Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Cl)([O-:16])=[O:15].[Cl-].[NH4+]>C(O)C>[CH3:2][C:3]([CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=1)([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1cccc([N+](=O)[O-])c1)C(=O)OCC

Procedure:
In ethanol (45 ml) was dissolved sodium (0.7 g), and diethyl methylmalonate (5.26 ml) and 3-nitrobenzyl chloride (5 g) were added thereto, followed by heating under reflux for 2 hours. The reaction mixture was ice-cooled, an aqueous saturated ammonium chloride was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give the title compound (9.724 g) as a pale yellow oil.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:37](=[O:38])[C:16]2=[CH:17][N:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[CH:35][CH:34]=[N:33]4)=[CH:28][CH:27]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:15]2=[N:14]1)(=O)=O.[N-:39]=[N+:40]=[N-:41].[Na+].C(=O)(O)[O-].[Na+]>CS(C)=O>[N:39]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:37](=[O:38])[C:16]2=[CH:17][N:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[CH:35][CH:34]=[N:33]4)=[CH:28][CH:27]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:15]2=[N:14]1)=[N+:40]=[N-:41]
Reactant: CS(=O)(=O)OCc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
[2-(3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)phenyl]methyl methanesulfonate (0.21 g, 0.51 mmol) was dissolved in dimethyl sulfoxide (10 mL) and treated with sodium azide (0.33 g, 5.1 mmol, 10 equiv). The mixture was stirred for 45 minutes at ambient temperature and then placed into a preheated oil bath at 80° C. for 1 hour. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (100 mL, aqueous saturated) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 5% methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.17 (1H, s), 8.46 (1H, d, J=2.5 Hz), 8.23 (1H, d, J=7.8 Hz), 7.83 (2H, d, J=8.6 Hz), 7.79 (1H, d, J=8.6 Hz), 7.72 (1H, m), 7.65-7.61 (1H, m), 7.57-7.54 (3H, m), 7.51 (1H, br d, J=7.6 Hz), 7.49-7.45 (3H, m), 6.53 (1H, m), 5.78 (2H, s), 4.60 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 473.1823 [(M+H)+; calculated for C27H21N8O: 473.1833].
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[S:5]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[S:17])=[CH:11][CH:10]=1)([OH:8])(=[O:7])=[O:6].[Na:18]>O>[Na:18].[S:5]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:16]([SH:17])=[N:3][N:2]=[N:1]2)=[CH:13][CH:14]=1)([OH:8])(=[O:6])=[O:7]
Reactant: O=S(=O)(O)c1ccc(N=C=S)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=S(=O)(O)c1ccc(-n2nnnc2S)cc1
Yield: 25 %

Procedure:
19.5 g of sodium azide was dissolved in 1.5 l of water, then 23.7 g of sodium 4-sulfophenylisothiocyanate synthesized in (1) above was added thereto. The resulting mixture was heated using a steam bath for 8 hours, followed by removing solids by filtration. After adding 125 ml of 20% sulfuric acid to the filtrate, it was concentrated under reduced pressure. Addition of 20 g of NaCl to the concentrate caused precipitation of crystals. The crystals were collected by filtration, then dissolved in a mixed solution of 80 ml of water and 20 ml of 2N HCl. Addition of NaCl thereto little by little caused precipitation of crystals. The crystals were collected by filtration and dried to obtain 7 g of Compound II-1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:7][OH:8])[CH3:2].[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22].O>CCCCCC>[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:11]([OH:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:22]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: CCOc1cc(CO)ccc1O
Solvent: CCCCCC
Solvent: O
Product: CCOc1cc(COC(=O)CCCCCCC(C)C)ccc1O
Temperature: 50 °C
Yield: 89.1 %

Procedure:
3-Ethoxy-4-hydroxybenzyl alcohol (733 mg, 4.35 mmol), 8-methylnonanoic acid (751 mg, 4.35 mmol) and Novozyme 435 (100 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (50 ml) was added, and Novozyme 435 and the insoluble material were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give 3-ethoxy-4-hydroxybenzyl 8-methylnonanoate (1.25 g, yield 88.8%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].ClCCl>N1C=CC=CC=1>[C:13]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(OCCO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCOc1ccc(C=O)cc1
Temperature: 0 °C

