Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[Br:22]Br>C(Cl)(Cl)(Cl)Cl>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([Br:22])[C:1]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(OCc1ccccc1)C(Br)C(=O)OCc1ccccc1

Procedure:
To a solution of dibenzyl malonate (9.8 g, 34.46 mmole) in carbon tetrachloride (25 mL), bromine (10.14 g, 63.4 mmole) was added dropwise at room temperature over 4 h. The reaction mixture was irradiated with a 150 W lamp during the addition. The reaction mixture was quenched with water. The organic layer was separated and the aqueous layer was further extracted with dichloromethane (3 ×30 mL). The organic extracts were combined, washed with sodium hydrogen carbonate solution (3×50 mL) and brine solution 3×50 mL). The organic layer was dried over magnesium sulphate and concentrated. The residue was purified by column chromatography (9:1 Hex:EtOAc) to afford intermediate 2 as an orange oil. Yield 3.8 g, 30%
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[CH3:24]>>[CH3:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[NH:14][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(-c2cccnc2)n1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1

Procedure:
Thus, Imatinib is obtained by a synthetic route comprising reacting 2-chloro-4-(3-pyridyl)-pyrimidine with 2-amino-4-nitro-toluene to obtain N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine, which is subsequently reduced and reacted with 4-(4-methyl-piperazine-1-ylmethyl)-benzoyl chloride to yield the final product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:27]1(=[O:33])(=[O:32])[CH2:31][CH2:30][CH2:29][NH:28]1>>[O:32]=[S:27]1(=[O:33])[CH2:31][CH2:30][CH2:29][N:28]1[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: O=S1(=O)CCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C#N)CC2)c(C)c1
Yield: 92.6 %

Procedure:
Using 5-bromo-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1.24 g) described in Preparation Example 246 and isothiazolidine 1,1-dioxide (0.47 g) and by the reaction and treatment in the same manner as in Example 262, the title compound (1.26 g) was obtained.
Reaction SMILES: [N:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15](=[O:17])[CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[C:18]2[C:23]3[S:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:22]=3[C:21]([N+:31]([O-])=O)=[CH:20][CH:19]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CC(O)=O.[Zn]>[NH2:31][C:21]1[C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][C:23]=2[C:18]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[NH:8][C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:16][C:15]3=[O:17])=[CH:19][CH:20]=1
Reactant: O=c1cc(N2CCOCC2)[nH]c2c(-c3ccc([N+](=O)[O-])c4c3sc3ccccc34)cccc12
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(-c2cccc3c(=O)cc(N4CCOCC4)[nH]c23)c2sc3ccccc3c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
In a round bottom flask, 2-morpholin-4-yl-8-(1-nitro-dibenzothiophen-4-yl)-1H-quinolin-4-one (24)(365 mg; 0.798 mmol) was suspended in AcOH (5 mL). Zinc powder (5223.3 mg; 7.98 mmol) was added to this solution and the reaction was stirred at room temperature overnight. The reaction mixture was filtered through Celite™, washed successively with methanol (4×25 mL) and DCM (4×25 mL). The combined organic layers were evaporated under reduced pressure. The residue was stirred with water (50 mL) and aqueous ammonia (15 mL) was added to the solution. The resultant precipitate was collected by filtration. The residue was dried and did not require further purification. The product was obtained as a yellow solid (291.3 mg). Yield=85.4%. Mass Spec.: (m/z) 428.4 [M+1]+ (Rt=3.83 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:48]=[C:47]([CH3:49])[CH:46]=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:41]([CH3:42])=[CH:40][C:39]([C:43]6[N:48]=[C:47]([CH3:49])[CH:46]=[CH:45][N:44]=6)=[CH:38][C:37]=5[CH3:50])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1ccnc(-c2cc(C)c(Br)c(C)c2)n1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6nccc(C)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-4-methyl-pyrimidine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 26): tR=0.96 min; Mass spectrum (ESI+): m/z=539 [M+H]+.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CO.[CH3:22][C:23]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](=[N:36][O:37][CH3:38])[CH:34]=[O:35]>CCOCC>[CH3:38][O:37][N:36]=[C:33]([C:34]1[O:35][CH:12]=[N:11][CH:10]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][C:24]1[CH:39]=[C:40]([CH3:43])[CH:41]=[CH:42][C:23]=1[CH3:22]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CON=C(C=O)c1ccccc1COc1cc(C)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: CON=C(c1cnco1)c1ccccc1COc1cc(C)ccc1C
Yield: 44.6 %

