Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[C:12]([O:15][C:16]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH:24]([O:29][C:30](=[O:32])[CH3:31])[O:25][C:26](=[O:28])[CH3:27])=[CH:18][C:17]=1[O:33][CH3:34])(=[O:14])[CH3:13]>O>[C:12]([O:15][C:16]1[C:17]([O:33][CH3:34])=[CH:18][C:19]([CH:24]([O:25][C:26](=[O:28])[CH3:27])[O:29][C:30](=[O:32])[CH3:31])=[C:20]([N+:1]([O-:4])=[O:2])[C:21]=1[O:22][CH3:23])(=[O:14])[CH3:13]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(OC(C)=O)OC(C)=O)cc(OC)c1OC(C)=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C(OC(C)=O)OC(C)=O)c([N+](=O)[O-])c(OC)c1OC(C)=O
Temperature: -15 °C
Yield: 96 %

Procedure:
32 cm3 of 100% nitric acid are cooled to -30° C. 100 cm3 of acetic anhydride then 40 g (0.123 mole) of 4-acetoxy-1-diacetoxymethyl-3,5-dimethoxybenzene are added with stirring. The temperature is left to increase to about -15° C. After stirring at this temperature for 30 minutes, the reaction mixture is poured into iced water. After filtration, washing with water and drying under vacuum, 43.8 g of the desired product are obtained in the form of a slightly yellow powder (yield=96%).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C(NC(C)C)(C)C.[Br:13][C:14]1[N:19]=[C:18]([CH2:20][C:21]#[N:22])[CH:17]=[CH:16][CH:15]=1.BrCCBr>C1COCC1.O.C(OCC)(=O)C>[Br:13][C:14]1[N:19]=[C:18]([C:20]2([C:21]#[N:22])[CH2:2][CH2:1]2)[CH:17]=[CH:16][CH:15]=1
Reactant: N#CCc1cccc(Br)n1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: BrCCBr
Product: N#CC1(c2cccc(Br)n2)CC1
Temperature: 0 °C

Procedure:
n-Butyllithium (6.66 ml, 10.7 mmol) was added to a cooled (0° C.) solution of diisopropylamine (1.52 ml, 10.7 mmol) in THF (10 mL) and maintained at 0° C. for 30 minutes. The reaction was then cooled to −78° C. and a solution of (6-bromopyridin-2-yl)acetonitrile (Example 235, Step 1) (1 g, 5.08 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction was maintained at −78° C. for 1 hour, and then 1,2-dibromoethane (0.92 ml, 10.7 mmol) was added. The reaction was allowed to warm to room temperature and maintained at room temperature for 3 days. The mixture was then diluted with water and ethyl acetate and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography afforded the title compound.
Reaction SMILES: C[Si](C)(C)[O:3][CH2:4][CH2:5][N:6]([CH2:19][CH3:20])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>CO.C1COCC1.C1COCC1>[OH:3][CH2:4][CH2:5][N:6]([CH2:19][CH3:20])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1
Reactant: CCN(CCO[Si](C)(C)C)c1ccc(C#C[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#Cc1ccc(N(CC)CCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of 5.0 g, that is 15 mmole of 4-[(2-trimethylsiloxyethyl)ethylamino]trimethylsilylethynylbenzene, prepared in the previous step, dissolved in 60 mL of methanol-THF (1:1) mixture, 33 ml, that is 33 mmole, of 1M tetrabutylammonium fluoride in THF, from Aldrich Chemical Co. was added dropwise. The solution was stirred at room temperature for 1 hour. Ethyl ether was added and the mixture was extracted with water. The organic layer was separated, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude product was flash column chromatographed on silica gel with 35% ethyl acetate-hexane to produce 2.5 g of a viscous yellow oil at an 88% yield.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([Cl:10])[CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CCCCCCC.C(Cl)(Cl)Cl>O1CCCC1.O.[Cl-].[Na+].O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:10][C:4]1[CH:3]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCCCCCC
Product: O=Cc1ccc(-c2ccccc2)cc1Cl
Temperature: 80 °C
Yield: 66.7 %