Procedure:
A mixture of the crude 4-(2-hydroxyethoxy)benzaldehyde (30 g, 0.18 mol) and acetic anhydride (40 g, 0.40 mol) was dissolved in 125 mL of dry pyridine and heated at reflux for 3 hr, after which time the reaction mixture was poured onto ca. 200 g of crushed ice. The crude oil was taken up into 150 mL of dichloromethane and washed twice with 5% HCl (2×75 mL) and once with brine (1×75 mL). The organic layer was then dried with sodium sulfate and the solvent was removed under reduced pressure. The crude residue was distilled at 148° C. (1×10-3 mm) to give 12.9 g (25% overall yield) of a slightly cloudy liquid.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.[NH:12]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>CC#N>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][N:12]([CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:18]
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)CNCC(=O)OCC
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN(CC(=O)OCC)Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
A suspension of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (12.0 g, 34.6 mmol) and diethyl iminodiacetate (7.0 mL, 39.1 mmol) in CH3CN (350 mL) was treated with triethylamine (10.7 mL, 76.1 mmol). After stirring at room temperature under N2 for 4 h, the solvent was removed in vacuo. The resulting yellow slurry was partitioned between H2O (400 mL) and EtOAc (400 mL), and the aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1) gave the title compound (6.55 g, 51%) as a light tan oil: MS (ESI) m/e 374 (M+H)+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].O1CCCC1.[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CON(C)[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1CCCCC1>[C:26]1([C:25](=[O:32])[C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C#Cc1ccccc1
Reactant: CON(C)C(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=C(C#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
Place lithium diisopropylamide (10 mL of a 1.5M solution in cyclohexane) and tetrahydrofuran (40 mL) under an argon atmosphere and cool to 0° C. Add, by dropwise addition, phenylacetylene (1.65 mL, 15 mmol). Remove the cooling bath and stir for 30 minutes as room temperature. Cool the yellow solution to 0° C. and add, by dropwise addition, N-methoxy-N-methylbenzamide (3.04 mL, 20 mmol). Remove the cooling bath and stir for 30 minutes at room temperature. Pour onto ethyl ether and water, separate the organic phase and dry (MgSO4). Filter and evaporate the solvent in vacuo to yield an oil. Purify by silica gel chromatography (2% ethyl acetate/hexane) then purify further by distillation (2×) to yield 1.9 g of the title compound; bp 210° C. in vacuo.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[OH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>C1COCC1.C(OC(=O)C)C>[CH:5]1([CH2:4][N:10]2[CH2:11][CH2:12][CH:7]([OH:6])[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: OC1CCNCC1
Reactant: BrCC1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1CCN(CC2CC2)CC1
Reaction time: 8 h
Yield: 46.7 %

Procedure:
Add bromomethylcyclopropane (2.025 g, 15 mmol) to a solution of 4-hydroxypiperidine (3.035 g, 30 mmol) in THF (10 mL) and stir the mixture overnight. Dilute the mixture with ethylacetate, wash with saturated NaHCO3 solution, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel, eluting with 8% 2M NH3-methanol in CH2Cl2) provides 1.087 g (47%) of the title compound: mass spectrum (ion spray): m/z=156.2 (M+1); 1H NMR (CDCl3, ppm): 3.60 (m, 1H), 2.81 (m, 2H), 2.16 (d, 1H), 2.10 (m, 3H), 1.84 (m, 2H), 1.53 (m, 3H), 0.79 (m, 1H), 0.44 (m, 2H), 0.00 (m, 2H).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].CC[N:26]([CH2:29][CH3:30])CC>CCO>[N+:21]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH:26][CH2:29][C@H:30]1[CH2:4][CH2:5][CH2:6][O:7]1)[C:6]([N:8]([CH2:9][C:10]([F:11])([F:13])[F:12])[CH2:14][C:15]([F:16])([F:17])[F:18])=[O:7])([O-:23])=[O:22]
Reactant: CCN(CC)CC
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CCO
Product: O=C(c1ccc(NC[C@H]2CCCO2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (78 mg, 0.224 mmol) and R-(−)-tetrahydrofurfurylamine (0.025 mL, 0.246 mmol) in 3 mL of EtOH containing Et3N (0.047 mL, 0.336 mmol). The product was purified by flash chromatography on silica gel using 2:1/hexanes:EtOAc as eluent. Yield: 96 mg (95%); 1H NMR (CDCl3) 1.72 (m, 1H), 1.99 (m, 2H), 2.13 (m, 1H), 3.99 (m, 1H), 3.53 (m, 1H), 3.85 (m, 1H), 3.97 (m, 1H), 4.25 (m, 5H), 6.99 (d, J=8.98 Hz, 1H), 7.53 (d, J=8.98 Hz, 1H), 8.30 (s, 1H), 8.51 (brs, 1H); MS (ESI) 430.31 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([OH:17])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[C:24]([O-])([O-])=O.[K+].[K+].IC>O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([O:17][CH3:24])=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)c(OC)c(-c2ccccc2)c1
Reaction time: 18 h
Yield: 99 %

