Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH:7]=[C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[C:17]([NH:19][C:20]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=4)[CH:16]=[C:15]([CH3:30])[CH:14]=3)=[CH:11][N:12]=2)[CH2:5][CH2:4][CH:3]1[C:31]([O:33][CH3:34])=[O:32].[H][H]>[Pd].CO>[CH3:1][C:2]1([CH3:35])[CH2:7][CH:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[C:17]([NH:19][C:20]4[N:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][N:21]=4)[CH:16]=[C:15]([CH3:30])[CH:14]=3)=[CH:11][N:12]=2)[CH2:5][CH2:4][CH:3]1[C:31]([O:33][CH3:34])=[O:32]
Reactant: [H][H]
Reactant: COC(=O)C1CCC(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)=CC1(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCC(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Yield: 60.5 %

Procedure:
10% Palladium on carbon (30 mg, 0.028 mmol) was taken up in methanol (1 mL) under argon. A solution of the product from Step 1 (141 mg, 0.281 mmol) in methanol (3 mL) was then added. A hydrogen balloon was attached and the flask was evacuated and backfilled with hydrogen. The mixture was allowed to stir over the weekend. The reaction was filtered through celite and concentrated under reduced pressure. The resulting residue was taken up in methanol (3 mL) and added to a flask containing 10% Palladium on carbon (30 mg, 0.028 mmol) in 1 mL methanol. A hydrogen balloon was attached and the flask was evacuated and backfilled with hydrogen and stirred for 24 hours. The reaction was filtered through celite and concentrated under reduced pressure. The resulting residue was taken up in methanol (3 mL) and added to a flask containing 10% Palladium on carbon (30 mg, 0.028 mmol) in 1 mL methanol. A hydrogen balloon was attached and the flask was evacuated and backfilled with hydrogen and stirred for one week. The mixture was then filtered through a plug of celite and the celite was washed methanol. The filtrate was concentrated under reduced pressure to afford methyl 2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (87 mg, 0.17 mmol, 62% yield) as a light yellow oily solid. MS ESI: [M+H]+ m/z 505.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[I:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:20]([C:19]3[CH:23]=[CH:24][C:16]([I:15])=[CH:17][CH:18]=3)=[O:21])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(Cl)c1ccc(I)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Yield: 95.6 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 8 and using 1-(3,5-dimethylpyridin-2-yl)piperazine (3.8 g) described in Preparation Example 47 and 4-iodobenzoyl chloride (5.3 g), the title compound (8 g) was obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl.[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])([CH3:15])([CH3:14])[CH3:13]>C(OCC)(=O)C>[C:12]([C:16]1[CH:21]=[C:20]([C:1](=[O:3])[CH3:2])[CH:19]=[CH:18][C:17]=1[OH:22])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1ccc(O)c(C(C)(C)C)c1
Temperature: 0 °C
Yield: 55 %

Procedure:
Acetyl chloride (287 g) was added to a mixture of aluminum chloride (488 g) and methylene chloride (1.8 l) at −60° C. while stirring. 2-tert-Butylphenol (500 g) was added at −70° C. to −50° C. over a period of 1.5 hours, and the temperature was then raised to 0° C. The reaction mixture was poured into ice and extraction was performed with ethyl acetate. The organic layer was washed with brine, the solvent was distilled off under reduced pressure, methanol (1 l) and potassium carbonate (300 g) were added to the residue and the mixture was stirred at room temperature for 2 hours. After adding water to the reaction mixture and neutralizing it with concentrated hydrochloric acid, extraction was performed with ethyl acetate and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane was added to the residue and the resulting crystals were filtered off to yield the title compound (352 g) as white crystals.
Reaction SMILES: [OH2:1].[OH-].[Na+].[OH:4][C:5]1[CH2:9][CH2:8][C:7](=O)[C:6]=1[CH2:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>C(O)(=O)C>[OH:1][CH:8]1[CH2:9][C:5](=[O:4])[C:6]([CH2:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:7]1
Reactant: COC(=O)CCC#CCCC1=C(O)CCC1=O
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)CCC#CCCC1=CC(O)CC1=O
Temperature: 100 °C
Reaction time: 25 h
Yield: 76 %

Procedure:
To the compound [VIII-1] (28.3 g, 0.12 mole) are added water (1200 g) and acetic acid (1.5 g), and the pH value thereof is adjusted to pH 4.4 with 5% aqueous sodium hydroxide solution. The mixture is heated with stirring at 100° C. for 25 hours. After completion of the reaction, the reaction mixture is cooled, extracted twice with methyl isobutyl ketone (300 ml) and separated. Methyl isobutyl ketone is distilled off from the organic layer to give a mixture (21.5 g, yield; 76%) of 4-hydroxy-2-(6-methoxycarbonyl-3-hexynyl)-2-cyclopentenone (racemic 4-hydroxycyclopentenone) and 3-hydroxy-2-(6-methoxycarbonyl-3-hexynyl)-2-cyclopentenone [IX-1] (ratio thereof=6:4).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(O)c1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c1

