Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:10][C:11]1[N:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([S:17]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Yield: 89 %

Procedure:
The title compound was prepared as described for Example 25 using N-isopropylpiperazine and 6-chloropyridine-3-sulfonyl chloride (described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750). Yield: 89%: 1H NMR (CDCl3, 400 MHz) δ 8.73 (d, J=3 Hz, 1 H), 7.96 (dd, J=8, 3 Hz, 1 H), 7.48 (d, J=8 Hz, 1 H), 3.12-3.01 (m, 4 H), 2.76-2.63 (m, 1 H), 2.63-2.54 (m, 4 H), 0.99 (d, J=7 Hz, 6 H); 13C NMR (CDCl3, 100 MHz) δ 156.1, 149.3, 138.2, 131.7, 125.0, 54.8, 48.0, 46.7, 18.7; MS (ES) m/z 304 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C[C@@H](OC)[C@H](F)[C@H]1C(O)=O)=O)(C)(C)C.ClC(N(C)C)=C(C)C.[Br:45][C:46]1[C:47]([F:53])=[C:48]([CH:50]=[CH:51][CH:52]=1)[NH2:49].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16](=[O:18])[NH:49][C:48]1[CH:50]=[CH:51][CH:52]=[C:46]([Br:45])[C:47]=1[F:53])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CO[C@H]1[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C[C@@H]1F
Reactant: Nc1cccc(Br)c1F
Agent: CC(C)=C(Cl)N(C)C
Agent: CO[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)[C@H]1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1[C@@H](C(=O)Nc2cccc(Br)c2F)N(C(=O)OC(C)(C)C)C[C@@H]1F
Reaction time: 2 h

Procedure:
To a solution of (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (prepared as described in Scheme B25, 100 mg, 0.380 mmol) in CH2Cl2 (2.4 mL) at 0° C. under nitrogen atmosphere was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (50.8 mg, 0.38 mmol) and the mixture was stirred at this temperature for 2 h. 3-Bromo-2-fluoroaniline (144 mg, 0.76 mmol) was then added, followed by DIPEA (0.265 mL, 1.52 mmol) and the mixture was stirred at RT for 1 h. The reaction mixture was concentrated and the crude residue was purified by preparative HPLC (Waters Sunfire C18-ODB, 5 μm, 30×100 mm, eluent: 0-0.5 min 5% CH3CN in H2O Flow: 5 mL/min, 0.5-18.5 min 5 to 100% CH3CN/H2O Flow: 40 mL/min, 18.5-20 min 100% CH3CN, CH3CN and H2O both containing 0.1% TFA). The purified HPLC fractions were neutralized by addition of a saturated aqueous solution of Na2CO3, the layer were separated and the aqueous layer was extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. White solid. Rf, TLC (c-hexane/EtOAc 1:1)=0.75; MS (UPLC): 435.1/437.1 [M+H]+, 433.1/435.1 [M−H]−; tR (HPLC conditions f): 2.06 min.
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:17])[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:8]=1[CH3:28])C.Cl.[NH:33]([C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1)[NH2:34].O>CO>[C:39]([C:38]1[CH:41]=[CH:42][C:35]([NH:33][N:34]=[CH:4][C:5]#[C:6][C:7]2[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:17])[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)[C:8]=2[CH3:28])=[CH:36][CH:37]=1)#[N:40]
Reactant: N#Cc1ccc(NN)cc1
Reactant: CCOC(C#Cc1nc(C(=O)OC)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C)OCC
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(C#CC=NNc2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 45 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
In a 100 mL round-bottomed flask, methyl 6-(3,3-diethoxyprop-1-ynyl)-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxylate (SM2, 1.136 g, 2.59 mmol) and 4-hydrazinylbenzonitrile hydrochloride (0.508 g, 3.00 mmol) were stirred in methanol (25 mL) and water (2.5 ml) under air at 65° C. After 1 h, the mixture was allowed to cool to 45° C., water (50 ml) was added and the mixture then cooled to RT. After stirring for 30 minutes, the solid was filtered off, washed with water (100 ml) and then air dried to give methyl 6-(3-(2-(4-cyanophenyl)hydrazono)prop-1-ynyl)-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxylate (1.18 g, 95%) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[Cl:11][C:12]1[C:13]([F:37])=[N:14][C:15](NCC(OC)=O)=[C:16]([Cl:30])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([CH:27]([CH3:29])[CH3:28])[CH:20]=1>>[Cl:11][C:12]1[C:13]([F:37])=[N:14][C:15]([NH:1][CH2:2][CH2:3][C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5])=[C:16]([Cl:30])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH:27]([CH3:29])[CH3:28])[CH:20]=1
Reactant: COC(=O)CNc1nc(F)c(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c1Cl
Reactant: NCCC(=O)NCC(=O)O
Product: CC(C)c1cc(Oc2c(Cl)c(F)nc(NCCC(=O)NCC(=O)O)c2Cl)ccc1O

