Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[NH2:17][C:12]1[C:11]2=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:22]=4)[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:3][CH:4]=3)[N:16]2[N:15]=[CH:14][N:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)cc1
Product: CS(=O)(=O)Nc1ccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)cc1
Yield: 16 %

Procedure:
Using a procedure similar to that of Example 5, with 7-(4-amino-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and methanesulfonyl chloride as starting materials, 30 mg (16%) of the desired product was Isolated. 1H NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1 H), 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.10 (s, 3H); ES-MS m/z 510.17 [M+H]+, HPLC RT (min) 3.07.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([N+:20]([O-:22])=[O:21])=[C:4]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[CH3:31][N:32]1[CH:36]=[C:35]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[C:5]([N+:20]([O-:22])=[O:21])=[C:4]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH:3]=2)[CH:34]=[N:33]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(NCc2ccc3ncccc3c2)c1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c(NCc3ccc4ncccc4c3)n2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a mixture of tert-butyl 6-chloro-3-nitro-2-(quinolin-6-ylmethylamino)pyridin-4-ylcarbamate (860 mg, 2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (416 mg, 2 mmol) and Na2CO3 (424 mg, 4 mmol) in dioxane (20 mL) and H2O (2 mL) under N2 was added Pd(dppf)Cl2 (163 mg, 0.2 mmol). The reaction was stirred at 80° C. under N2 overnight. After cooled to room temperature, the mixture was concentrated and purified by chromatography to afford the title compound (950 mg). MS (m/z): 476 (M+1)+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([OH:22])[C:14]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C(O)=C(C(CS(C2C=CC=C([Cl:49])C=2)(=O)=O)=CC=1)C(OC)=O.O1C=CC(B(O)O)=C1>>[Cl:49][C:3]1[CH:2]=[C:1]([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:22])[C:14]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1O
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(-c2ccoc2)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(3-chlorobenzenesulphonylmethyl)-2-hydroxy-benzoate (Intermediate 54) and furan-3-yl boronic acid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][CH:11]=[CH2:12])=[O:7])([CH3:4])[CH3:3].C(N1CCOCC1)C.[CH2:24]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])[CH3:25].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:24]([O:26][C:27]([N:29]1[CH2:30][CH2:31][N:32]([C:13](=[O:15])[C@@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:10][CH:11]=[CH2:12])[CH2:33][CH2:34]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)N1CCNCC1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCC)CC1
Reaction time: 1 h

Procedure:
To a solution of 540 mg Boc-L-Allylglycine in 5 ml DMF were added 0.32 ml N-ethylmorpholine, 0.37 ml ethoxycarbonylpiperazine and 0.83 g TOTU at 0° C. The solution was stirred for 1 h before being diluted with ethyl acetate and extracted subsequently with aqueous LiCl (4%), 0.1 M HCl and half-saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7](C)[C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[CH2:13](O)C>[Pd]>[NH2:6][C:5]1[CH:7]=[C:8]([CH3:13])[C:2]([CH3:1])=[CH:3][C:4]=1[NH2:10]
Reactant: CCO
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Agent: [Pd]
Product: Cc1cc(N)c(N)cc1C
Reaction time: 2 h
Yield: 96 %

