Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][N:52]([C:55](=[O:57])[CH3:56])[CH2:51][CH2:50]2)=[CH:45][CH:44]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:32]1[CH2:33][CH2:34][CH:29]([CH2:28][NH:27][C:4]2[C:5]3[C:10]([C:11]4[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=4)=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:42][C:43]3[CH:44]=[CH:45][C:46]([N:49]4[CH2:50][CH2:51][N:52]([C:55](=[O:57])[CH3:56])[CH2:53][CH2:54]4)=[CH:47][CH:48]=3)[N:3]=2)[CH2:30][CH2:31]1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NCC4CCN(C(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(NCC4CCNCC4)c4c(-c5ccncc5)c[nH]c4n3)cc2)CC1
Temperature: 135 °C
Reaction time: 68 h
Yield: 33 %

Procedure:
A mixture of tert-butyl 4-((2-chloro-5-(pyridine-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (90 mg, 0.15 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (66 mg, 0.30 mmol) and TMSCl (0.100 mL, 0.79 mmol) in nBuOH (4 mL) was stirred at 135° C. for 68 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (26 mg). MS 526.47 (M+H); UV 202.6, 259.2, 304.3 nm.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:36])([CH3:35])[C:23]([O:25]CC1C=CC(OC)=CC=1)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:36])([CH3:35])[C:23]([OH:25])=[O:24])=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COc1ccc(COC(=O)C(C)(C)CCCOC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(C)(C)C(=O)O
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate (8.24 g, 16.5 mmol) in CH2Cl2 (100 mL) at room temperature, was added trifluoroacetic acid (5 mL). After 1 h at room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 3→5% MeOH in CH2Cl2), to give 6.00 g of 5-(N-CBz-L-valyloxy)-2,2-dimethylvaleric acid. The compound can be activated and directly esterified to a drug or further modified as described below.
Reaction SMILES: C(O)(=O)CCCC.NC1C=CNC(=O)C=1N(C1C=CC(C2C=CC=CC=2C2NN=NN=2)=CC=1)C.[NH2:35][C:36]1[C:37](=[O:50])[NH:38][CH:39]=[CH:40][C:41]=1[NH:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Br[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]#[N:66])=[CH:55][CH:54]=1>>[CH2:43]([NH:42][C:41]1[CH:40]=[CH:39][NH:38][C:37](=[O:50])[C:36]=1[NH:35][CH2:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]#[N:66])=[CH:57][CH:58]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: Nc1c(NCc2ccccc2)cc[nH]c1=O
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: CN(c1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1c(N)cc[nH]c1=O
Solvent: CCCCC(=O)O
Product: N#Cc1ccccc1-c1ccc(CNc2c(NCc3ccccc3)cc[nH]c2=O)cc1

Procedure:
A mixture of 1.02 g of valeric acid, 3.59 g of 4-amino-2-oxo-3-[2'-(tetrazol-5-yl)biphenyl-4-yl-methylamino]-1,2-dihydropyridine (obtainable by reacting 3-amino-4-benzylamino-1,2-dihydro-2-oxopyridine with 4-bromomethyl-2'-cyanobiphenyl to give 4-benzylamino-3-(2'-cyanobiphenyl-4-ylmethylamino)-1,2-dihydro-2-oxopyridine, reacting the latter with trimethyltin azide according to Example 13 to give 4-benzylamino-3-[2'-(tetrazol-5-yl)biphenyl-4-ylmethylamino-1,2-dihydro-2-oxopyridine, and removing the benzyl group by hydrogenolysis] and 50 g of polyphosphoric acid is heated at 140° for 5 hours. 4-amino-2-oxo-3-[N-2'-(tetrazol-5-yl)biphenyl-4-ylmethyl-N-valerylamino]-1,2-dihydro-pyridine and 2-oxo-3-[2'-(tetrazol-5-yl)biphenyl-4-ylmethylamino]-4-valerylamino-1,2-dihydropyridine are formed in situ as intermediates. The mixture is cooled, poured on to ice, rendered alkaline with sodium hydroxide solution and worked up in conventional manner to give 2-butyl-4-oxo-3-[2'-(tetrazol-5-yl)biphenyl-4-ylmethyl]-4,5-dihydro-3H-imidazo[4,5-c]pyridine, m.p. 167°.
Reaction SMILES: COC1C=C(C=CC=1OC)C[N:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:14]=2)[C:10](=O)[C:9]([C:27]#[N:28])=[CH:8]1.[Cl-:34].[Li+]>O=P(Cl)(Cl)Cl>[Cl:34][C:10]1[C:9]([C:27]#[N:28])=[CH:8][N:7]=[CH:12][C:11]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:14]=1
Reactant: COCCOc1cc(-c2cn(Cc3ccc(OC)c(OC)c3)cc(C#N)c2=O)ccc1OC
Reactant: [Cl-]
Agent: [Li+]
Solvent: O=P(Cl)(Cl)Cl
Product: COCCOc1cc(-c2cncc(C#N)c2Cl)ccc1OC
Yield: 78.2 %