Procedure:
To a solution of 5 g (22.78 mmol) of 4-bromo-2-chlorobenzaldehyde in 30 ml of tetrahydrofurane are successively added 3.47 g (28.47 mmol) of phenylboronic acid, 4.72 g (34.17 mmol) of potassium carbonate dissolved in 15 ml of water and 263 mg (0.01 equivalent) of tetrakis(triphenylphosphine) palladium. The reaction mixture is heated at 80° C. for 3 hrs. The reaction mixture is then cooled to ambient temperature and poured on 150 ml of brine. The watery layer is extracted three times with dichloromethane and the combined organic layers are successively washed by a 1M solution of sodium hydroxide, brine and filtered over a ChemElut cartridge to yield after concentration 4.6 g of a brown solid. Column chromatography (gradient heptane/chloroforme) yielded 3.29 g (65% yield) of 3-chlorobiphenyl-4-carbaldehyde as a white solid; mp=90-91° C.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:22]([NH:24][C@H:25]([C:27](O)=[O:28])[CH3:26])=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH2:30]([O:32][CH:33]([O:45][CH2:46][CH3:47])[CH2:34][C@@H:35]([NH2:44])[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH3:31]>>[CH2:46]([O:45][CH:33]([O:32][CH2:30][CH3:31])[CH2:34][C@@H:35]([NH:44][C:27](=[O:28])[C@H:25]([CH3:26])[NH:24][C:22](=[O:23])[C@H:17]([C@H:18]([CH2:20][CH3:21])[CH3:19])[NH:16][C:14](=[O:15])[C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH:4][C:1](=[O:3])[CH3:2])[CH2:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH3:47]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(C)=O)C(=O)N[C@@H](C)C(=O)O
Reactant: CCOC(C[C@@H](N)CC(=O)OC(C)(C)C)OCC
Product: CCOC(C[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(C)=O)[C@@H](C)CC)OCC

Procedure:
0.24 g (0.6 mmol) of acetyl-L-tyrosyl-L-isoleucyl-L-alanine (Example 7, Step A2) and 0.16 g (0.6 mmol) of (3R)-3-amino-4-t-butoxycarbonyl-butyraldehyde diethyl acetal (Example 1, Step B4) are coupled and the end product is isolated according to the method described in Example 1, Step 1, using proportional amounts of reagents and solvents.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[CH:40]=[CH:39][O:38][CH:37]=3)(=[O:35])=[O:34])[C:27]=2[F:41])[CH:5]=[CH:4][N:3]=1.[CH3:42][Zn]C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[F:41][C:27]1[C:28]([NH:32][S:33]([C:36]2[CH:40]=[CH:39][O:38][CH:37]=2)(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][C:26]=1[C:9]1[N:10]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[S:12][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:42])[N:7]=1
Reactant: C[Zn]C
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nccc(-c2sc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
1,1-dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)-amino]phenyl}-1,3-thiazol-2-yl)-1-piperidinecarboxylate (150 mg, 0.242 mmol) was dissolved into 1,4-dioxane (3 mL) and the solution was degassed for 10 min. PdCl2(dppf)-CH2Cl2 adduct (13.83 mg, 0.017 mmol) and dimethylzinc (0.242 mL, 0.484 mmol) were added to the reaction mixture. The reaction mixture was stirred at 80° C. for 1 h. The reaction was quenched with methanol (3 mL) and water (10 mL) and extracted with EtOAc (3×). The extract was dried over Na2SO4, filtered, and concentrated. The residue was purified using column chromatography (40% to 100% EtOAc/hexane) to give the title compound (118 mg). MS (ESI): 600.3 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=4[O:23][C:24]([F:27])([F:26])[F:25])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:28]([O:30]CC)=O)=[N:3]1.[Cl-].[NH4+].[Li][N:36]([Si](C)(C)C)[Si](C)(C)C>O1CCCC1>[CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=4[O:23][C:24]([F:25])([F:26])[F:27])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:28]([NH2:36])=[O:30])=[N:3]1
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(Br)cc3OC(F)(F)F)nc1-2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nc(C(N)=O)c2c1-c1nc(Nc3ccc(Br)cc3OC(F)(F)F)ncc1CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Ethyl 1-methyl-8-(2-trifluoromethoxy-4-bromophenylamino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (330 mg, 0.64 mmol) was suspended in 10 mL of tetrahydrofuran. Ammonium chloride (106 mg 2.0 mmol) and LiN(TMS)2 1 N in THF (4.0 mL, 4.0 mmol) were added. The mixture was stirred at room temperature for 0.5 h. The solvent was then evaporated to dryness, the residue suspended in water and filtered to afford 288 mg (93% yield) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O[C:21]1[CH:30]=CC(C(OC)=O)=C[CH:22]=1.C1(CCO)C=CC=CC=1>>[C:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=2)[CH:3]=[CH:2][CH:30]=[CH:21][CH:22]=1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Reactant: COC(=O)c1ccc(O)cc1
Solvent: OCCc1ccccc1
Product: O=C(O)CNC(=O)c1ccc(OCCc2ccccc2)cc1
Yield: 74 %