Procedure:
p-Toluenesulfonylmethylisocyanide (0.23 g, 1.2 mmol), potassium carbonate (0.18 g, 1.3 mmol) and methanol (2 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetaldehyde (0.30 g, 1 mmol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with brine (80 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl oxazol-5-yl ketone O-methyloxime (0.15 g, 44.6%) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CN(C)C=O>[C:7]1([C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1COCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
Morpholine (0.47 g, 5.39 mmol) (Wako Pure Chemical Industries, Ltd.), triphenylchloromethane (1.50 g, 5.39 mmol) (Wako Pure Chemical Industries, Ltd.), and potassium carbonate (0.75 g, 5.39 mmol) (Wako Pure Chemical Industries, Ltd.) were added to N,N-dimethylformamide (5 mL) (Wako Pure Chemical Industries, Ltd.), and the mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the reaction solution, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane (Wako Pure Chemical Industries, Ltd.):ethyl acetate (Wako Pure Chemical Industries, Ltd.)=9:1 as an eluent), to thereby obtain the title compound (0.42 g, 71% yield).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.O=C1C2C(=CC=CC=2)C(=O)[N:14]1[O:23][CH2:24][C:25]1[N:26]([CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:27]2[C:36]3[N:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:30]=[CH:29][C:28]=2[N:37]=1.[OH-].[NH4+:50].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:50][C:29]1[C:28]2[N:37]=[C:25]([CH2:24][O:23][NH2:14])[N:26]([CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:47])[CH3:46])[C:27]=2[C:36]2[N:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N:30]=1
Reactant: CC(C)(C)OC(=O)NCCCn1c(CON2C(=O)c3ccccc3C2=O)nc2cnc3cccnc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCCn1c(CON)nc2c(N)nc3cccnc3c21
Reaction time: 4 h

Procedure:
mCPBA (2.33 g, 13.5 mmol) was added to a suspension of tert-butyl 3-(2-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propylcarbamate (4.86 g, 9.67 mmol) in chloroform (50 mL). The reaction mixture was allowed to stir for 4 hours, then concentrated ammonium hydroxide (27 mL) and p-toluenesulfonyl chloride (2.03 g, 10.6 mmol) were added. The reaction mixture was allowed to stir overnight at room temperature, then was filtered. The filtrate was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with chloroform (2×40 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to afford a brown solid that was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 0-30% CMA in chloroform) to afford 1.00 g of tert-butyl 3-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}propylcarbamate as a yellow solid that contained some minor impurities.
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[CH:12]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:13][CH2:14][CH3:15].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]1([CH2:12][CH2:13][CH:14]2[CH2:15][O:9]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC=Cc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CCC2CO2)cc1
Temperature: 25 °C

Procedure:
3-chlorobenzenecarboperoxoic acid (12.1 g, 54.0 mmol) is added in one portion to a solution of 3-buten-1-ylbenzene (7.15 g, 54.1 mmol) in CH2Cl2 at 0° C. followed by warming to 25° C. overnight. Saturated NaHCO3 was added and the mixture separated and the resulting clear oil (8.0 g, quant.) was carried forward without further purification: LC-MS (ES) m/z=149 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]([C:17]4[C:18]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=5)=[N:19][NH:20][CH:21]=4)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:29]C)=[CH:4][CH:3]=1.[ClH:31].C(OCC)(=O)C>CO>[ClH:31].[ClH:31].[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]([C:17]4[C:18]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=5)=[N:19][NH:20][CH:21]=4)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[OH:29])=[CH:4][CH:3]=1
Reactant: COc1nc2ccc(-c3c[nH]nc3-c3ccc(F)cc3)cc2n1-c1ccc(F)cc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1nc2ccc(-c3c[nH]nc3-c3ccc(F)cc3)cc2n1-c1ccc(F)cc1