Procedure:
A solution of 1-(3,4-dimethoxybenzyl)-5-[4-methoxy-3-(2-methoxyethoxy)phenyl]-4-oxo-1,4-dihydro-pyridine-3-carbonitrile (300 mg, 0.666 mmol) and lithium chloride (LiCl, 254 mg, 6 mmol) in 2.5 mL of POCl3 was heated at reflux for 2.5 h. The excess POCl3 was removed by evaporating in vacuo and then was co-evaporated with toluene. The residue was dissolved in 100 mL ethyl acetate and washed with ice-cold 1 N aqueous sodium hydroxide. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated in vacuo, and the resulting solid was triturated with isopropyl alcohol to yield 166 mg (78% yield) of 4-chloro-5-[4-methoxy-3-(2-methoxyethoxy)phenyl]-nicotinonitrile as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:16]N1C(=O)CCC1=O>CC#N.CCOC(C)=O>[CH2:9]([O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:16])[CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To a stirred solution of 2-amino-3-benzyloxypyridine (42.0 g, 0.21 mol) in CH3CN (600 mL) at 0° C. was added N-bromosuccinimide (37.1 g, 0.21 mol) over 30 minutes. The mixture was stirred for 0.5 hr, after which the reaction was then diluted with EtOAc (900 mL) and partitioned with H2O (900 mL). The organic layer was washed with brine and dried (Na2SO4), filtered and concentrated to dryness under vacuum to yield 3-benzyloxy-5-bromo-pyridin-2-ylamine (31.0 g, 0.11 mol, 53%). 1H NMR (CDCl3, 300 MHz) δ 4.63-4.78 (brs, 2H), 5.04 (s, 2H), 7.07 (d, 1H, J, 1.8 Hz), 7.33-7.42 (m, 5H), 7.73 (d, 1H, J, 1.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:33])[CH:9]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[CH2:10][NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:34]([S-:36])#[N:35].[K+].BrBr>C(O)(=O)C>[C:12]([NH:11][CH2:10][CH:9]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:22][CH2:21]1)[CH:8]([OH:33])[C:5]1[CH:4]=[CH:3][C:2]2[N:1]=[C:34]([NH2:35])[S:36][C:7]=2[CH:6]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(C(O)C(CNC(=O)c2ccccc2)N2CCC(Cc3ccccc3)CC2)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(C(O)C(CNC(=O)c3ccccc3)N3CCC(Cc4ccccc4)CC3)cc2s1
Reaction time: 2 h

