27]=4)=[N:20][C:18]2=[O:19])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C1Oc2ccc(CCc3cccc(F)c3)cc2N=C1NC(=O)NC1CCN(CCCNC(=O)OC(C)(C)C)CC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCCN1CCC(n2cc3c(nc2=O)Nc2cc(CCc4cccc(F)c4)ccc2O3)CC1
Temperature: 100 °C

Procedure:
A solution of {3-[4-(3-{2-dimethylaminomethylene-6-[2-(3-fluoro-phenyl)-ethyl]-2H-benzo[1,4]oxazin-3-yl}-ureido)-piperidin-1-yl]-propyl}-carbamic acid tert-butyl ester (310 mg, 0.510 mmol, 1 equiv) in acetic acid (15 mL) was placed in a microwave reactor vessel. The reaction was placed under an argon atmosphere then heated to 100° C. in a microwave reactor for 90 min. LCMS analysis indicated the desired product was obtained, but partial loss of Boc had occurred. The acetic acid solution was concentrated then the residue was dissolved in tetrahydrofuran (25 mL) and treated with potassium carbonate (600 mg, 4.34 mmol, 8.5 equiv) and di-tert-butyl dicarbonate (190 mg, 0.872 mmol, 1.7 equiv). After stirring for 30 min at 23° C. the reaction mixture was partitioned between ethyl acetate and water (60 mL each). The organic layer was separated and washed with saturated brine solution (50 mL) then dried (MgSO4), filtered and concentrated. The residue was dissolved/suspended in 1:1 ethyl acetate:heptane (10 mL, hot). After cooling the solid was collected via filtration. The solid was adsorbed onto silica gel (5 g) then purified using an Isco CombiFlash automated chromatography system. The product was eluted through and 40 g silica gel cartridge with 2 M ammonia in methanol in dichloromethane (0-8% 2 M ammonia in methanol linear gradient over 24 column volumes at a flow rate of 40 mL/min) to give 94 mg (0.167 mmol, 33%) of the title compound as a pale yellow solid.