Procedure:
A mixture of 4,6-dimethyl-2-nitroaniline (1.66 g, 10.0 mmole) and 10% Pd/C (200 mg) in ethanol (35 mL) was hydrogenated for 2 h at room temperature under 25 psi H2. The catalyst was removed by filtration with celite and the solvent was removed by rota-evaporation to give 1.300 g (96%) of 1,2-diamino-4,5-dimethylbenzene as a brown solid. 1H NMR (CDCl3): 6.449 (s, 1H), 6.469 (s, 1H), 3.327 (br, 2H), 3.259 (br, 2H), 2.190 (s, 3H), 2.159 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1>CN(C=O)C.O>[NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1
Reactant: CC(C)(N)CO
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(N)COc1ccc(C#N)cn1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-2-methyl-1-propanol (0.5 mL, 5.60 mmol), in DMF (20 mL) was added NaH 60% (0.67 g, 16.80 mmol) and then 6-chloronicotinonitrile (2.03 g, 11.22 mmol). The mixture heated to 70° C. for 2 hours and then stirred at room temperature overnight. The reaction mixture was taken up in H2O and extracted with EtOAc. The organic phase was washed with water (3×), dried over Na2SO4 and concentrated under reduced pressure to provide the titled compound as a pale yellow solid. MS (DCI) m/z 235 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17](=[O:26])(=[O:25])[N:18]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH3:19])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>C1COCC1>[CH3:24][N:22]([CH3:23])[CH2:21][CH2:20][N:18]([CH3:19])[S:17]([C:4]1[S:3][CH:2]=[C:6]([C:7]2[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=2[CH3:16])[CH:5]=1)(=[O:25])=[O:26]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N(C)CCN(C)C)sc2Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)N(C)CCN(C)C)c2)s1
Temperature: -70 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
N-(5-{2-Bromo-5-[(2-dimethylamino-ethyl)-methyl-sulfamoyl]-thiophen-3-yl}-4-methyl-thiazol-2-yl)-acetamide obtained in Step I as described above (750 mg; 1.56 mmol; 1 eq), is dissolved in anhydrous THF (60 ml). The reaction mixture is cooled down to −70° C. and put under nitrogen. n-Butyllithium (6.2 ml; 1.6 M; 12.5 mmol; 8 eq) is added dropwise. The reaction is stirred 1 hour and is quenched with water. Solvents are evaporated and the resulting residue is dissolved in EtOAc, washed with water (2 times), brine and dried over MgSO4. After evaporation of the solvent, the resulting product is suspended in a mixture of ether-DCM and filtered, affording Compound (36) as a brown solid (582 mg; 87%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].[OH-].[Na+]>[Cu].N1C2C(=CC=CC=2)C=CC=1>[NH:6]1[C:7]2[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: NCCc1ccccc1Cl
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Product: c1ccc2c(c1)CCN2
Yield: 95.7 %

Procedure:
Into a 100 ml reaction flask equipped with a condenser, a thermometer and a stirrer, 15.56 g (0.1 mol) of 2-chlorophenethylamine, 22.0 g (0.11 mol) of a 20% sodium hydroxide aqueous solution and 0.176 g (0.5 mol %) of quinoline copper were charged, and reacted at 110° C. for 8 hours. The reaction mixture thereby obtained was subjected to liquid separation to separate the aqueous layer from the organic layer. The organic layer was washed with an acid and distilled to obtain 11.4 g of indoline (boiling point: 94°-95° C./11 mmHg). The purity was 99.5%, and the yield was 96%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1.F[B-](F)(F)F.[CH3:24][O+](C)C>C(Cl)Cl>[CH3:24][O:18][C:16]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:17]=1
Reactant: COc1cccc(C=CC2CCCCC(=O)N2)c1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(C=Cc2cccc(OC)c2)CCCC1

Procedure:
The product of Example 163 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[OH-].[Na+]>C(O)C>[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:2][C:1]([C:4]2[CH:13]=[CH:12][C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)=[O:3])=[CH:18][CH:17]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)c1ccc(C=CC(=O)c2ccc3c(c2)CCCC3)cc1

Procedure:
A solution of 2.61 g of 6-acetyl-1,2,3,4-tetrahydronaphthalene (15 mmoles) (1), 2.23 g of p-dimethylaminobenzaldehyde (15 mmoles), and 0.66 g of sodium hydroxide in 50 ml of ethanol was stirred under nitrogen at about 60° for 90 hr. The reaction mixture was cooled in an ice bath, and the precipitated solid 3-[4-(dimethylamino)phenyl]-1-(5,6,7,8-tetrahydroaphthalen-2-yl)-2-propen-1-one was collected by filtration and washed with cold ethanol. Yield: 3.0 g (61%); m.p. 134° to 135°. λmax (CHCl3); 410 nm (ε=17,200); 266 nm (17,600). Calcd for C21C23NO: C, 82.59; H, 7.59; N, 4.59. Found: C, 80.38, 80.41; H, 7.30, 7.30; N, 3.59, 3.97.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13]O)=[CH:4][C:3]=1[CH3:15].O1CCCC1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][CH2:13][C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:15])[CH:4]=1
Reactant: Cc1cc(-c2oncc2CO)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(-c2oncc2CCl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a mixture of 5-(4-chloro-3-methylphenyl)-4-isoxazolylmethanol (5.80 g), tetrahydrofuran (20 ml) and toluene (80 ml) was added dropwise thionyl chloride (4.63 g) at 0° C. and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were filtrated and recrystallized from ethyl acetate-hexane to give 4-chloromethyl-5-(4-chloro-3-methylphenyl) isoxazole (5.47 g, yield 87%) as a colorless prism. melting point: 84–85° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].[CH2:14](O)[CH2:15][OH:16]>C1(C)C=CC=CC=1.CCOC(C)=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:16][CH2:15][CH2:14][O:6]2)[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1cc(Br)cc(C2OCCO2)c1
Yield: 85.2 %