Procedure:
To a stirred solution of 5.3 g of (+) threo 1-(p-amino-phenyl)-2-(4-benzylpiperidin-1-yl)-3-benzoylaminopropan-1-ol and 4.6 g of KSCN in 100 ml of glacial acetic acid was added dropwise a solution of 1.95 g of Br2 in 25 ml of glacial acetic acid at room temperature. After stirring for 2 h., the yellow sospension was filtered and the solution was poured into 100 ml of concentrated ammonium solution. The cloudy basic solution was extracted with ethyl acetate dried and evaporated. The residue was chromatographed on silica gel elutin with ethylacetate/cyclohexane ½, providing providing 3.7 g of the title compound, m.p. 160-162° C., [α]20D=+20.3±0.5.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:12])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16]>>[CH3:16][CH2:15][CH:14]([NH:13][C:2]1[C:3]([NH2:12])=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:11]=1)[CH2:17][CH3:18]
Reactant: Nc1nc2ccccc2nc1Cl
Reactant: CCC(N)CC
Product: CCC(CC)Nc1nc2ccccc2nc1N
Temperature: 120 °C
Yield: 78 %

Procedure:
A thick-walled microwave bottle equipped with a stirbar was charged with 3-chloroquinoxalin-2-amine (1.0 equiv) and 20 volume equivalents of 3-aminopentane. The bottle was fitted with a septum and cap and heated to 120° C. in a microwave for 30 min. The resulting solution was concentrated in vacuo. Flash chromatography (20%-60% EtOAc/Hexanes) provided the title compound (78%) as a yellow solid. LCMS m/z (APCI)=231.1 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:14]Br.CO.O>C(O)(=O)C.Br>[Br:14][CH2:2][C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C(=O)CBr)cc1
Temperature: 15 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
At 15° C., methyl 4-acetylbenzoate (2.23 g) was dissolved in a hydrobromic acid acetic acid solution (30%, 10 ml). Bromine was gradually added dropwise to the reaction mixture to maintain its temperature at 15° C. After stirring for 10 minutes, the reaction mixture was cooled to 4° C. A mixed solvent of methanol (50 ml) and water (50 ml) was added to the reaction mixture for crystallization, followed by washing with hexane. By the collection through filtration, the title compound (2.29 g, 71%) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=O.[NH:15]1[CH2:21][C:19](=[O:20])[NH:18][C:16]1=[O:17].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=[C:21]1[NH:15][C:16](=[O:17])[NH:18][C:19]1=[O:20]
Reactant: COc1cc(OC)c(OC)cc1C=O
Reactant: O=C1CNC(=O)N1
Solvent: NCCO
Solvent: O
Product: COc1cc(OC)c(OC)cc1C=C1NC(=O)NC1=O
Yield: 93.3 %

Procedure:
A mixture of 2,4,5-trimethoxybenzaldehyde (2.503 g.) and hydantoin (1.275 g., 1 molar ratio) in water (15 ml) was heated to 70°. Monoethanolamine (1.17 g.) was added and the suspension was stirred and heated at 90°-92° (bath temperature) for 4 hours. Isolation in the usual manner gave the title compound as a yellow solid (3.306 g.), m.p. 276°-277° decomp. Crystallization from dioxane did not raise the melting point.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:23]([C:25]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:28]=[CH:27][C:26]=1O)#[N:24].C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([O:20][C:26]3[CH:27]=[CH:28][C:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:30][C:25]=3[C:23]#[N:24])=[O:19])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Reactant: CCCCCCCCCCc1ccc(O)c(C#N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCCCCCc1ccc(OC(=O)c2ccc(-c3ncc(CCCCCCC)cn3)cc2)c(C#N)c1

Procedure:
29.8 g of 4-(5-heptylpyrimidin-2-yl)-benzoic acid (obtained from 4-(5-heptylpyrimidin-2-yl)-benzonitrile by saponification) and 25.9 g of 2-cyano-4-decylphenol are esterified with one another as described in Example 22 with addition of 21.0 g of dicyclohexylcarbodiimide. 2-Cyano-4-decylphenyl 4-(5-heptylpyrimidin-2-yl)-benzoate is obtained.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([N:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:18]=[O:19].[H-].[Na+]>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][C:10]([N:12]1[CH2:16][CH2:15][N:14]([CH2:18][OH:19])[C:13]1=[O:17])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC(=O)N1CCNC1=O)OCC
Reactant: C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)N1CCN(CO)C1=O)OCC

