Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:29])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]C)=[O:26])[CH:20]=2)=[O:17])[CH:11]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:10][CH:9]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38].[OH-].[K+]>CO.O>[C:33]([O:32][C:30]([CH:11]1[CH2:10][CH:9]([S:37]([C:40]2[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=2)(=[O:38])=[O:39])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:12]1[C:13](=[O:29])[CH2:14][NH:15][C:16](=[O:17])[NH:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[C:25]([OH:27])=[O:26])=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(S(=O)(=O)c3ccc(C)cc3)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)C2CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc3cccc(C(=O)O)c3)C2c2ccccc2F)cc1
Yield: 12.5 %

Procedure:
A The process is performed as described in Example 1A, but starting with 2.2 g of tert-butyl (2RS,4SR,5RS)-5-(2-fluorophenyl)-1-{2-[3-(3-methoxycarbonylphenyl)ureido]acetyl}-4-(4-methylphenyl)sulphonyl-2-pyrrolidinecarboxylate and 0.19 g of potassium hydroxide in a mixture of 60 cm3 of methanol and 20 cm3 of distilled water. After treatment, 0.27 g of (2RS,4SR,5RS)-3-(3-{2-[2-tert-butoxycarbonyl-5-(2-fluorophenyl)-4-(4-methylphenyl)sulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid is obtained [Rf=0.5; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD at a temperature of 373 K, δ in ppm): 1.52 (s, 9H): C(CH3)3); from 2.35 to 2.55 and 2.79 (2 mts, 1H each: CH2 at 3); 2.45 (s, 3H: ArCH3); 3.66 and 3.96 (broad d and d respectively, J=17 Hz, 1H each: COCH2N); 4.05 (mt, 1H: H4); 4.62 (t, J=8 Hz, 1H: H2); 5.70 (d, J=3 Hz, 1H: H5); from 7.00 to 7.55 (mt, 8H: aromatic H); 7.80 (mt, 1H: H of the aromatic at 5 (H6)); 7.85 (d, J=8 Hz, 2H: H of the aromatic at 4 (ortho to the CH3)); 8.00 Ct, J=1.5 Hz, 1H: aromatic H CH2: ortho to the COOH))].
Reaction SMILES: [OH-].[Na+].C([S:6][CH2:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=O)C>CO>[SH:6][CH2:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C)CSC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C(C)CS
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
At -20° C., 3N NaOH (150 mL, 450 mmol) was added dropwise to a solution of ethyl 3-(acetyl-thio)-2-methylpropanoate (66.47 g, 349 mmol, Step 1) in 700 mL of MeOH and the mixture was stirred at that temperature for 30 min. 25% Aq NH4OAc was then added and the title thiol was extracted with EtOAc, dried over MgSO4, concentrated and distilled to yield 42.52 g (82%) of the title compound as an oil; bp: 96-98° C./15 mmHg. 1H NMR (CDC13): δ1.21-1.36 (6H, m), 1.50 (1H, t, SH), 2.66 (2H, m), 2.81 (1H, m), 4.19 (2H, q).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[O:35][N:34]=2)=[CH:29][CH:28]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC(O)=O>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:25][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[O:35][N:34]=2)=[CH:31][CH:32]=1
Reactant: NC(=O)c1cc(-c2ccc(C=O)cc2)no1
Reactant: CC1Cc2ccccc2N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC1Cc2ccccc2N1Cc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
To a solution of 2-methylindoline (21 μL, 0.16 mmol) in dichloroethane (1 mL) was added Na(OAc)3BH (88 mg, 0.415 mmol). The mixture was stirred at room temperature under argon for 20 min. A slurry of 3-(4-formyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 20; 20 mg, 0.093 mmol) in dichloroethane (1 mL) was added, followed by AcOH (20 μL). The reaction mixture was stirred at room temperature overnight. 