Procedure:
The same reactions as in Example 9 (9a) and (9b) were conducted using methyl 4-hydroxybenzoate (2.23 g, 14.7 mmol) and 2-phenylethanol (1.80 mL, 15.1 mmol) to give 3.23 g of the title compound (light yellow powder, yield: 74%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Br.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([NH:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[S:21][C:22]=2[CH3:23])=[CH:14][CH:13]=1.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:19]=[C:20]([N:24]3[C:25]([CH3:29])([CH3:28])[CH2:26][O:27][C:31]3=[O:33])[S:21][C:22]=2[CH3:23])=[CH:16][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1sc(NC(C)(C)CO)nc1-c1ccc(Br)cc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(N2C(=O)OCC2(C)C)nc1-c1ccc(Br)cc1
Reaction time: 2 h
Yield: 1270.7 %

Procedure:
Diisopropylethylamine (10.0 mL, 57.4 mmol) was added under nitrogen to a mixture of 2-{[4-(4-bromophenyl)-5-methyl-1,3-thiazol-2-yl]amino}-2-methylpropan-1-ol hydrobromide (5.2 g, 1.2 mmol), prepared in the previous step, and 120 mL of methylene chloride at room temperature. A white solid formed. The mixture was cooled to ice bath temperature and triphosgene (5.2 g, 1.8 mmol) in 60 mL of methylene chloride was added dropwise over approximately 2 h. After the addition, the reaction became homogeneous. The reaction was stirred at ice bath temperature for approximately 2 h and then at room temperature overnight. The reaction was extracted with aqueous sodium hydroxide and the solvent removed under reduced pressure to give 5.6 g of a solid. Purification of the solid on a Horizon™ Flash Collector (the Biotage FLASH 25+™ cartridge) using a linear gradient of 36% methylene chloride in hexane to 75% methylene chloride in hexane gave the title compound (2.77 g, 63%) as a white solid, mp 175-176.5° C.; MS (ESI) m/z 367 [M+H]+. Anal. Calcd for C15H15BrN2O2S: C, 49.06; H, 4.12; N, 7.63. Found: C, 48.94; H, 4.19; N, 7.56.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:49])[C@@H:24]([NH:25][C:26](=[O:48])/[C:27](/[C:35]4[N:36]=[C:37]([NH:40]C(OC(C)(C)C)=O)[S:38][CH:39]=4)=[N:28]\[O:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:50][CH2:51][S:52][C:53]2[N:54]=[N:55][NH:56][CH:57]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.O>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.C(O)C>[NH2:40][C:37]1[S:38][CH:39]=[C:35](/[C:27](=[N:28]/[O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)/[C:26]([NH:25][C@@H:24]2[C:23](=[O:49])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:50][CH2:51][S:52][C:53]4[N:54]=[N:55][NH:56][CH:57]=4)[CH2:19][S:20][C@H:21]23)=[O:48])[N:36]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2CCCC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCSc4c[nH]nn4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Solvent: C[N+](=O)[O-]
Product: Nc1nc(/C(=N/OC2CCCC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCSc4c[nH]nn4)CS[C@H]23)cs1
Reaction time: 0.83 h
Yield: 52.5 %

Procedure:
To a suspension of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-cyclopentyloxyiminoacetamido]-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (258 mg: 0.304 mMol.) in a mixture of anisole (1 ml) and nitromethane (4 ml) at -30° C. is added a solution of aluminum chloride (0.25 g: 1.88 mMol.) in anisole (1 ml), and the mixture is stirred for 50 minutes. The reaction mixture is diluted with ethanol (2 ml), stirred at the same temperature for 5 minutes, mixed with 1N-hydrochloric acid (4 ml) and water (200 ml), and stirred at room temperature for 5 minutes. The aqueous layer is taken, washed with ethyl acetate, concentrated under reduced pressure to remove remaining organic solvents, and subjected to chromatography over styrene-divinylbenzene copolymer (methanol : water=4:1) to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-cyclopentyloxyiminoacetamido]-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid (93 mg) as white solid. Yield: 53%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([Cl:14])[CH:4]=1.[C-:15]#[N:16].[K+].C(O)C>O>[Cl:14][C:5]1[CH:4]=[C:3]([CH2:2][C:15]#[N:16])[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: [C-]#N
Reactant: CCOC(=O)c1ccc(CBr)cc1Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(CC#N)cc1Cl
Yield: 16 %

