Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](O)=[N:7][N:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O.C(N(C(C)C)CC)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:15])=[N:7][N:6]=[CH:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nncc2cc(Br)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nncc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
A mixture of 6-bromophthalazin-1(2H)-one (17, 2.6 g, 12 mmol) in phosphorous oxychloride (11 mL, 116 mmol) was treated with diisopropylethylamine (2.0 mL, 12 mmol). The mixture was stirred at room temperature for 30 min, then warmed up to a temperature of between about 95-100° C. and stirred under nitrogen. The suspension (reaction) became a deep brown solution in about 30 min, then a yellow solid precipitated out. After about 3 h, all of the starting material was converted, as appeared by TLC, to product (M+1=243, 245). After the mixture was cooled down to room temperature, it was diluted with 50 mL CHCl3 and cooled down to 0° C. The precipitate was filtrated, washed with 10 mL ice cool CHCl3, collected and dried under vacuum, to afford 1.96 g of 6-bromo-1-chlorophthalazine 18, as yellow solid. Found MS (ES+): 243, 245 (M+H)+.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=O.C([O-])(=O)C.[Na+].O>O1CCCC1>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: O=C(O)C1=CCS[C@@H]2C(NC(=O)C(=NOCc3ccc(F)cc3)c3csc(NC(=O)C(F)(F)F)n3)C(=O)N12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCc2ccc(F)cc2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 111 %

Procedure:
A mixture of 7-[2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-2-(4-fluorobenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.9 g.), sodium acetate (4.1 g.), water (αml.) and tetrahydrofuran (30 ml.) was treated in a similar manner to that of Example 16-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(4-fluorobenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.68 g.), m.p. 203° to 207° C. (dec.).
Reaction SMILES: [CH2:1]1[O:22][C:21]2[CH:20]=[CH:19][C:5]([CH2:6][N-:7][C:8](=O)[CH2:9][CH2:10][N:11]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:4][C:3]=2[O:2]1.B.C1COCC1>C1COCC1>[CH2:1]1[O:22][C:21]2[CH:20]=[CH:19][C:5]([CH2:6][NH:7][CH2:8][CH2:9][CH2:10][N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:17]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(CCN1C=CC=CC=C1)[N-]Cc1ccc2c(c1)OCO2
Agent: B
Solvent: C1CCOC1
Product: C1=CC=CN(CCCNCc2ccc3c(c2)OCO3)C=C1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
3,4-methylenedioxybenzyl-(3-azepin-1-yl-propionyl)-amide (20 g, 69 mmole) was dissolved in THF and treated with a solution of Borane/THF (1M, 138 mL, 138 mmole) and heated to reflux for 5 hours. Added another 60 mL borane/THF and heated for 4 hours. The reaction was cooled to room temperature and quenched by the careful addition of ethanol (20 mL) and then 6 N HCl (100 mL). The mixture was concentrated at reduced pressure and redissolved in 6N HCl (200 mL) and methanol (100 mL) and heated gently for 15 minutes. After cooling the solution was extracted once with ether (100 mL) and then basified to pH 12 with aqueous sodium hydroxide. This was then extracted with ethyl acetate (3×200 mL) and the combined ethyl acetate extracts were dried over anhydrous sodium sulfate, filtered and concentrated at reduced pressure to give 15 g of the product. 1H NMR (CDCl3, 300 MHz) δ6.82 (s, 1H); 6.76 (s, 2H); 5.95 (s, 2H); 3.7 (s, 2H); 2.7-2.46 (m, 8H); 1.7-1.5 (m, 10H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([O:10][CH3:11])=[O:9].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[CH3:11][O:10][C:8](=[O:9])[CH:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COC(=O)Cc1cccn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc([N+](=O)[O-])cc1)c1cccn1C
Temperature: 0 °C
Yield: 96.6 %

Procedure:
Methyl 1-methylpyrrole-2-acetate (5.32 g, 34.73 mmol) and 4-fluoro-nitrobenzene (4.9 g, 34.73 mmol) were dissolved in dry DMF (100 ml), and the solution was cooled to 0° C. under nitrogen. Sodium hydride powder (1.75 g, 72.93 mmol) was added in portions. After 30 min the reaction mixture was quenched with 1 M HCl and the product was extracted into ether. The organic extracts were washed with water and brine, and dried over magnesium sulfate. The solvent was removed in vacuo to give methyl-2-(1-methylpyrrol-2-yl)-2-(4-nitrophenyl)acetate (9.20 g, 97%) as a red oil. ##STR62##