Procedure:
15 mg 1-(4-fluorophenyl)-6-[3-(4-fluorophenyl)-1H-4-pyrazolyl]-2-methoxy-1H-benzo [d] imidazole obtained in Example 139 was dissolved in methanol, then 2 mL of 4 N hydrochloric acid/ethyl acetate was added thereto, and the solvent was evaporated. The residue was crystallized from methanol/ether and then washed with ethyl acetate to give 12 mg of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6](OS(C)(=O)=O)[CH2:5][CH2:4]1.[C-:14]#[N:15].[Na+].C(=O)(O)[O-].[Na+].O>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([C:14]#[N:15])[CH2:5][CH2:4]1
Reactant: CON1CCC(OS(C)(=O)=O)CC1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CON1CCC(C#N)CC1
Temperature: 55 °C
Yield: 86.6 %

Procedure:
200 mg Methanesulfonic acid 1-methoxy-piperidin-4-yl ester (from Step 2), 251 mg tetrabutylammonium cyanide and 272 mg sodium cyanide were mixed in 1 ml dimethylsulfoxide, and heated to 55° C. for 18 hours. Then the mixture was cooled to room temperature, 1 ml saturated aqueous sodium bicarbonate and 3 ml water were added, and extracted three times with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated. The residue was purified by chromatography on silica gel with ethyl acetate/cyclohexane (1:1, then 2:1, then pure ethyl acetate) as a solvent. 116 mg 1-methoxy-piperidine-4-carbonitrile was obtained.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[C:12]([C:13](=[O:14])[N:5]2[CH2:4][CH2:3][NH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].O>C1C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][CH:1]1[CH:6]2[C:7]3[C:12]([C:13](=[O:14])[N:5]2[CH2:4][CH2:3][NH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: O=C1c2ccccc2C2CNCCN12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CC1NCCN2C(=O)c3ccccc3C12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
A solution of 1,2,3,4,6,10b-hexahydropyrazino[2,1-a]isoindol-6-one (described in Example 8, 7.5 g, 0.04 mol) in 150 ml of benzene is added to sodium hydride (1.7 g of a 50% dispersion in mineral oil, 0.036 mol) in 200 ml of benzene and stirred at room temperature for 30 min. A solution of ethyl bromoacetate (8.8 g, 0.044 mol) in 150 ml of benzene is added and the reaction is refluxed with stirring for 3 hr and cooled. Water is cautiously added and the benzene layer is separated, washed with water, dried, and evaporated. The residue is chromatographed on silica gel using 50% acetone in benzene and the eluates are evaporated to give 6-oxo-1,2,3,4,6,10b-hexahydropyrazino[2,1-a]isoindole-1-acetic acid ethyl ester (5.5 g), nmr (CDCl3) δ1.3(t), 2.4-2.6(m), 2.8-3.5(m), 4.2(q), 4.6(m) and 7.3-7.7(m).
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[H-].[Na+].[CH2:20](Br)[C:21]#[CH:22].CO>CN(C)C=O>[C:4]1(=[O:12])[N:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:22][C:21]#[CH:20])[C:1](=[O:17])[C:2]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CCOCCO
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: C#CCOCCOCCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a stirred solution of compound 15 (1.39 g, 5.91 mmol) in N,N-dimethylformamide (25 mL) was added NaH (0.33 g, 80%) dropwise. After complete NaH addition, stirring was continued for 0.5 h at room temperature and then cooled to 0° C. Propargyl bromide 4 (1.24 μL, 11.13 mmol) was added, and stirring was continued for 0.5 h at 0° C., then for 2 h at room temperature. After careful addition of methanol to decompose excess NaH, the solvent was evaporated and crude product was purified by flash column chromatography (3:2 to 1:1 to 2:3 hexane-ethyl acetate) to give compound 16 as a solid (591 mg, 36.6%) having an RF of 0.41 (solvent 3:2 hexane-ethyl acetate). See FIG. 9.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]([O:13][C:14]([N:16]([C:24]1[NH:25][CH:26]=[C:27]([CH:29]=[O:30])[N:28]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:15])([CH3:12])[CH3:11]>CN(C=O)C.CCOC(C)=O>[CH3:12][C:10]([O:13][C:14]([N:16]([C:24]1[NH:28][C:27]([CH:29]=[O:30])=[C:26]([Br:8])[N:25]=1)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[O:15])([CH3:9])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C=O)c[nH]1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)c(C=O)[nH]1
Temperature: 50 °C
Yield: 40.9 %