Procedure:
264 Gm (1 mol) of 1-(Diethylphosphonoacetyl)-imidazolidin-2-one and 33 gm of paraformaldehyde (1.1 mol) were dissolved in 2.5 liters of tetrahydrofuran; and after the addition of about 0.3 gm of sodium hydride, the solution was refluxed for one hour. After the solvent had been distilled off, there remained 1-(diethylphosphonoacetyl)-3-hydroxymethylimidazolidin-2-one as a yellowish, viscous liquid. The determination of the total formaldehyde and the free formaldehyde gave a degree of hydroxymethylation amounting to 100%. The compound had the formula ##EQU12##
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7](#[N:10])[CH:8]=[CH2:9]>CO>[C:7]([CH2:8][CH2:9][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6])#[N:10]
Reactant: C=CC#N
Reactant: NCCCCN
Solvent: CO
Product: N#CCCNCCCCN
Reaction time: 12 h
Yield: 79.8 %

Procedure:
To a solution of 1,4-diaminobutane (8.6 g, 97.6 mmol) in methanol (3.0 ml) was added a solution of acrylonitrile (6.2 g, 116.8 mmol) in methanol (3.0 ml) at 0° C., and the mixture was stirred for 12 hours. Evaporation of the solvent in vacuo afforded N-(2'-cyanoethyl)-1,4-diaminobutane as a colorless oil (11.0 g, 80%). 1H NMR (400 MHz, CDCl3) δ: 1.45 (4H, br, --CH2CH2 --), 2.46 (2H, t), 2.58 (2H, t), 2.62 (2H, t) and 2.84 (2H, t).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:11](=[O:10])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1
Reactant: Cc1nc(N)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(NC(=O)OC(C)(C)C)n1
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 6-chloro-2-methylpyrimidin-4-amine (1.0 equiv.) in THF (0.17M) was added BOC2O (1.1 equiv.) and DMAP (cat.). The reaction was allowed to stir overnight, then concentrated to a yellow crude, and filtered through a pad of SiO2 eluting with EtOAc and hexanes (1:1) to afford an off-white solid (78%). LCMS (m/z): 244.1 (MH+); LC Rt=3.69 min.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[C:24]([F:25])=[CH:23][C:13]2[O:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[CH:17]=[N:18][C:12]=2[CH:11]=1.CCOCC>C1(C)C(C)=CC=CC=1>[Br:9][C:10]1[C:24]([F:25])=[CH:23][C:13]2[O:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C@H:17]3[C@H:2]([C:1]([OH:7])=[O:8])[CH2:3][CH2:4][C:5](=[O:6])[N:18]3[C:12]=2[CH:11]=1
Reactant: O=C1CCCC(=O)O1
Reactant: Fc1cc2c(cc1Br)N=Cc1ccccc1O2
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: O=C(O)[C@@H]1CCC(=O)N2c3cc(Br)c(F)cc3Oc3ccccc3[C@@H]12
Temperature: 140 °C
Yield: 74.6 %

Procedure:
Glutaric anhydride (7.2 g, 63 mmol) was added to a stirred solution of 8-bromo-7-fluoro-dibenz[b,f][1,4]oxazepine (46.5 mmol) in xylene (26 mL) and the mixture was heated to 140° C. for 120 h. The reaction mixture was allowed to cool to ambient temperature, ether was added and the solution extracted (3×) with 2M NaOH. The pH of the combined extracts was adjusted to pH 4 by adding 3M hydrochloric acid. The product was collected by filtration and dried to yield the title compound (14.1 g, 81%) which was used without further purification. 1H-NMR (400 MHz, CDCl3) 2.03-2.14 (m, 1H), 2.31-2.4 (m, 1H), 2.53-2.62 (m, 1H), 2.67-2.81 (m, 1H), 3.55-3.60 (m, 1H), 5.46-5.49 (m, 1H), 7.05-7.09 (d, J=8.6, 1H), 7.11-7.32 (m, 4H), 7.56-7.59 (d, J=7.8, 1H). (m/z)=406+408 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([OH:13])[CH3:12])[CH:10]=1)[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:6]=[CH:5]2.[Cl:22][C:23]([Cl:27])([Cl:26])[C:24]#[N:25].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>ClCCl>[Cl:22][C:23]([Cl:27])([Cl:26])[C:24](=[NH:25])[O:13][CH:11]([C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]2[C:8]=1[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[N:6]=[CH:5]2)[CH3:12]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: ClCCl
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Reaction time: 0.5 h