Procedure:
By use of β-alanyl-glycine in place of glycine methyl ester for the preparation of Compound 1e followed by deprotection as described for example 2.
Reaction SMILES: [CH3:1][N:2]1[N:11]=[N:10][C:9]2[N:5]([CH:6]=[N:7][C:8]=2[C:12]([NH2:14])=O)[C:3]1=[O:4].C1C=CC(OC2C=CC(P3(SP(C4C=CC(OC5C=CC=CC=5)=CC=4)(=S)S3)=[S:29])=CC=2)=CC=1>C(Cl)Cl>[CH3:1][N:2]1[C:3](=[O:4])[N:5]2[CH:6]=[N:7][C:8]([C:12](=[S:29])[NH2:14])=[C:9]2[N:10]=[N:11]1
Reactant: S=P1(c2ccc(Oc3ccccc3)cc2)SP(=S)(c2ccc(Oc3ccccc3)cc2)S1
Reactant: Cn1nnc2c(C(N)=O)ncn2c1=O
Solvent: ClCCl
Product: Cn1nnc2c(C(N)=S)ncn2c1=O

Procedure:
A mixture of temozolomide (3 g, 15.5 mmol) and Belleau's reagent (4.49 g, 8.5 mmol) was refluxed in DCM (80 mL) overnight. The reaction was quenched with water and the precipitate was filtered and washed with diethyl ether to give the pure title compound as an orange solid. (2.75 g, 84%). δH, (DMSO-d6): 9.92 (1H, s), 9.45 (1H, s), 8.81 (1H, s), 3.85 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.O>N1C=CC=CC=1>[CH:18]1([C:21]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:22])[CH2:20][CH2:19]1
Reactant: O=C(Cl)C1CC1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Solvent: O
Solvent: c1ccncc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CC4)nc23)CC1
Reaction time: 1.5 h
Yield: 56.7 %

Procedure:
A solution of 0.300 gm (1.30 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine in 40 mL pyridine was heated to 50° C. To this solution was added 0.13 mL (1.43 mMol) cyclopropanecarbonyl chloride and the reaction mixture was stirred for 1.5 hours. An additional 0.10 mL of cyclopropanecarbonyl chloride were added and the reaction mixture was stirred for an additional hour. The reaction mixture was treated with 1.0 mL of water and was then concentrated under reduced pressure. The residue was diluted with 3:1 chloroform:isopropanol and the solution washed sequentially with water, dilute aqueous sodium hydroxide, and saturated aqueous sodium chloride. The organic phase was then dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to radial chromatography (silica gel, 1 mm), eluting with a gradient of dichloromethane (5-10% methanol) containing 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure. The residue was recrystallized from ethanol/water to provide 0.22 gm (55.9%) of the title compound as a crystalline solid.
Reaction SMILES: C(BC(C(C)C)C)(C(C)C)C.[CH2:12]([C:15]1([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[O:20][C:19](=[O:21])[N:18]([N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]1)[CH:13]=[CH2:14].C1C[O:40]CC1>>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:15]2([CH2:12][CH2:13][CH2:14][OH:40])[O:20][C:19](=[O:21])[N:18]([N:22]([CH3:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)=[CH:35][CH:34]=1
Reactant: C1CCOC1
Reactant: C=CCC1(c2ccc(F)cc2)CCN(N(C)c2ccccc2)C(=O)O1
Agent: CC(C)C(C)BC(C)C(C)C
Product: CN(c1ccccc1)N1CCC(CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
At 0° C., 2M 2-methyl-2-butene in THF (15 mL, 30 mmol) was added to BH3.DMS (1.5 mL, 15 mmol, 10M) in THF (3 mL) and stirred for 1 h to afford a 0.83 M THF solution of disiamylborane. In a separate flask, disiamylborane (0.1 mL, 0.08 mmol) was added to 6-allyl-6-(4-fluorophenyl)-3-(methyl(phenyl)amino)-1,3-oxazinan-2-one (6 mg, 0.018 mmol) in THF (1 mL) at 0° C. The reaction was warmed to rt overnight. The reaction was cooled to 0° C. and quenched with H2O (1 mL) and stirred for 15 min at rt. NaBO3 (22 mg, 0.22 mmol) was added and the reaction was stirred for 2 h. The solvent was evaporated and the crude material purified by prep HPLC to afford 6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-(methyl(phenyl)amino)-1,3-oxazinan-2-one (1.16 mg). LC/MS Method 1 tR=1.51 min m/z=359 (M+1).
Reaction SMILES: C(OC(C1C=C(C2C=CC=C(F)C=2)C=C(O)C=1)=O)(C)(C)C.[C:22]([O:26][C:27](=[O:51])[C:28]1[CH:33]=[C:32]([O:34]CC2C=CC=CC=2)[CH:31]=[C:30]([C:42]2[CH:50]=[CH:49][C:45]3[O:46][CH2:47][O:48][C:44]=3[CH:43]=2)[CH:29]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:51])[C:28]1[CH:33]=[C:32]([OH:34])[CH:31]=[C:30]([C:42]2[CH:50]=[CH:49][C:45]3[O:46][CH2:47][O:48][C:44]=3[CH:43]=2)[CH:29]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)cc(-c2ccc3c(c2)OCO3)c1
Agent: CC(C)(C)OC(=O)c1cc(O)cc(-c2cccc(F)c2)c1
Product: CC(C)(C)OC(=O)c1cc(O)cc(-c2ccc3c(c2)OCO3)c1