1 M Na2CO3 solution was added and the mixture was extracted with CHCl3 (3×25 mL). The organic layer was washed with brine, dried (Na2SO4), evaporated, and purified by chromatography (11-20% acetone/CH2Cl2) to give 3-[4-(2-methyl-2,3-dihydro-indol-1-ylmethyl)-phenyl]-isoxazole-5-carboxylic acid amide (25 mg, 54%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.36 (br. s., 1H), 7.98 (br. s., 1H), 7.85 (d, J=8.2 Hz, 2H), 7.56 (s, 1H), 7.48 (d, J=7.8 Hz, 2H), 6.99 (d, J=7.2 Hz, 1H), 6.84-6.94 (m, 1H), 6.53 (t, J=7.4 Hz, 1H), 6.31 (d, J=7.8 Hz, 1H), 4.45 (d, J=16.3 Hz, 1H), 4.14-4.27 (m, 1H), 3.57-3.76 (m, 1H), 3.12 (dd, J=15.8, 8.6 Hz, 1H), 2.56 (dd, J=16.0, 9.4 Hz, 1H), 1.25 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)([CH3:3])C.CO[C:29](=O)[CH2:30][C:31]1C=CC(I)=[CH:33][CH:32]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:4][C:5]1([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[CH2:7][CH2:6]1)[C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)benzene (Intermediate 71, 60.0 mg, 0.20 mmol) and methyl-(4-iodophenyl)acetate (Reagent B, 66.0 mg, 0.24 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (15.0 mg, 0.08 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (56 mg, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-7% EtOAc-hexanes) afforded 64.0 mg (81%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[Cl:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>C1COCC1>[Cl:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]([NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:21]
Reactant: Cc1cccc(N)n1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)C(Cl)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 124.4 %

Procedure:
To an ice-cooled solution of 6-methylpyridin-2-amine [CAS 1824-81-3] (5.22 g, 44.08 mmol) in 350 mL anhydrous THF was added diisopropylethylamine (15.36 mL, 88.16 mmol). Chloro(phenyl)acetyl chloride [CAS 2912-62-1] (10.0 g, 52.9 mmol) was added dropwise and the resulting mixture was stirred for 1 h while cooling was maintained. The mixture was partitioned between ethyl acetate and water and the organic phase was washed with brine. The organic phase was filtered through a Whatman filter and the volatile components were removed by the use of a rotary evaporator to give title compound (14.3 g) in ˜80% purity (LC-MS). The crude material was forwarded directly to the next step.
Reaction SMILES: [Na+].[CH3:2][C:3]1[C:11]2[C:10]([C:12]([O-:14])=O)=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)=[CH:17][CH:16]=3)=[N:7][C:6]=2[N:5]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[N:4]=1.CCN(C(C)C)C(C)C.[C:43]([O:47][C:48]([N:50]1[CH2:57][C:54]2([CH2:56][CH2:55]2)[NH:53][CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl.O>[C:43]([O:47][C:48]([N:50]1[CH2:57][C:54]2([CH2:55][CH2:56]2)[N:53]([C:12]([C:10]2[C:11]3[C:3]([CH3:2])=[N:4][N:5]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[C:6]=3[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)=[CH:17][CH:16]=3)[CH:9]=2)=[O:14])[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCNC2(CC2)C1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)[O-])c12
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC34CC4)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a suspension of 300 mg of 3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid sodium salt in 7.5 ml of DCM were added 0.12 ml of Hünig's base, 376 mg of BEP and 146 mg of 4,7-diaza-spiro[2.5]octane-7-carboxylic acid tert-butyl ester. The reaction was stirred overnight at r.t. For workup it was diluted with water and DCM and the layers were separated. The organic layer was washed with water twice, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/EtOAc gradient) to obtain 280 mg (66%) of the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.CS(O[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[CH:32][C:33]4[N:34]([C:36]([C:39]([F:42])([F:41])[F:40])=[N:37][N:38]=4)[N:35]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)(=O)=O.[C:43]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:45])[CH3:44].[OH-].[Na+]>CC(N(C)C)=O>[C:43]([N:46]1[CH2:51][CH2:50][N:49]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]5[N:34]([C:36]([C:39]([F:41])([F:40])[F:42])=[N:37][N:38]=5)[N:35]=4)[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[CH2:48][CH2:47]1)(=[O:45])[CH3:44]