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:41])=[C:4]([S:20]([N:23](CC2C=CC(OC)=CC=2OC)[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([F:41])=[C:4]([S:20]([NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)(=[O:21])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)c(Cl)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1Cl
Yield: 162 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (344 mg, 0.31 mmol) prepared in Example 80a, triethylsilane (0.50 mL), trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL), to yield the title compound (227 mg, 88%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[CH:6]=1.I.[CH2:14]=O.[PH2](O)=O.[OH-].[NH4+]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[C:6]=1[CH3:14]
Reactant: C=O
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Agent: I
Agent: O=[PH2]O
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(C)c(C)c1C

Procedure:
2,4-Dimethyl-5-carbethoxy-pyrrole (0.83 g), acetic acid (10 ml), hydriodic acid (10 ml) and paraformaldehyde (0.60 g) were stirred 3 hours at 25° C. under nitrogen. Hypophosphorous acid (50%, about 1 ml) was added, dropwise to decolourize the solution. The cooled solution (0° C.) was made basic with ammonium hydroxide and the product was extracted with ether (2 × 20 ml). The extract was dried over magnesium sulfate, filtered, and the ether removed in a rotating evaporator at 20° C. Recrystallization of the residue from benzene gave the product, 0.58 g (64%), m.p. 125°-126° C. (lit3 m.p. 126° C.).
Reaction SMILES: CNC1C=CC(C#CCCCO)=CC=1.[Si:15]([O:22][C@H:23]([C:45]1[CH:54]=[CH:53][C:52]([OH:55])=[C:51]2[C:46]=1[CH:47]=[CH:48][C:49](=[O:56])[NH:50]2)[CH2:24][N:25]([CH3:44])[CH2:26][CH2:27][CH2:28][C:29]#[C:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37]C(=O)C(F)(F)F)=[CH:33][CH:32]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[NH2:37][C:34]1[CH:35]=[CH:36][C:31]([C:30]#[C:29][CH2:28][CH2:27][CH2:26][N:25]([CH3:44])[CH2:24][C@@H:23]([C:45]2[CH:54]=[CH:53][C:52]([OH:55])=[C:51]3[C:46]=2[CH:47]=[CH:48][C:49](=[O:56])[NH:50]3)[O:22][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])=[CH:32][CH:33]=1
Reactant: CN(CCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CNc1ccc(C#CCCCO)cc1
Product: CN(CCCC#Cc1ccc(N)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 49, using instead Intermediate 102 as a substrate. ES/MS calcd. for C29H40N3O3Si+ 506.3. Found m/z=506.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.Br[CH2:23][CH2:24][C:25]1([OH:28])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:23][CH2:24][C:25]3([OH:28])[CH2:27][CH2:26]3)[C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1
Reactant: OC1(CCBr)CC1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCC2(O)CC2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (150 mg, 0.405 mmol, intermediate 8) in DMF (5 mL) was added 1-(2-bromoethyl)cyclopropanol (94 mg, 0.568 mmol) followed by potassium carbonate (84 mg, 0.609 mmol) and TBAI (catalytic amount). The resulting mixture was stirred at 50° C. overnight. The reaction was diluted with ethyl acetated and washed with brine. The organic phase was dried and concentrated to give crude product which was purified via silica gel chromatography eluting with petroleum ether/ethyl acetate (5:1 to 2:1) to give 8-bromo-7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (150 mg, 81.6% yield) as light yellow solid. LCMS retention time 1.523 min; LCMS MH+ 455.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1.[I:40]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[CH3:37][Si:34]([CH3:36])([CH3:35])[CH2:33][CH2:32][O:31][CH2:30][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:38])[CH3:39])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:40])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a mixture of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (5 g, 8.65 mmol) in DMF (15 mL) was added N-iodosuccinimide (1.86 g, 8.27 mmol) and the resulting mixture was allowed to stir at room temperature for 1 hour. The mixture diluted with EtOAc (100 mL), washed with water (20 mL). The aqueous layer was extracted with EtOAc (20 mL) once, and combined organic layer was washed with water (20 mL) three times, brine once and dried (MgSO4). After concentration, the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hex (0-30%) gave tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (4.55 g, 75%). (Note: DMF could be replaced by acetonitrile.)