Procedure:
To a solution of (±)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethanol (575 mg, 1.55 mmol) and trichloroacetonitrile (1.55 mL, 15.5 mmol) in dichloromethane (15 mL) at room temperature was added diazabicycloundecene (50 μL, 0.33 mmol). After stirring 30 min, the reaction was concentrated and purified by column chromatography (10% EtOAc/Hex+0.5% Et3N) to give 780 mg (98%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 8.30 (s, 1H), 7.92 (d, J=2.4, 1H), 7.79 (d, J=1.5, 1H), 7.69 (d, J=1.8, 1H), 6.67 (q, J=6.4, 1H), 6.25 (d, J=11.6, 1H), 5.70 (d, J=11.6, 1H), 3.42-3.60 (m, 3H), 1.76 (d, J=6.4, 3H), 1.19 (m, 2H), 0.75-1.02 (m, 2H), -0.06 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.2, 135.6, 133.1, 128.0, 127.9, 127.6, 123.2, 114.8, 91.4, 80.2, 72.7, 66.1, 22.5, 17.8, −1.4.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=1[F:21])=[O:4].[OH-].[Na+].Cl>CO.O.CCOC(C)=O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:6]2[N:7]([CH3:12])[C:8](=[O:11])[CH:9]=[CH:10][C:5]=2[C:3]([OH:4])=[O:2])=[C:15]([F:21])[CH:16]=1
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)O)ccc1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester in MeOH (1.5 mL) was added 1 M NaOH (800 uL, 0.902 mmol). The reaction mixture was stirred at 60° C. for 4 hours and then at room temperature for 16 hours. The reaction mixture was diluted with H2O, acidified with 2 M HCl until the pH was 1-2, and then diluted with EtOAc. The organic layer was separated and washed with saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure to yield 0.053 g (97%) desired product as a pale orange solid. MS ESI (+) m/z 341, 343 (M+, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 10.0 (s, 1H), 7.87 (d, 1H), 7.65 (d, 1H), 7.35 (d, 1H), 6.95 (t, 1H), 6.16 (d, 1H), 3.19 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14]C)=O)[NH:9]2)=[CH:5][CH:4]=1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[NH2:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([Cl:49])=[C:37]([O:39][C:40]2[CH:41]=[C:42]([CH:45]=[C:46]([Cl:48])[CH:47]=2)[C:43]#[N:44])[CH:38]=1.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C.O.CO>[Cl:49][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][NH:31][C:12]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)=[O:14])=[CH:38][C:37]=1[O:39][C:40]1[CH:41]=[C:42]([C:43]#[N:44])[CH:45]=[C:46]([Cl:48])[CH:47]=1
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3)[nH]c2c1
Reaction time: 1 h
Yield: 37.8 %