Procedure:
At ambient temperature, to a stirred mixture containing 2′-hydroxy-[1,1′;3′,1″]terphenyl-5′-carboxylic acid methyl ester (1.232 g, 4.049 mmol) and K2CO3 (0.6155 g, 4.454 mmol) in N,N-DMF (10.1 mL) was added iodomethane (0.353 mL, 5.67 mmol). After 18 h, the reaction was diluted with H2O (100 mL) and the reaction was stirred vigorously. The resulting precipitate was collected, dissolved in CH2Cl2, dried (K2CO3) and concentrated to give 1.167 g, (99%) of the title compound. 1H NMR (DMSO-d6) δ 3.16 (s, 3H), 3.87 (s, 3H), 7.41-7.53 (m, 6H), 7.58-7.60 (m, 4H), 7.89 (s, 2H).
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1.[CH3:15]O>>[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:15])=[O:11])=[CH:8][N:7]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)nc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)nc1

Procedure:
To methanol (100 ml) in an ice bath was added thionyl chloride (16 ml) followed by addition of 6-hydroxynicotinic acid (10 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:13](=[O:27])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH3:10])[C:5]([C:34]#[N:35])=[CH:4][N:3]=1.C(=N[OH:39])C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:13](=[O:27])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH3:10])[C:5]([C:34]([NH2:35])=[O:39])=[CH:4][N:3]=1
Reactant: C[C@H](Nc1nc(N)ncc1C#N)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Reactant: CC=NO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nc(N)ncc1C(N)=O)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-amino-4-((1-(8-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile (69) (30.4 mg, 0.066 mmol) in anhydrous toluene (1 mL), acetaldoxime (10 μL, 0.13 mmol), palladium acetate (2 mg, 0.0066 mmol) and triphenyl phosphine (4 mg, 0.013 mmol) were added and the resulting mixture was stirred at 80° C. for 2 h. Additional amounts of acetaldoxime (10 μL, 0.13 mmol), palladium acetate (2 mg, 0.0066 mmol) and triphenyl phosphine (4 mg, 0.013 mmol) were added and stirring was continued at 80° C. for 2 h. The mixture was allowed to cool to RT, quenched with water (30 mL), and then extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-8.5% MeOH-DCM) to afford the desired product, (S)-2-amino-4-((1-(8-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carboxamide (79) as a white solid. ESI-MS m/z: 481.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1SC)=[C:8]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:7]([F:19])=[CH:6][C:5]=2[Br:20]>[Ni].O1CCOCC1>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:7]([F:19])=[CH:6][C:5]=2[Br:20]
Reactant: CSc1c(C)[nH]c2c(Br)cc(F)c(N3CCOCC3)c12
Agent: [Ni]
Solvent: C1COCCO1
Product: Cc1cc2c(N3CCOCC3)c(F)cc(Br)c2[nH]1
Yield: 65.3 %

Procedure:
Raney nickel (400 g) was added to a solution of 58 g of 2-methyl-3-methylthio-4-morpholino-5-fluoro-7-bromoindole in 1 l of dioxane and the mixture was allowed to react at room temperature for 4 hours. After completion of the reaction Raney nickel was removed by filtration, and the filtrate was concentrated under reduced pressure. 33 g of 2-methyl-4-morpholino-5-fluoro-7-bromoindole was obtained.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:13]3[N:17]4[CH:18]=[C:19]([C@@H:22]([N:27]5[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:28]5)[C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:21][C:16]4=[N:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:40][N:41]1[C:45]([CH3:55])(B2OC(C)(C)C(C)(C)O2)[CH:44]=[CH:43][NH:42]1>>[CH3:40][N:41]1[C:45]([C:2]2[C:11]([CH3:12])=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([C:13]4[N:17]5[CH:18]=[C:19]([C@@H:22]([N:27]6[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH2:28]6)[C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:21][C:16]5=[N:15][N:14]=4)=[N:9]3)=[CH:4][CH:3]=2)([CH3:55])[CH:44]=[CH:43][NH:42]1
Reactant: Cc1c(Br)ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Reactant: CN1NC=CC1(C)B1OC(C)(C)C(C)(C)O1
Product: Cc1c(C2(C)C=CNN2C)ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12