Procedure:
A mixture of 3-bromo-5-trifluoromethyl benzaldehyde (10 gm, 39.523 mmol), ethylene glycol (6.63 ml, 118.568 mmol) and PTSA.H2O (150 mg, 0.79 mmol) in anhydrous toluene (60 ml) was heated to reflux under Dean-stark conditions for 6 h. The reaction mixture was diluted with EtOAc (100 ml) and washed with water (150 ml) and brine solution (150 ml). Organic layer was dried over Na2SO4, filtered and evaporated in vacuum to afford 11 g crude as a colorless liquid which was purified by column chromatography (100-200 silica gel mesh), eluted with 5% EtOAc in Hexane to afford the desired compound (10 g) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]([CH2:7][CH2:8][CH3:9])=[N:4][CH:3]=1.CO[CH:12]([N:15]([CH3:17])[CH3:16])OC.C(N(CC)CC)C>ClC1C=CC=CC=1>[Cl:1][C:2]1[C:3](=[CH:12][N:15]([CH3:17])[CH3:16])[N:4]=[C:5]([CH2:7][CH2:8][CH3:9])[N:6]=1
Reactant: COC(OC)N(C)C
Reactant: CCCc1ncc(Cl)[nH]1
Solvent: CCN(CC)CC
Solvent: Clc1ccccc1
Product: CCCC1=NC(=CN(C)C)C(Cl)=N1

Procedure:
A solution of 5-chloro-2-propyl-1H-imidazole (0.72 g, 5 mmol), dimethoxymethyldimethylamine (0.77 g, approximately 92 percent pure, 6 mmol) and triethylamine (0.10 g, 1 mmol) in chlorobenzene (25 ml) was heated for 1 hour at 60° C. and for 2 hours under reflux. Removing the solvent in a rotavapor gave the title compound in virtually quantitative yield. Data concerning the product was:
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[C:14]([OH:19])[C:15]([OH:18])=[CH:16][CH:17]=1>>[Cl:11][C:12]1[C:13]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[C:14]([OH:19])[C:15]([OH:18])=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)O)cc1
Reactant: Oc1ccc(Cl)cc1O
Product: Cc1ccc(S(=O)(=O)c2c(Cl)ccc(O)c2O)cc1

Procedure:
In a manner analogous to that described in Example 5a), p-toluenesulphinic acid is oxidatively condensed with 4-chloro-1,2-benzenediol. On recrystallisation from 1,2-dichloroethane, 4-chloro-(4-methylphenylsulphonyl)-1,2-benzenediol is obtained in the form of colourless crystals having a melting point of 162°-164°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[N:15]=1>>[C:21]1(=[O:30])[N:20]([C:16]2[N:15]=[C:14]([NH:13][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[N+:1]([O-:3])=[O:2])[CH:19]=[CH:18][CH:17]=2)[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: Nc1cccc(N2C(=O)c3ccccc3C2=O)n1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: O=C(Nc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1[N+](=O)[O-]
Yield: 80.2 %

Procedure:
Using the procedure described in Example 93, Part A, 2-nitrobenzoyl chloride (2.3 mmol) and 2-amino-6-phthalimidopyridine (2.1 mmol) yielded 654 mg (80%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:23])[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][Si:25]([CH3:28])([CH3:27])Cl>C(N(CC)CC)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([O:23][Si:25]([CH3:28])([CH3:27])[CH3:24])[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:15][CH:16]([CH3:21])[O:17][CH:18]([CH3:20])[CH2:19]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: CC1CN(CC(C)C(O)c2ccc(C(C)(C)C)cc2)CC(C)O1
Solvent: CCN(CC)CC
Product: CC1CN(CC(C)C(O[Si](C)(C)C)c2ccc(C(C)(C)C)cc2)CC(C)O1
Yield: 102.1 %