Procedure:
3.1 g (11.2 mmol) of ethyl 4-(bromomethyl)-2-chlorobenzoate are added dropwise to a solution composed of 0.94 g (14.3 mmol) of potassium cyanide, 3.75 ml of water and 8.8 ml of ethanol, heated under reflux. After refluxing for 3 hours, the medium is poured over 200 ml of water, and extracted with ethyl acetate. The organic phase is washed with a dilute HCl solution and then with water saturated with NaCl. The oil obtained after concentration of the organic phase is purified by flash chromatography on silica (hexane-ethyl acetate 1:0 to 1:1 gradient). 0.4 g of a brown solid is obtained (Yield=16%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Br:12][C:13]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([CH2:24][OH:25])=[CH:18]2>C(Cl)Cl>[Br:12][C:13]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([CH:24]=[O:25])=[CH:18]2
Reactant: OCc1ccc2c(Br)cc(F)cc2c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc2c(Br)cc(F)cc2c1
Reaction time: 2 h
Yield: 88 %

Procedure:
Pyridinium chlorochromate (PCC, 1.9 g, 9.0 mmol) was added to a solution of 31 (1.1 g, 4.5 mmol) in DCM (15 mL), and the mixture was stirred for 2 h prior to filtration through a short pad of silica gel. The filtrate was then concentrated rotary evaporation, and purified by column chromatography to give 5-bromo-7-fluoro-2-naphthaldehyde (32) (88%). 1H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 8.34 (d, J=8.8 Hz, 1H), 8.29 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.77 (dd, J=8.0, 2.3 Hz, 1H), 7.64 (d, J=8.6 Hz, 1H). GC-MS (ES) for C11H6BrFO [M+1]+253.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@@H:14]([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:21]=[N:22][C:23]2[C:24](=O)[CH2:25][CH2:26][C:27]=2[CH:28]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl>[Cl:19][C:20]1[CH:28]=[C:27]2[CH2:26][CH2:25][CH:24]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]4([CH3:17])[C@@H:14]([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9]4)[CH:7]=3)[C:23]2=[N:22][CH:21]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COC[C@@H]1F
Reactant: O=C1CCc2cc(Cl)cnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C[C@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)N=C(N)COC[C@@H]1F
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a solution of (5R,6R)-5-(5-amino-2-fluoro-phenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylamine (intermediate A10B) (20 mg, 78.4 μmol) in 1,2-dichloroethane (200 μl) was added at 23° C. under inert atmosphere 3-chloro-5,6-dihydro-[1]pyrindin-7-one (14.4 mg, 86.2 μmol) and acetic acid (9.41 mg, 8.97 μl, 157 μmol) and the solution was stirred at 23° C. for 30 min. Then sodium triacetoxyborohydride (24.9 mg, 118 μmol) was added and the mixture was stirred at 23° C. for 4 h. After addition of 1 M HCl (1 ml) and stirring for 10 min, the aqueous layer was washed once with dichloromethane, then treated with sat. Na2CO3-sol. to achieve pH 14 and extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and evaporated to give a crude product, which was purified by basic preparative HPLC to give (5R,6R)-5-(5-(3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylamino)-2-fluorophenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (11 mg, 27.0 μmol, 34.5% yield) as a colorless oil. MS (ISP): m/z=407.3.3 [(M+H)+] and 409.3 [(M+2+H)+].
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[CH:12]1([C:18]([C:20]2[C:21]([N:26]([CH2:30][CH3:31])[C:27](=[O:29])[CH3:28])=[N:22][CH:23]=[CH:24][CH:25]=2)=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>O>[CH:12]1([C:18]2[C:20]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:26]([CH2:30][CH3:31])[C:27](=[O:29])[CH:28]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCN(C(C)=O)c1ncccc1C(=O)C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)cc(C2CCCCC2)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Under ice-cooling, 2.9 g of 90% potassium tert-butoxide was added to 70 ml of tetrahydrofuran solution containing 6.4 g of N-(3-cyclohexylcarbonyl-2-pyridyl)-N-ethylacetamide, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was mixed with water and extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (toluene-ethyl acetate) to give 4.5 g of 4-cyclohexyl-1-ethyl-1,8-naphthyridin-2(1H)-one.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]([CH3:14])[CH2:3]1.O=[C:16]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:17]([CH:16]([NH:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]([CH3:14])[CH2:3]1)[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CN1CC(N)C(=O)Nc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)NC1CN(C)c2ccccc2NC1=O
Reaction time: 8 h