Procedure:
NBS (0.206 g, 1.156 mmol) was added to a solution of bis(1,1-dimethylethyl)(4-formyl-1H-imidazol-2-yl)imidodicarbonate (0.300 g, 0.964 mmol) in DMF (3 mL). The mixture was heated at 50° C. for 3 hrs. The reaction mixture was diluted with EtOAc and washed 2× with water. The organic layer was dried over sodium sulfate and concentrated. Chromatography (EtOAc:hexane) gave the desired product (0.154 g, 41%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 10.54 (br. s., 1H), 9.54 (s, 1H), 1.50 (s, 18H). ES MS: m/z 390.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:8])([CH3:7])[C:4]#[C:5][CH3:6].[Br:9][CH:10]([CH2:14][CH3:15])[C:11](Br)=[O:12].C(N(CC)CC)C.O>ClCCl>[Br:9][CH:10]([CH2:14][CH3:15])[C:11]([NH:2][C:3]([CH3:8])([CH3:7])[C:4]#[C:5][CH3:6])=[O:12]
Reactant: CC#CC(C)(C)N
Reactant: CCC(Br)C(=O)Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC#CC(C)(C)NC(=O)C(Br)CC
Temperature: 3 °C

Procedure:
4-Amino-4-methylpent-2-yne hydrochloride (5.0 g) was dissolved in dry dichloromethane (200 ml) and cooled to 3° C. with stirring. 2-Bromobutyryl bromide (6.25 g) was added followed by the dropwise addition of dry triethylamine (10.93 ml) whilst maintaining the reaction at 5° C. The suspension, which had formed during the reaction, was stirred at ambient temperature for 1 hour and water was added. The organic phase was separated, washed with water, dried over magnesium sulphate then evaporated under reduced pressure. The residue was fractionated by chromatography (silica; hexane/diethyl ether, 3:1 by volume) to give the required product, 5.2 g, as a colourless solid, mp 79–81° C.
Reaction SMILES: [CH2:1]([O:17][C:18]([O:20][CH2:21][C:22](=[CH2:32])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:33][S:34](Cl)(=[O:36])=[O:35].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:17][C:18]([O:20][CH2:21][C:22](=[CH2:32])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][S:34]([CH3:33])(=[O:36])=[O:35])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: C=C(COCCCCCCO)COC(=O)OCCCCCCCCCCCCCCCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(COCCCCCCOS(C)(=O)=O)COC(=O)OCCCCCCCCCCCCCCCC
Reaction time: 2.5 h

Procedure:
3-Hexadecyloxycarbonyloxy-1-(6-hydroxyhexyloxy)-2-methylenepropane (from Preparation 51) (0.54 g) and methanesulfonyl chloride (0.20 g) were stirred in methylene chloride at 0° C. Pyridine (6 ml) was added and stirring continued for 15 minutes at 0° C. and for 2.5 hours at 22° C. Methylene chloride (10 ml) was added, and the organic phase was washed with water (3×15 ml), dried over magnesium sulfate, filtered and evaporated in vacuo to dryness. Purification was achieved by chromatography on silica gel 60 (70-230 mesh, 15 g) eluting with chloroform/ether/pentane 1:1:10 followed by chloroform/ether 1:1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13](I)[N:14]=[C:7]3[C:6]=2[CH:16]=1.[CH:17]([N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)([CH3:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:24]4[N:20]([CH:17]([CH3:19])[CH3:18])[N:21]=[CH:22][N:23]=4)[N:14]=[C:7]3[C:6]=2[CH:16]=1
Reactant: CC(C)n1cncn1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 100 °C
Yield: 5.7 %