Procedure:
A solution of 0.65 g (5.4 mmol) 3-hydroxybenzonitrile, 1.5 g (5.3 mmol) of 3-(2-quinolinylmethyloxy)benzyl chloride, and 0.75 g (5.4 mmol) of potassium carbonate in 15 ml of DMF is heated at 60° C. overnight. The reaction mixture is poured into water. The precipitated product is collected on a filter and purified by dry column chromatography to give 3-[3-(2-quinolinylmethyloxy)benzyloxy]benzonitrile. (MP 86-87° C.)
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][C:7]([CH3:11])=[CH:8][CH2:9]Br.[N+:12]([C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)([O-:14])=[O:13]>C(#N)C>[CH3:6][C:7]([CH3:11])=[CH:8][CH2:9][N:16]1[CH:17]=[CH:18][N:19]=[C:15]1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CC(C)=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)=CCn1ccnc1[N+](=O)[O-]

Procedure:
Sodium bicarbonate (0.42 g, 50 mmol) and dimethylallyl bromide (3.28 g, 22 mmol) were added to a suspension of 2-nitroimidazole (2.26 g, 20 mmol) in dry acetonitrile (10 mL). The mixture was stirred under reflux for 16 hours. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was filtered, and dried with anhydrous sodium sulfate. Removal of the solvent gave an oil which was recrystallized from petroleum ether (35-50° C.). Yield 1.83 g, m.p. 48-49° C. 1H NMR (CDCl3) δ7.24 (s, 1H), 7.22 (s, 1H), 5.46 (m, 1H), 5.1 (d, 2H), 1.91 (s, 3H) and 1.90 (s, 3H).
Reaction SMILES: S(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(=O)(=O)C.[NH:20]1[CH2:26][CH2:25][CH2:24][C@@H:21]1[CH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[OH:23][CH2:22][C@H:21]1[CH2:24][CH2:25][CH2:26][N:20]1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)OCCc1ccc(N2CCOCC2)cc1
Reactant: OC[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: OC[C@H]1CCCN1CCc1ccc(N2CCOCC2)cc1
Temperature: 70 °C

Procedure:
4-Morpholinophenethyl mesylate (0.43 g, 1.51 mmol), D-prolinol (0.17 g, 1.66 mmol) and sodium carbonate (0.40 g, 2.89 mmol) were added to acetonitrile (20 ml), and they were stirred under heating at 70° C. overnight. The reaction mixture was cooled and then filtered. The filtrate was evaporated to dryness under reduced pressure, and the residue was distributed into water and ethyl acetate. The intended product was extracted from ethyl acetate layer with 1 M hydrochloric acid. The aqueous layer was neutralized and the product was again extracted with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure to obtain (R)-2-hydroxymethyl-1-(4-morpholinophenethyl)pyrrolidine in the form of a light yellow solid (0.44 g, 1.5 mmol, 100%). This product was dissolved in dichloromethane (10 ml). Triethylamine (0.29 ml, 2.1 mmol) and methanesulfonyl chloride (0.15 ml, 1.9 mmol) were added to the obtained solution at 0° C., and they were stirred at room temperature for 1 hour. The reaction mixture was distributed into 5% aqueous sodium hydrogencarbonate solution and dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (1:1), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(morpholinophenethyl)piperidine in the form of a white solid (0.30 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12](=[O:17])C(F)(F)F)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.[OH-:18].[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([OH:17])=[O:18])=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Cc1[nH]c2cc(Cl)ccc2c1C(=O)C(F)(F)F
Agent: [Na+]
Solvent: O
Product: Cc1[nH]c2cc(Cl)ccc2c1C(=O)O
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of 0.57 g (2.2 mmol) 1-(6-chloro-2-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 21.7 ml (86.8 mmol) aqueous 4 M sodium hydroxide solution was heated at reflux for 45 min. After cooling to room temperature the reaction mixture was diluted with water and extracted with tert-butyl methyl ether (2×50 ml). The aqueous layer was cooled to 0-5° C., acidified (pH 1-2) with concentrated aqueous hydrochloric acid solution and extracted with ethyl acetate (3×100 ml). The combined ethyl acetate layers were dried over sodium sulfate and concentrated in vacuo to give the title compound (0.14 g, 31%) as an off-white solid.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>C1C=CC=CC=1>[C:1]([Cl:22])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Solvent: c1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.9 %