Reactant: CC(=O)N1CCNCC1
Reactant: CS(=O)(=O)OCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
DIPEA (107 mL, 613.00 mmol) was added to 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (99 g, 204.33 mmol) and N-acetylpiperazine (28.8 g, 224.77 mmol) in DMA (500 mL). The resulting solution was stirred at 110° C. for 1 hour. The reaction mixture was cooled to room temperature and the solvents were evaporated. The residue was dissolved in ethyl acetate (1 L) and the solution was washed with water (1 L). The aqueous was re-extracted with ethyl acetate (1 L) and the combined organics were washed with brine (1 L), dried over MgSO4, filtered and evaporated to give crude product. The aqueous layer was basified to pH 12 with 2M NaOH, then extracted with ethyl acetate (1 L), washed with brine (1 L), dried over MgSO4, filtered and evaporated to give further crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM then 5% MeOH in DCM. Pure fractions were evaporated to give 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (81 g, 77%) as a solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[Br:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=1>C(C(C)=O)C>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][Br:23])=[CH:27][CH:28]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: BrCCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCc1c(OCc2ccc(CCBr)cc2)ccc(C(C)=O)c1O

Procedure:
To a solution of 1-(2,4-dihydroxy-3-propylphenyl)ethanone (10.0 g; 0.051 m) in dry methyl ethyl ketone (100 ml) was added dried anhydrous sodium carbonate (27 g; 5 mol eq) and sodium iodide (0.5 g). To the stirred suspension was added 4-(2-bromoethyl)phenylmethylbromide (14.2 g; 0.051 m) (literature preparation) and the suspension gently heated at reflux overnight. The cooled suspension was evaporated under reduced pressure, the residue taken up in water and extracted with dichloromethane (×2). The organic extract was washed with aqueous sodium hydroxide (2N), then water, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a yellow oil. The oil was chromatographed on a U30 Sorbsil column using dichloromethane to give a pale yellow oil which crystallised on standing to a white crystalline solid; recrystallised from ethanol m.p. 66°-70° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([NH2:17])=[O:16])=[C:4]2[N:3]=1.CC(O[CH2:22][C:23]1[CH2:32][S:31][C@@H:26]2[C@H:27]([NH2:30])[C:28](=[O:29])[N:25]2[C:24]=1[C:33]([OH:35])=[O:34])=O.B(F)(F)F.O>C(#N)C>[NH2:30][C@@H:27]1[C:28](=[O:29])[N:25]2[C@@H:26]1[S:31][CH2:32][C:23]([CH2:22][S:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[N:5]3[N:12]=[CH:13][C:14]([C:15](=[O:16])[NH2:17])=[C:4]3[N:3]=1)=[C:24]2[C:33]([OH:35])=[O:34]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: NC(=O)c1cnn2c(C(F)(F)F)cc(S)nc12
Agent: FB(F)F
Solvent: CC#N
Solvent: O
Product: NC(=O)c1cnn2c(C(F)(F)F)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](N)[C@H]4SC3)nc12
Reaction time: 5 h

Procedure:
A mixture of 1.60 g of 5-mercapto-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and 1.66 g of (7R)-7-aminocephalosporanic acid in 120 ml of acetonitrile was treated while stirring with 20 ml of a 20 percent solution of boron trifluoride in acetonitrile and stirred at 20° for a further 5 hours. 100 ml of water were added and the mixture was concentrated in a vacuum to a volume of about 80 ml. The pH was adjusted to 2.8 with 25 percent aqueous ammonia. After stirring for 1 hour, the precipitate obtained was filtered, washed in succession with water, acetone and ether and dried. There was obtained (6R,7R)-7-amino-3-[[(3-carbamoyl-7-(trifluoromethyl)pyrazolo[1,5-a]-pyrimidin-5-yl)thio]methyl]-8-oxo-5thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12]O[C:10](=O)[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[CH3:35])[CH2:16]C=O)[C:2]1[CH:7]=[CH:6]C=C[CH:3]=1.[N:37]1[NH:38]C=C2C=1CCC(N)C2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)C(C)C)(C)C>ClC(Cl)C.C(#N)C>[CH2:28]([O:27][C:23]1[CH:22]=[C:21]([CH3:35])[C:20]([CH2:19][C@@H:15]2[CH2:16][CH2:10][N:9]([CH:8]3[CH2:12][CH2:6][C:7]4[C:2](=[CH:3][NH:37][N:38]=4)[CH2:1]3)[C:14]2=[O:36])=[C:25]([CH3:26])[CH:24]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C[C@H](CC=O)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: NC1CCc2n[nH]cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCc2ccccc2)cc(C)c1C[C@@H]1CCN(C2CCc3n[nH]cc3C2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