Procedure:
To 10-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.5 g, 3.8 mmol), 1-isopropyl-1H-1,2,4-triazole (0.40 g, 3.0 mmol), CuI (1.8 g, 9.5 mmol), Pd(OAc)2 (0.071 g, 0.32 mmol), and cesium carbonate (2.6 g, 7.9 mmol) was added DMF (20 mL). The reaction mixture was allowed to stir and heat at 100° C. for 24 hours in a sealed vial. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through celite. The filtrate was concentrated under reduced pressure. To the crude residue was added EtOAc and the solid was collected by filtration. The filtrate was concentrated and the crude material was dissolved in DMF and purified by reverse phase HPLC to provide 187 (64 mg, 5%). 1H NMR (400 MHz, DMSO) δ 8.43 (dd, J=47.5, 31.0, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.60-7.39 (m, 1H), 7.04 (d, J=8.7, 1H), 5.74 (dt, J=13.2, 6.6, 1H), 4.76-4.33 (m, 4H), 1.49 (d, J=6.6, 6H). MS (ESI(+)): m/z 374.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[C:11](O)(=[O:14])[C:12]#[CH:13].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[C:3]([CH3:10])[CH:4]=1)(=[O:14])[C:12]#[CH:13]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CC(=O)Oc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
To a stirred solution of 4-bromo-3,5-dimethylphenol (40.87 g, 203.3 mmol) and propiolic acid (20.91 g, 298.5 mmol) in CH2Cl2 (400 mL) was added DCC (50.78 g, 246.1 mmol) in CH2Cl2 (100 mL) and DMAP (0.82 g, 6.7 mmol) at 0° C. The mixture was stirred at room temperature for 3 h and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexanes:EtOAc:CH2Cl2=20:1:10). The fractions containing the desired compound were concentrated. To the concentrate added hexane and the precipitated solid was collected by filtration. The solid was washed with hexane and dried to give the title compound 6-1 (26.12 g, 51% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.[F-].[K+]>O1CCOCC1>[Cl:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([C:11]([F:22])([F:21])[F:10])[CH:17]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Oc1ccc(Br)c(Cl)c1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: Oc1ccc(-c2cccc(C(F)(F)F)c2)c(Cl)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
4-Bromo-3-chlorophenol (518 mg, 2.5 mmol), 3-(trifluoromethyl)phenylboronic acid (617 mg, 3.25 mmol), potassium fluoride (435 mg, 7.5 mmol) palladium acetate (28 mg, 0.125 mmol) and S_phos (102 mg, 0.25 mmol) were stirred in dioxane (10 mL) at 80° C. for 4 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The EtOAc was dried over MgSO4 and evaporated. The residue was resubjected to the reaction conditions and was redissolved in dioxane (10 mL). 3-(trifluoromethyl)phenylboronic acid (380 mg, 2 mmol), potassium fluoride (348 mg, 6 mmol) palladium acetate (14 mg, 0.0625 mmol) and S_phos (51 mg, 0.125 mmol) were added and the reaction stirred at 80° C. for a further 4 hours. The reaction mixture was worked up as before and the crude product was chromatographed on silica eluting with a gradient of heptane:ethyl acetate 100:0 to 75:25. Fractions containing product were evaporated. The resulting material was chromatographed on silica eluting with a gradient of cyclohexane:triethylamine:isopropyl alcohol 95:5:0 to 95:5:10 to give the title compound (310 mg, 1.14 mmol, 45%) as a colourless gum.