Procedure:
The 3-amino-5-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one (0.267 g) is dissolved in 5 ml of methanol and 0.288 g of ethyl 2-oxo-4-phenylbutyrate is added. This is followed by the addition of a solution of 88 mg of sodium cyanoborohydride in 3 ml of methanol and 0.8 ml of glacial acetic acid. The reaction is stirred overnight under nitrogen and concentrated. The residue is dissolved in 20 ml of methylene chloride and washed with 10 ml of cold saturated sodium carbonate. After drying over magnesium sulfate the solution is concentrated and the residue purified to give 3-[N-(1-carboethoxy-3-phenylpropyl)amino]-5-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:4]=1[CH:5](O)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1.Cl>[Zn].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:4]=1[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1
Reactant: COc1ccc(OC)c(C(O)c2cccc(N)c2)c1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(OC)c(Cc2cccc(N)c2)c1
Reaction time: 2 h
Yield: 76.7 %

Procedure:
To 300 ml of acetic acid were added 96 g of zinc powder and 50 g of the 2,5-dimethoxy-3'-aminobenzhydrol prepared in (b) then 240 ml of a 35% hydrochloric acid aqueous solution was added dropwise at 80° C. After 30 minutes the same amount of the 35% hydrochloric acid solution was further added. After 2 hours of stirring, the mixture was cooled and the supernatant liquid was separated, to which an aqueous solution of sodium hydroxide was added until the pH became 5. An oily product deposited which was extracted with ethyl acetate and washed with an aqueous solution of sodium bicarbonate. Drying with sodium sulfate followed by distillation under a reduced pressure on an oil bath whereby a distillation fraction boiling in the range 170° to 175° C was collected provided 36 g of crystals with a melting point of 81° to 84° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:29])[CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]2[NH:14][N:15]=[C:16]([CH3:17])[C:11]2=[C:10]([CH2:18][N:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][CH2:21][C:20]2([CH3:28])[CH3:27])[CH:9]=1.CCN(C(C)C)C(C)C.Br[CH2:40][C:41]([O:43][CH3:44])=[O:42].C(OCC)(=O)C>C1COCC1.O>[CH3:44][O:43][C:41](=[O:42])[CH2:40][N:22]1[CH2:21][C:20]([CH3:28])([CH3:27])[N:19]([CH2:18][C:10]2[CH:9]=[C:8]([C:7]3[CH:6]=[CH:5][C:4]([OH:29])=[CH:3][C:2]=3[F:1])[N:13]=[C:12]3[NH:14][N:15]=[C:16]([CH3:17])[C:11]=23)[CH2:24][C:23]1([CH3:25])[CH3:26]
Reactant: COC(=O)CBr
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CC(C)(C)NCC3(C)C)c12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CC(C)(C)N(Cc2cc(-c3ccc(O)cc3F)nc3[nH]nc(C)c23)CC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 30 mg of 3-fluoro-4-[3-methyl-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol in 1 ml of dry THF were added 13 mg of DIPEA and 11 mg of methyl bromoacetate. The reaction was stirred at r.t. for 2 h and then heated in a microwave reactor for 3 h at 120° C. Then ethyl acetate and water were added and the pH was adjusted to 7-8. The phases were separated and the aqueous phase was extracted with ethyl acetate twice. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. After purification by preparative HPLC (C18 column, acetonitrile/water gradient) 12 mg (37%) of the title compound were obtained.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([Cl:19])[N:13]=1>C1COCC1.C(Cl)Cl>[CH2:1]([S:8][C:16]1[CH:15]=[C:14]([Cl:19])[N:13]=[C:12]([NH2:11])[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1nc(Cl)cc(SCc2ccccc2)n1
Reaction time: 8 h
Yield: 39.4 %

Procedure:
Benzylmercaptan (0.14 g, 1.11 mmol) was treated with NaH (60% in mineral oil, 67 mg, 1.66 mmol) in dry THF (15 ml) for 30 minutes. 2-Amino-4,6-dichloropyrimidine (0.2 g, 1.22 mmol) was added and the mixture was stirred overnight. The mixture was diluted with methylenechloride, washed with water, then brine, dried over MgSO4, and concentrated to give 0.11 g of 4-(benzylthio)-6-chloropyrimidin-2-amine.