Procedure:
10 g (0.03 mole) of 1-(p-tert.-butyl-phenyl)-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-1-propanol (obtanied according to Example 2) were dissolved in 160 ml of petroleum ether with 4.4 ml of triethylamine at room temperature and 3.4 g of trimethylchlorosilane in 40 ml of petroleum ether were added dropwise. The precipitate was filtered off and the filtrate was concentrated. 12 g (98% of theory) of 1-(p-tert.-butyl-phenyl)-1-trimethylsilyloxy-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-propane were obtained as a viscous oil.
Reaction SMILES: C=C([O:4][C:5](=O)[NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:14]([CH3:34])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][N:19]=[C:18]([N:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:24])[CH:17]=3)[CH:10]=[CH:9][C:8]=1[F:35])C.[CH3:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH2:41].C1CCN2C(=NCCC2)CC1.CCOC(C)=O>O1CCOCC1>[CH3:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH:41][C:5]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:14]([CH3:34])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][N:19]=[C:18]([N:23]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH3:24])[CH:17]=3)[CH:10]=[CH:9][C:8]=1[F:35])=[O:4]
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(N(C)Cc4ccc(OC)cc4)cc3nc2C)ccc1F
Reactant: CC(C)(C)CCN
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CN(C)c2cc3nc(C)c(-c4ccc(F)c(NC(=O)NCCC(C)(C)C)c4)cc3cn2)cc1
Temperature: 80 °C
Yield: 85.4 %

Procedure:
Treat a solution of prop-1-en-2-yl(2-fluoro-5-(7-((4-methoxybenzyl)(methyl)amino)-2-methyl-1,6-naphthyridin-3-yl)phenyl)carbamate (0.398 g, 0.818 mmol) and 3,3-dimethylbutylamine (0.166 g, 1.636 mmol) in dioxane (10 mL) with DBU (0.025 ml, 0.164 mmol) and heat at 80° C. overnight. Cool to RT, add EtOAc and wash with 10% LiCl, then brine. Dry the organic layer over MgSO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (370 mg, 85%). 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.37 (s, 1H), 8.22 (d, J=7.9 Hz, 1H), 7.99 (s, 1H), 7.26 (dd, J=11.4, 8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.98 (m, 1H), 6.85 (d, J=8.5 Hz, 2H), 6.73 (s, 1H), 6.55 (t, J=5.5 Hz, 1H), 4.86 (s, 2H), 3.69 (s, 3H), 3.08 (m, 5H), 2.48 (s, 3H), 1.33 (m, 2H), 0.88 (s, 9H); MS (ESI) m/z: 530.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+]>CO.C(OCC)C>[F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1c(F)cccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COc1c(F)cccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of 3-fluoro-2-methoxy-benzaldehyde (3.41 g, 22.1 mmol) in methanol (20 mL) is slowly added portionwise sodium borohydride (1.00 g, 26.6 mmol). The reaction is stirred at room temperature under nitrogen overnight. The reaction is diluted with diethyl ether, washed with water twice, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3.02 g (87%) of the title compound as a clear colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.09-6.92 (m, 3H), 4.65 (d, 2H), 3.97 (s, 3H), 2.14 (t, 1H, OH).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].S(=O)(=O)(O)O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([O:16][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of benzyloxycarbonyl-L-alanine (160 g., 0.72 mole), anhydrous dichloromethane (270 ml.), condensed isobutylene (700 ml.), and concentrated sulfuric acid (7.5 ml.) is shaken in a Parr apparatus at room temperature for 3 days. The isobutylene is allowed to evaporate at room temperature overnight and the residue is dissolved in 1 1. of ether. The resulting solution is washed with 1N sodium bicarbonate and brine. After drying over anhydrous MgSO4, the solvent is removed at reduced pressure to give 195 g. of benzyloxy-L-alanine, t-butyl ester as a yellow oil which is used without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[C:21](O)(=[O:23])[CH3:22].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[C:21]([N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[O:10])[CH:12]=2)[CH2:17]1)(=[O:23])[CH3:22]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Reactant: CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 0.046 m acetic acid, 111 mg HOBt, 276 mg EDC, 0.603 ml triethylamine and 7 ml DMF is stirred 4 h at ambient temperature. The reaction mixture is then purified by silica gel chromatography.
Reaction SMILES: BrC1C2C1CNC1C=CC=CC=12.BrC1C2C3CC3C(=O)NC=2C=CC=1.[Br:26][C:27]1[C:32]2[S:33][CH2:34][C:35](=O)[NH:36][C:31]=2[CH:30]=[CH:29][CH:28]=1>>[Br:26][C:27]1[C:32]2[S:33][CH2:34][CH2:35][NH:36][C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CSc2c(Br)cccc2N1
Agent: BrC1C2CNc3ccccc3C12
Agent: O=C1Nc2cccc(Br)c2C2CC12
Product: Brc1cccc2c1SCCN2