Combine a solution of (R)-4-((R)-4-Benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dimethyl-benzyl)-4-oxo-butyraldehyde (3.0 g, 6.2 mmol) and racemic 4,5,6,7-Tetrahydro-2H-indazol-5-ylamine (0.85 g, 6.2 mmol) in Dichloroethane (50 mL) and Acetonitrile (50 mL). Treat the solution with sodium triacetoxyborohydride (6.6 g, 31 mmol) and stir 1 hr at room temperature. Treat the reaction with N,N-Diisopropylethylamine (5.6 mL, 31 mmol) and stir overnight at room temperature. Concentrate the reaction to a residue. Quench the residue with saturated sodium carbonate and extract with EtOAc. Wash the organic with brine, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using CH2Cl2 and 2M Ammonia in MeOH to elute the pure product. Remove the solvent to afford 1.66 g (62%) of desired product. MS (m/e): 430 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.[C:22]([C:24]([NH:27][C:28](=[O:35])[CH:29]([NH2:34])[CH2:30][CH:31]([CH3:33])[CH3:32])([CH3:26])[CH3:25])#[N:23]>CN(C)C=O>[C:22]([C:24]([NH:27][C:28]([CH:29]([NH:34][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][Br:1])=[CH:11][CH:10]=1)[CH2:30][CH:31]([CH3:32])[CH3:33])=[O:35])([CH3:26])[CH3:25])#[N:23]
Reactant: CC(C)CC(N)C(=O)NC(C)(C)C#N
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)c1ccc(CBr)cc1)C(=O)NC(C)(C)C#N
Reaction time: 0.17 h

Procedure:
4-Bromomethylbenzoic acid (4.1 mmol), HOBt (4.1 mmol) and WSCD.HCI (4.1 mmol) are dissolved in dimethylformamide (7 ml) and stirred for 10 min. 2-Amino-4-methyl-pentanoic acid (cyano-dimethyl-methyl)-amide (4.1 mmol) is added in DMF (3 ml) and the reaction mixture is stirred at RT overnight. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, 10% citric acid, brine, sodium bicarbonate, brine and dried over magnesium sulfate and evaporated. The crude product is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 185-187° C., Rf=0.43 (n-hexane:ethyl acetate=1:1) is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[Cl:8].CN(C)C1C=CC=CC=1.[Br:20][CH2:21][C:22](Br)=[O:23].O>C(Cl)(Cl)Cl>[Cl:10][C:3]1[C:2]([NH:1][C:22](=[O:23])[CH2:21][Br:20])=[C:7]([Cl:8])[CH:6]=[C:5]([CH3:9])[N:4]=1
Reactant: Cc1cc(Cl)c(N)c(Cl)n1
Reactant: O=C(Br)CBr
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: O
Product: Cc1cc(Cl)c(NC(=O)CBr)c(Cl)n1
Yield: 72.8 %

Procedure:
3-Amino-2,4-dichloro-6-methylpyridine (48.0 g, 271.1 mmol) was dissolved in chloroform (384 mL), and N,N-dimethylaniline (39.4 g, 325.1 mmol) was added to the solution. A solution of bromoacetyl bromide (65.7 g, 325.5 mmol) in chloroform (96 mL) was added dropwise to the mixture under stirring and under cooling with ice. The resultant mixture was stirred for 1 hour at the same temperature and for 1 hour at room temperature. Subsequently, under cooling with ice, a solution of bromoacetyl bromide (27.4 g, 135.7 mmol) in chloroform (48 mL) was further added to the resultant mixture, followed by stirring for 1 hour at room temperature. Water (288 mL) was added to the reaction mixture, and the resultant mixture was stirred for 12 hours at room temperature. The reaction mixture was stirred for 2 hours under cooling with ice, and the precipitated crystals were collected through filtration. The crystals were washed with cold ethanol (96 mL) and dried at 50° C. by use of a blower, to thereby yield 58.81 g of N-(2,4-dichloro-6-methylpyridin-3-yl)-2-bromoacetamide (yield: 73%) as colorless crystals.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:26][NH:25][CH2:24]1.[CH2:34](N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:25]4[CH2:24][C:23]([CH3:22])([N:27]([CH3:34])[C:28](=[O:33])[C:29]([F:32])([F:30])[F:31])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCN(CC)CC