Procedure:
Methyl 6-(methyloxy)-1H-indole-2-carboxylate (0.025 g, 0.13 mmol) was dissolved in THF:methanol:water/1:1:1 (3 mL) and lithium hydroxide (0.01 g, 0.38 mmol) was added. The reaction was stirred for 1 h, at which time another portion of lithium hydroxide (0.01 g, 0.38 mmol) was added. The reaction was stirred for 1 h, acidified with 10% aqueous citric acid to pH 4-5 and extracted with EtOAc (3×5 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. To the crude intermediate was added 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), DIPEA (0.025 mL, 0.13 mmol) and DMF (1 mL) and then stirred overnight. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and evaporated to afford the title compound (0.015 g, 26%) as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.38 (d, 1H), 8.88-8.93 (m, 1H), 7.77 (d, 1H), 7.59 (d, 1H), 7.42-7.48 (m, 2H), 7.35 (d, 1H), 7.26 (dd, 1H), 7.23 (d, 1H), 7.04 (d, 1H), 6.84 (d, 1H), 6.66 (dd, 1H), 4.47 (d, 2H), 3.73 (s, 3H). MS: m/z 466.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[N:32]=[C:31]([C:33]([NH:35][CH2:36][C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=5)=[O:34])[C:30]([OH:44])=[CH:29][CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[C:45]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[CH:28]=[CH:29][C:30]5[O:44][CH2:45][N:35]([CH2:36][C:37]6[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=6)[C:33](=[O:34])[C:31]=5[N:32]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(C(=O)NCc4ccc(F)cn4)n3)cc12
Reactant: O=C([O-])[O-]
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)C(=O)N(Cc3ccc(F)cn3)CO4)cc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
To a solution of 6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-N-((5-fluoropyridin-2-yl)methyl)-3-hydroxypicolinamide (30 mg, 0.05 mmol) and Cs2CO3 (47 mg, 0.14 mmol) in DMF (3 mL) at 100° C. was added chloroiodomethane (13 mg, 0.07 mmol) under N2 protection dropwise. The mixture was stirred at 100° C. for 3 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic phase was dried over Na2SO4 After concentration, the residue was purified by prep-HPLC to give the product of 2-(4-fluorophenyl)-5-(3-((5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydro-2H-pyrido[2,3-e][1,3]oxazin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 60%). 1H-NMR (CDCl3, 400 MHz) δ 8.33 (s, 1H), 7.90˜7.94 (m, 3H), 7.69 (d, J=8.8 Hz, 1H), 7.56 (s, 1H), 7.40˜7.44 (m, 2H), 7.31˜7.36 (m, 1H), 7.13 (t, J=8.8 Hz, 2H), 6.19 (br s, 1H), 5.43 (s, 2H), 4.82 (s, 2H), 3.15 (s, 3H), 2.92 (d, J=4.8 Hz, 3H), 2.85 (s, 3H). MS (M+H)+: 634.
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([C:22](C)(C)[O:23][SiH2]C(C)(C)C)=[CH:21][C:16]=3[N:15]=[C:14]2[NH:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:41]4[CH:42]=[N:43][CH:44]=[CH:45][C:46]=4[O:47][CH3:48])[CH:39]=3)[N:34](COCC[Si](C)(C)C)[N:33]=2)[CH2:9][CH2:8]1)(C)(C)C.Cl>C(O)C>[OH:23][CH2:22][C:20]1[CH:19]=[CH:18][C:17]2[N:13]([CH:10]3[CH2:11][CH2:12][CH:7]([OH:6])[CH2:8][CH2:9]3)[C:14]([NH:31][C:32]3[C:40]4[C:35](=[CH:36][CH:37]=[C:38]([C:41]5[CH:42]=[N:43][CH:44]=[CH:45][C:46]=5[O:47][CH3:48])[CH:39]=4)[NH:34][N:33]=3)=[N:15][C:16]=2[CH:21]=1
Reactant: COc1ccncc1-c1ccc2c(c1)c(Nc1nc3cc(C(C)(C)O[SiH2]C(C)(C)C)ccc3n1C1CCC(O[Si](C)(C)C(C)(C)C)CC1)nn2COCC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Product: COc1ccncc1-c1ccc2[nH]nc(Nc3nc4cc(CO)ccc4n3C3CCC(O)CC3)c2c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 18 %

Procedure:
(1-(4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl)-5-(tert-butyl-dimethyl-silanyloxymethyl)-1H-benzoimidazol-2-yl)-(5-(4-methoxy-pyridin-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-yl)-amine (165 mg, 0.000196 mol) was dissolved in ethanol (6.0 mL). To this solution was added 12 M HCl (2.0 mL) and the reaction was stirred at 100° C. for 1.5 hours. The reaction was evaporated to dryness and the residue was purified by preparative HPLC to yield 17.1 mg of the title compound as the TFA salt.