Reaction SMILES: [Mg].[Br:2][CH:3]1[CH2:5][CH2:4]1.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=O)=[CH:10][CH:9]=1.[Cl-].[NH4+]>O1CCCC1>[Br:2][CH2:3][CH2:4][CH2:5][C:15]1[C:16]2[C:11](=[CH:10][CH:9]=[C:8]([O:7][CH3:6])[CH:17]=2)[CH2:12][CH2:13][CH:14]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: BrC1CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CCCBr)=CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
To tetrahydrofuran (100 ml), in which magnesium (2.9 g) was suspended, was gradually added dropwise under ice-cooling bromocyclopropane (14.4 g, 119 mmol.) under argon atmosphere. The mixture was stirred for 30 minutes at room temperature, to which was added dropwise a tetrahydrofuran (50 ml) solution of 7-methoxy-1-tetralone (15 g, 85.1 mmol.), which was heated for 2 hours under reflux. The reaction mixture was cooled to room temperature, to which was poured a saturated aqueous solution of ammonium chloride, followed by extracting the organic substance with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was dissolved in acetic acid (100 ml), to which was added 20% hydrobromic acid (75 ml). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, which was poured into a saturated aqueous solution of sodium hydrogencarbonate, and the organic substance was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (ethyl acetate hexane=1:9) to afford the titled compound (20 g, yield 84%, oily).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[F:12][C:13]1[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH:20]=1)[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:21][C:3]2[CH:2]=[CH:7][C:6]([CH3:8])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[C:17]([CH:20]=1)[C:18]#[N:19]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: N#Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(Oc2ccc(F)cc2C#N)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
In a 3-necked 5 L flask, equipped with a mechanic stirrer, a condenser, and a J-Kem temperature probe, a solution of 5-fluoro-2-nitrotoluene (158 g, 1.02 mol) in N,N-dimethylacetamide (500 mL) was added to a mixture of 5-fluoro-2-hydroxybenzonitrile (147 g, 1.07 mol) and potassium carbonate (163 g, 1.2 mol) in N,N-dimethylacetamide (573 mL) at room temperature. The mixture was heated to 100° C. After 8 hours, the reaction mixture was cooled to room temperature and water (3400 mL) was added in an ice bath. The precipitate was filtered, washed with water (1073 mL×2), and dried in vacuum (40° C.) to give (264 g, 90%) of the desired compound as a brown solid. MS (APCI-) m/z 272 (M−1) was detected. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, 1H, J=9 Hz), 7.41-7.48 (m, 1H), 7.38 (m, 1H), 7.07-7.14 (m, 1H), 6.88-7.10 (m, 1H), 2.63 (s, 3H).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][C:19]2=[O:32])=[CH:12][CH:11]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][N:18]([CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][NH:7][CH3:6])=[CH:11][CH:12]=2)[C:19](=[O:32])[CH:20]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN(Cc1ccc(CCn2ccc(OCc3ccccc3)cc2=O)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(CCn2ccc(OCc3ccccc3)cc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 100 mg (0.22 mmol) {4-[2-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-ethyl]-benzyl}-methyl-carbamic acid tert-butyl ester (example 19.1a) in DCM is added at RT 0.70 mL trifluoro-acetic acid. The reaction mixture is stirred 2 h at RT, neutralized with aqueous saturated NaHCO3-solution and is diluted with water and DCM. The layers are separated, the aqueous phase is extracted twice with DCM. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([O:26][C:27]2[CH:36]=[C:35]([CH3:37])[C:30]3[NH:31][C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)[CH:20]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C.C(Cl)Cl>[CH3:37][C:35]1[C:30]2[NH:31][C:32](=[O:34])[O:33][C:29]=2[CH:28]=[C:27]([O:26][C:21]2[CH:20]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[N:24]=[C:23]([CH3:25])[N:22]=2)[CH:36]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Oc2cc(C)c3[nH]c(=O)oc3c2)cc(N2CCC3(CC2)OC(=O)Nc2ncccc23)n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