Procedure:
The title compound was prepared using a procedure analogous to bromo-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinoline except that 7-bromo-3,7b-dihydro-1H-cyclopropa[c]quinolin-2(1aH)-one was replaced with 8-bromo-2H-benzo[b][1,4]thiazin-3(4H)-one. LCMS, [M+H]+=231.9. 1H NMR (400 MHz, MeOD) δ 6.86-6.80 (m, 1H), 6.73 (t, J=7.9 Hz, 1H), 6.52 (dd, J=8.1, 1.3 Hz, 1H), 3.56-3.49 (m, 2H), 3.09-3.01 (m, 2H).
Reaction SMILES: [N+](C1C=CC(C[CH:9]2[C:14]([Cl:15])=[C:13]([C:16]([O-:18])=[O:17])[N:12]3[C:19](=[O:38])[CH:20]([NH:21][C:22](=[O:37])[C:23]([C:29]4[N:30]=[C:31]([NH:34][CH:35]=[O:36])[S:32][CH:33]=4)=[N:24][O:25][CH2:26][CH2:27][CH3:28])[C@H:11]3[S:10]2)=CC=1)([O-])=O.CO.O>[C].[Pd].O1CCCC1>[CH:35]([NH:34][C:31]1[S:32][CH:33]=[C:29]([C:23](=[N:24][O:25][CH2:26][CH2:27][CH3:28])[C:22]([NH:21][CH:20]2[C:19](=[O:38])[N:12]3[C:13]([C:16]([OH:18])=[O:17])=[C:14]([Cl:15])[CH2:9][S:10][C@H:11]23)=[O:37])[N:30]=1)=[O:36]
Reactant: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(Cl)C(Cc3ccc([N+](=O)[O-])cc3)S[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 85.5 %

Procedure:
A suspension of 4-nitrobenzyl-7-[2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 2.4 g.), 10% palladium carbon (1.0 g.), methanol (24 ml.), water (3.6 ml.) and tetrahydrofuran (48 ml.) was subjected to catalytic reduction under ordinary pressure at room temperature. After removing insoluble substance by filtration, the filtrate was concentrated in vacuo. Water and ethyl acetate were added to the residue, and adjusted to pH 8 with a saturated aqueous solution of sodium bicarbonate. The insoluble substance was removed by filtration, and the aqueous layer was separated. Ethyl acetate was added to the solution, adjusted to pH 2.0 with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution and extract were combined together, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo, and the residue was triturated with diethyl ether and collected by filtration to give 7-[2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.6 g.).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]([C:15]([O:17]CC)=O)[CH2:12][C:11]=3[CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([NH2:24])[CH:22]=[CH2:23]>C(O)C>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]([C:15]([NH:24][CH2:21][CH:22]=[CH2:23])=[O:17])[CH2:12][C:11]=3[CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1Cc2cc(-c3ccccc3)ccc2O1
Reactant: C=CCN
Solvent: CCO
Product: C=CCNC(=O)C1Cc2cc(-c3ccccc3)ccc2O1

Procedure:
An ethanol solution of 1E and an excess of 2-propenamine was refluxed for 2.5 days. The excess amine and the solvent were evaporated under reduced pressure. The resulting gum was recrystallized from methylene chloride/hexane to give 1, as a white solid, mp: 112° C.