Procedure:
A solution of 20.0 g of linolic acid in 70 ml of dry benzene was placed in a flask and kept swept therein with nitrogen for displacement of the entrapped air and 14.8 g of phosphorus pentachloride was added meanwhile thereto as divided in five split portions. The resultant reaction mixture was stirred at normal room temperature for 12 hours and then refluxed for two hours. Then, the reaction solution was distilled to expel benzene and the products of a secondary reaction, i.e. phosphoryl trichloride and hydrogen chloride and the residue was subjected to vacuum distillation to produce 14.0 g of linolic acid chloride (boiling point 155° C./1.5 mmHg; yield 76%).
Reaction SMILES: [Cl:1][CH:2]([O:4][C:5]([N:7]([CH3:15])[C:8](=[N:11][N+:12]([O-:14])=[O:13])SC)=[O:6])[CH3:3].[Cl:16][C:17]1[S:18][C:19]([CH2:22][NH2:23])=[CH:20][N:21]=1>C(Cl)(Cl)Cl>[Cl:1][CH:2]([O:4][C:5]([N:7]([CH3:15])[C:8]([NH:23][CH2:22][C:19]1[S:18][C:17]([Cl:16])=[N:21][CH:20]=1)=[N:11][N+:12]([O-:14])=[O:13])=[O:6])[CH3:3]
Reactant: NCc1cnc(Cl)s1
Reactant: CSC(=N[N+](=O)[O-])N(C)C(=O)OC(C)Cl
Solvent: ClC(Cl)Cl
Product: CC(Cl)OC(=O)N(C)C(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a stirred solution of N-(1-chloroethoxycarbonyl)-S,N-dimethyl-N'-nitroisothiourea (6.50 g) in CHCl3 (15 ml) was added a solution of 2-chloro-5-thiazolylmethylamine (3.78 g) in CHCl3 (5 ml) dropwise below -20° C. over 20 minutes. After stirring at -20° C. for 30 minutes, insolubles were removed by filtration and the filtrate was concentrated in vacuo. The residue was applied to column chromatography on silica gel. The column was eluted with hexane-AcOEt (1:1) to afford 3.50 g of 1-(1-chloroethoxycarbonyl)-3-(2-chloro-5-thiazolylmethyl)-1-methyl-2-nitroguanidine (Compound No. 12) as an orange oil.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[OH-].[Na+].Cl[C:12](=[CH:17][C:18]([F:21])([F:20])[F:19])[C:13]([F:16])([F:15])[F:14]>CN(C)C=O>[F:14][C:13]([F:16])([F:15])[CH2:12][C:17]1([C:18]([F:21])([F:20])[F:19])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: FC(F)(F)C=C(Cl)C(F)(F)F
Reactant: Oc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
11 g of pyrocatechol were dissolved in 200 ml of dimethylformamide and the solution was treated with 18 g of 45% strength by weight aqueous sodium hydroxide solution. The mixture was treated dropwise at 75° C. with 20 g of 2-chloro-1,1,1,4,4,4-hexafluoro-2-butene. Stirring was continued for 30 minutes at 75° C. The batch was subsequently poured into 500 ml of ice-water and extracted using diethyl ether. The organic phase was washed with water, dried with magnesium sulphate and concentrated. Finally, the product was distilled under a high vacuum. The yield was 15 g (=56%), and the boiling point 60° C. at 10 mbar. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -59.0 and -84.6 ppm. 1H-NMR: 3.02 ppm.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2[N:9]=[C:10]([CH2:49][CH2:50][CH3:51])[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[N:29](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:28]=[N:27][N:26]=4)=[CH:15][CH:14]=3)[C:5]=2[CH:4]1[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH3:2].C(O)(=O)/C=C/C(O)=O>C(O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2[N:9]=[C:10]([CH2:49][CH2:50][CH3:51])[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[NH:29][N:28]=[N:27][N:26]=4)=[CH:15][CH:14]=3)[C:5]=2[CH:4]1[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH3:2]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)N(CC)CC2
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OCC)N(CC)CC2
Yield: 87.8 %

Procedure:
A mixture of ethyl 5-ethyl-2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.10 g), fumaric acid (1.2 g) ane ethanol (20 ml) is refluxed for one hour. The mixture is evaporated, and the residue is dissolved in chloroform, and the mixture is washed with a saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 5-ethyl-2-n-propyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.65 g) as a white foam.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].[CH:16]#[N:17]>>[OH:10][CH:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:16]#[N:17]
Reactant: C#N
Reactant: O=CCCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: N#CC(O)CCc1ccccc1
Reaction time: 0.5 h

Procedure:
In a 300 ml flask, 134 g of 3-phenylpropanal and 1.4 g of 10% aqueous sodium acetate solution were placed, to which 27 g of hydrocyanic acid was added in dropwise maintaining the reaction temperature at 20° to 25° C., thereafter the reaction mixture was kept standing for 30 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=O)=[O:17])[CH3:15])=[CH:10][CH:9]=1.C(C1NC=CN=1)([C:24]1[NH:25]C=CN=1)=O.C(=O)=O.CN>O1CCCC1>[CH3:24][NH:25][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CN
Agent: O=C=O
Solvent: C1CCOC1
Product: CNC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1
Reaction time: 0.33 h