90 mg (0.35 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 90 mg (0.31 mmol) 6-(6-chloro-2-methylpyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 200 μL (1.16 mmol) DIPEA in 1.5 mL DMF were stirred overnight at RT. Another 90 mg (0.35 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride and 200 μL (1.16 mmol) DIPEA were added and the mixture was stirred for 8 h at 60° C. The reaction mixture was mixed with water and stirred overnight. Then DCM was added and the mixture was stirred for a further 30 min. DCM was removed and the aqueous phase was suction filtered. The precipitate was washed with EtOH and dried.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.O>CN(C)C=O>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4]2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1c[nH]c2ccccc2c1=O
Reactant: COc1ccc(CCl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (3.17 g, 14.6 mmol) and 4-methoxybenzylchloride (2.18 mL, 16.0 mmol, 1.1 equiv) were combined in N,N-dimethylformamide (50 mL) and stirred at ambient temperature for 72 hours. The mixture was poured into water (500 mL) and extracted with dichloromethane (2×250 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was treated with water (500 mL), hexanes (500 mL) and ethyl acetate (500 mL) and aged for 30 minutes. The mixture was filtered and the solid was dissolved in dichloromethane (500 mL) and combined with the filtrate. The filtrate was partitioned and the aqueous layer was discarded. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](C=O)=[CH:5][C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3.[C:27]([C:32]1C=CC=C[C:33]=1P(=C)(C1C=CC=CC=1)C1C=CC=CC=1)([O:29][CH2:30][CH3:31])=[O:28].C(OCC)C>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:27](=[O:28])[CH:32]=[CH:33][C:4]1[C:3]([O:2][CH3:1])=[CH:16][C:15]2[CH:14]3[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)[CH:8]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:7][C:6]=2[CH:5]=1)[CH3:31]
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1C(=O)OCC
Reactant: COc1ccc(C2Cc3cc(C=O)c(OC)cc3C3CCCCC23)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cc2c(cc1OC)C1CCCCC1C(c1ccc(OC)cc1)C2
Yield: 74.6 %

Procedure:
Combine 3-Methoxy-9-(4-methoxy-phenyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthrene-2-carbaldehyde (1.77 g, 5.13 mmol), carboethoxy-methylene triphenylphosphorane (03.19 g, 9.03 mmol) in toluene (53 ml) and reflux 15 hours. Remove solvent in vacuo, slurry with diethyl ether and chromatograph the residue from the concentrated filtrate on silica gel with 20% ethyl acetate/hexanes, then 25% ethyl acetate/hexanes to yield the titled compound (1.61 g, 76%). MS m/z 421(M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:13]=2)[C:8]([CH3:50])=[N:7]1.[ClH:54]>CO.O1CCOCC1>[ClH:54].[F:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:41])=[O:42])[CH:13]=2)[C:8]([CH3:50])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Yield: 93.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (example 40 step 1) (232 mg, 0.315 mmol) was deprotected in methanol (5 ml), HCl in dioxane (5 ml). This afforded 198 mg (93.8% yield) of the titled compound. MS: m/z=651.1 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[NH2:10][CH2:11][CH2:12][S:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C.CC(O)=O>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:10][CH2:11][CH2:12][S:13][C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:8]
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)CCCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(CCCCCBr)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Bromohexanoyl chloride (46 μl, 0.31 mmol) was dissolved in 0.2 ml CH2Cl2 and added to a solution of H2N—CH2—CH2-STrt (100 mg, 0.28 mmol), DIEA (97 μl, 0.56 mmol) in CH2Cl2 (0.8 ml). The mixture was stirred for 2 h at RT. The reaction mixture was acidified with AcOH (50 μl) and the solvent was removed in vacuo. The residue was purified on silica gel (heptane/EtOAc=1:1) to obtain Br—(CH2)5—CONH—(CH2)2-STrt.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.Cl.Cl[C:21]1[N:22]([C:26]2[CH2:30][CH2:29][CH2:28][N:27]=2)[CH2:23][CH2:24][CH:25]=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:21]3[N:22]([C:26]4[CH2:30][CH2:29][CH2:28][N:27]=4)[CH2:23][CH2:24][CH:25]=3)[C:5]=2[CH:4]=1
Reactant: ClC1=CCCN1C1=NCCC1
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1O2
Agent: Cl
Product: FC(F)(F)c1ccc2c(c1)N(C1=CCCN1C1=NCCC1)c1ccccc1O2

Procedure:
Reaction of 2-trifluoromethylphenoxazine with 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords the free base, 2-TRIFLUOROMETHYL-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2YL]PHENOXAZINE, m.p. 140°-142° C., from n-hexane. Conversion of the free base affords 2-TRIFLUOROMETHYL-10-[1-(1-PYRROLIN-2-YL)2-PYRROLIN-2-YL]PHENOXAZINE HYDROCHLORIDE HYDRATE, m.p. 222.5°-229° C. (dec.)(corr.).