Reactant: CC1(NC(=O)C(F)(F)F)CNC1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C(=O)C(F)(F)F)C1(C)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
A mixture of 1.35 g (4.8 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.45 g (6.2 mmol) of 3-methyl-3-trifluoroacetamido-azetidine hydrochloride and 1 ml of triethylamine in 15 ml of pyridine is heated to reflux for 2 hours. The mixture is evaporated under vacuum, the residue is diluted with ice-cold water and filtered and the product is washed with water. 2.2 g of 1-cyclopropyl-6,8-difluoro-7-{3-methyl-3-[N-(methyl)trifluoroacetamido]-1-azetidinyl}-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point 291°-4° C., are thereby obtained, which product is then hydrolysed by heating it in a mixture of 4 ml of 10% sodium hydroxide and 20 ml of water with 1 ml of ethanol for 1 hour. The mixture is filtered while hot, the filtrate is acidified with acetic acid, the resulting mixture is filtered and the product is washed with water. 1.57 g of 1-cyclopropyl- 6,8-difluoro-7-(3-methyl-3-methylamino-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, melting point >300° C., are thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:17]=O)[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH:25]1[CH2:28][CH:27]([N:29]2[CH2:34][CH2:33][NH:32][C:31](=[O:35])[CH2:30]2)[CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:17][N:25]3[CH2:26][CH:27]([N:29]4[CH2:34][CH2:33][NH:32][C:31](=[O:35])[CH2:30]4)[CH2:28]3)[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[N:3]=1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Reactant: O=C1CN(C2CNC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C1CN(C2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4n3C3CCCCO3)C2)CCN1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
A mixture of 2-chloro-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purine-8-carbaldehyde (1.06 g, 3.01 mmol) and 4-azetidin-3-ylpiperazin-2-one (560 mg, 3.61 mmol) in DCE (60 mL) and DMF (20 mL) was allowed to stir at r.t. for 10 min before the addition of 4 Å powdered molecular sieves (3.0 g) followed by sodium triacetoxyborohydride (1.28 g, 6.04 mmol). The resulting mixture was allowed to stir for 64 h then filtered through Celite® which was washed with DCM. The filtrate was concentrated in vacuo and the resulting residue dissolved in EtOAc and washed with NaHCO3, H2O and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo affording the title compound as a yellow gum (997 mg, 67%). LCMS (method A): RT 2.19 and 2.11 min [M−C5H9O+H]+407.3
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8](=[O:12])(=O)(O)[OH:9]>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([S:8]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)(=[O:12])=[O:9])=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)O
Reactant: Oc1ccccc1
Product: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
According to DE-A-2,708,388, the reaction of phenol with sulfuric acid in the presence of a solvent, e.g. of an aromatic hydrocarbon, gives bis(4-hydroxyphenyl)sulfone and the isomeric 2,4,-dihydroxydiphenylsulfone in a ratio of about 3:1. In addition, as our own experiments have shown, a small amount of 6-hydroxy[1,3-bis(4-hydroxyphenylsulfonyl)]benzene is formed. The yield and purity of the target product are improved by continuously removing the solvent from the reaction by distillation or by distilling off the product after the reaction has been substantially completed, it being important to carry out the distillation in the temperature range of 160°-200° C., since only under these conditions is isomerization of the 2,4'-isomer to bis(4-hydroxyphenyl)sulfone achieved.