Procedure:
3.06 gm (10 millimols) of [1-(2'-fluoro-4 -biphenylyl)-ethylsulfinyl]-acetic acid of m.p. 164-165° C, were suspended in 50 ml of tetrahydrofuran, and 1.95 gm (12 millimols) of carbonyl-diimidazole were added to the suspension. The acid dissolved, accompanied by carbon dioxide evolution. After 20 minutes, dry methylamine was introduced until the mixture was saturated. After another hour, the mixture was evaporated in vacuo, and the residue was taken up in a mixture of dilute hydrochloric acid and ether. 2.55 gm (80% of theory) of the title compound, m.p. 136-137° C, were obtained from the ether phase after washing, drying, evaporation and recrystallization from toleuen/cyclohexane = 1/1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH3:10].C1COCC1.C([Li])CCC.C(O[B:25]1[O:33][C:30]([CH3:32])([CH3:31])[C:27]([CH3:29])([CH3:28])[O:26]1)(C)C>O>[CH2:9]([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:25]1[O:33][C:30]([CH3:32])([CH3:31])[C:27]([CH3:29])([CH3:28])[O:26]1)[CH3:10]
Reactant: CCSc1ccccc1Br
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A mixture of 14.1 g of 1-bromo-2-ethylsulfanylbenzene and 65 mL of THF was cooled to −70° C., and 44.7 ml of n-butyl lithium (1.63M hexane solvent) was added at a rate such that the internal temperature of the mixture was kept at −60° C. or less, and the mixture was stirred at −50° C. for 30 minutes. A mixture of 14 g of isopropoxyboronic acid pinacol ester and 5 mL of THF was added at a rate such that the internal temperature of the mixture was kept at −60° C. or less, and the mixture was heated to the room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 7.9 g of 2-ethylsulfanylphenylboronic acid pinacol ester.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[C:15]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[O:14][C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[NH:11][C:10]1=[O:25])C1C=CC=CC=1.CO>[OH-].[OH-].[Pd+2].C(O)(=O)C>[NH2:8][CH:9]1[C:15]2([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[O:14][C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[NH:11][C:10]1=[O:25]
Reactant: O=C1Nc2ccccc2OC2(CCCCC2)C1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: NC1C(=O)Nc2ccccc2OC12CCCCC2
Reaction time: 18 h
Yield: 132.8 %

Procedure:
3-(Dibenzylamino)-3H-spiro[benzo[b][1,4]oxazepine-2,1′-cyclohexan]-4 (5H)-one (0.3875 g, 908 μmol, Eq: 1.00) and 20% Pd(OH)2/C (0.47 g, 3.35 mmol, Eq: 3.68) were combined with MeOH (100 mL) and acetic acid (0.1 mL) and the mixture was hydrogenated at 50 psi. After 18 h, the mixture was filtered through Celite, the filtrate concentrated, the residue dissolved in MeCN/H2O and lyophilized to afford of the title compound as an off-white solid (0.297 g, 100%) which was used without purification. MS m/z 247.0 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:27])[C:9]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][N:23]=[C:24]([O:25]C)[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1)[C:5]#[N:6].B(Br)(Br)Br>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:27])[C:9]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][NH:23][C:24](=[O:25])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1)[C:5]#[N:6]
Reactant: COc1nccc2c(Nc3c(Cl)cc(C#N)cc3Cl)nc3ccncc3c12
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 85 °C

Procedure:
To a solution of 3,5-dichloro-4-[(10-methoxypyrido[4,3-c]-1,6-naphthyridin-6-yl)amino]benzonitrile (140 mg, 0.35 mmol) in chloroform (3 mL) was added boron tribromide (2.5 mL, 2.5 mmol, 1M in dichloromethane) and the mixture was heated at 85° C. for 45 min in a sealed tube. After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, followed by brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with MeOH in dichloromethane to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12](I)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.CC1(C)C(C)(C)OB([C:29]2[CH:33]=[CH:32][NH:31][N:30]=2)O1>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:29]4[CH:33]=[CH:32][NH:31][N:30]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Reactant: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Product: NC(=O)c1nc2n(c1-c1cc[nH]n1)CCOc1cc(F)c(Br)cc1-2

Procedure:
10-Bromo-9-fluoro-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (0.2 g) was reacted with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole similar to as described in Example 4 and triturated from water followed by methanol to give 107 mg of 10-bromo-9-fluoro-3-(1H-pyrazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. This intermediate was reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 3.3 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-(1H-pyrazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 396 (M)+.