Procedure:
Prepared as described in Example 191, using tert-butyl (S)-1-((R)-1-(3-(7-bromo-8-methylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate in place of 7-bromo-2,8-dimethylquinoline and using 1,5-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Step A. LCMS APCI (+) m/z 621 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14]([C:16](OC)=[O:17])=[CH:13][C:12]=2[CH:20]=1>CCOCC>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14]([CH2:16][OH:17])=[CH:13][C:12]=2[CH:20]=1
Reactant: COC(=O)c1cc2cc(Cl)ccc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To lithium aluminum hydride (26.5 mmol) and 50 ml ether, at -20° under nitrogen, is slowly added methyl 5-chlorobenzothiophene-2-carboxylate (6 g, 26.5 mmol). The mixture is then stirred at -20° for 10 minutes. After no starting material is detectable by thin layer chromatography, the mixture is quenched with 1 ml water, 1 ml 15% NaOH, and 3 ml water at -20°. The mixture is allowed to warm to RT and stirred for 15 hours. The mixture was then filtered and solvent evaporated to give 5-chlorobenzothiophene-2-methanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:10]([OH:13])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1.C(OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:10]([O:13][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CC(O[Si](C)(C)C(C)(C)C)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
1 g of (3RS,4S)-4-(tert-butoxycarbonyl)amino-6-methylhepten-3-ol was dissolved in 2 ml of dry DMF, and 743 mg of tert-butyldimethylchlorosilane and 700 mg of imidazole were added thereto. The mixture was stirred at room temperature overnight. Then, 160 ml of ethyl acetate was added to the reaction solution. The mixture was washed with cooled 1N hydrochloric acid, with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=30/1) to obtain 1.21 g of (3RS,4S)-4-(tert-butoxycarbonyl)amino-3-(tert-butyldimethylsilyl)oxy-6-methylheptene as colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.Cl.Cl[C:18]1[N:19]([C:23]2[CH2:27][CH2:26][CH2:25][N:24]=2)[CH2:20][CH2:21][CH:22]=1>>[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:18]3[N:19]([C:23]4[CH2:27][CH2:26][CH2:25][N:24]=4)[CH2:20][CH2:21][CH:22]=3)[C:4]=2[CH:3]=1
Reactant: ClC1=CCCN1C1=NCCC1
Reactant: Clc1ccc2c(c1)Nc1ccccc1O2
Agent: Cl
Product: Clc1ccc2c(c1)N(C1=CCCN1C1=NCCC1)c1ccccc1O2

Procedure:
Reaction of 2-chlorophenoxazine with 2-chloro-(1-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 2-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOXAZINE HYDROCHLORIDE, m.p. 262.5°-264.5° C. (dec.)(corr.), from ethanol-ether.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[S:22]1[C:26]2[CH2:27][CH2:28][CH2:29][C:25]=2[N:24]=[C:23]1[NH2:30]>>[S:22]1[C:26]2[CH2:27][CH2:28][CH2:29][C:25]=2[N:24]=[C:23]1[NH:30][C:18]([C:3]1[N:4]([CH3:17])[S:5](=[O:15])(=[O:16])[C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][C:7]=2[C:2]=1[OH:1])=[O:19]
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1nc2c(s1)CCC2
Product: CN1C(C(=O)Nc2nc3c(s2)CCC3)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 57 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 5,6-dihydro-4H-cyclopentathiazole-2-amine with a yield of 57% of theory.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:12][C:13]([OH:15])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:28]([O:31][CH2:32][CH:33]=[CH:34][C:35]1[CH2:42][S:41][C@H:40]2[N:37]([C:38](=[O:44])[C@H:39]2[NH2:43])[C:36]=1[C:45]([OH:47])=[O:46])(=[O:30])[CH3:29]>CN(C)C(=O)C.C(OCC)(=O)C>[C:28]([O:31][CH2:32]/[CH:33]=[CH:34]\[C:35]1[CH2:42][S:41][C@H:40]2[N:37]([C:38](=[O:44])[C@H:39]2[NH:43][C:13](=[O:15])[CH2:12][S:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:36]=1[C:45]([OH:47])=[O:46])(=[O:30])[CH3:29]
Reactant: O=C(O)CSc1ccc2ccccc2c1
Reactant: CC(=O)OCC=CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)OC/C=C\C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CSc3ccc4ccccc4c3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 10.5 g (48 mmol) of naphthalen-2-ylsulfanyl-acetic acid in 80 ml of N,N-dimethylacetamide were added 7.8 g (48 mmol) of 1,1′-carbonyldiimidazole and the reaction mixture was stirred for 0.5 h at 20° under an atmosphere of argon. To the yellow solution were added 11.93 g (0.5 mmol) of (Z and E)-(6R,7R)-3-(3-acetoxy-propenyl)-7-amino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid and stirring was continued for 3 h at 20°. The brown solution was diluted with ethyl acetate (0.5 1), washed with 1 N hydrochloric acid (0.2 1) and with water (5×0.1 1), dried over sodium sulfate and evaporated in vacuo. The remaining material was crystallized from ethyl acetate to give 11.7 g (58%) of (Z)-(6R,7R)-3-(3-acetoxy-propenyl)-7-[2-(naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a light brown solid.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[C:19]([CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[S:20][C:21]=1[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[C:3]([C:17]2[N:18]=[C:19]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[NH:8][S:9]([C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: Cc1nccc(-c2sc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccc(-c2sc(C3CCNCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-piperidinecarboxylate (115 mg, 0.192 mmol) in dichloromethane (2 mL) was added TFA (0.015 mL, 0.192 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to give 62 mg of the title compound. MS (ESI): 500.3 [M+1]+.