Procedure:
The title compound was prepared in the same way as 3′-fluoro-5-hydroxy-biphenyl-3-carboxylic acid tert-butyl ester starting from 3-benzo[1,3]dioxol-5-yl-5-benzyloxy-benzoic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[C:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([C:21](=[O:23])[CH3:22])=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccc(C(C)=O)cc4)CC3)c(OC)nc2c1
Yield: 93 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 93%). 1H NMR (300 MHz, CDCl3): δ 2.53 (s, 3H), 3.48 (s, 4H), 3.77 (s, 4H), 3.90 (s, 3H), 4.13 (s, 3H), 6.86 (d, J=8.7 Hz, 2H), 7.14-7.28 (m, 3H), 7.72 (d, J=8.4 Hz, 1H), 7.89 (d, J=9.0 Hz, 2H).
Reaction SMILES: [C:1]([O:7][CH2:8]Br)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[I-].[Na+].[I-].[NH2:13][C:14]1[S:15][CH:16]=[C:17](/[C:19](=[N:40]/[O:41][CH3:42])/[C:20]([NH:22][C@@H:23]2[C:38](=[O:39])[N:25]3[C:26]([C:35]([O-:37])=[O:36])=[C:27]([C@H:30]4[CH2:34][CH2:33][CH2:32][O:31]4)[CH2:28][S:29][C@H:24]23)=[O:21])[N:18]=1.[Na+]>CC(C)=O.C1(C)C=CC=CC=1.CN1CCCC1=O.C(OCC)(=O)C>[NH2:13][C:14]1[S:15][CH:16]=[C:17](/[C:19](=[N:40]/[O:41][CH3:42])/[C:20]([NH:22][C@@H:23]2[C:38](=[O:39])[N:25]3[C:26]([C:35]([O:37][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:36])=[C:27]([C@H:30]4[CH2:34][CH2:33][CH2:32][O:31]4)[CH2:28][S:29][C@H:24]23)=[O:21])[N:18]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C([C@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCBr
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C([C@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
Pivaloyloxymethyl bromide (247 mg, 1.27 mmol) and sodium iodide (247 mg, 1.65 mmol) in acetone (5 ml) were stirred for 30 min., filtered, and the filtrate concentrated in vacuo. The resulting iodide in toluene (3 ml) was added to a solution of sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(R)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (320 mg, 0.67 mmol) in N-methylpyrrolidinone (5 ml). After stirring for 30 min. at room temperature, the reaction mixture was diluted with ethyl acetate, washed successively with water (×3) and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 80% ethyl acetate in hexane to give the title compound as a yellow foam (297 mg, 78%); νmax (CH 2Cl2) 3387, 1786, 1752, 1735, 1686, 1605 cm-1 ; δH (CDCl3, 250 MHz) 1.22 (9H, s), 1.69 (1H, m), 1.98 (2H, m), 2.18 (1H, m), 3.43 and 3.62 (2H, ABq, J 18.0 Hz), 3.80-3.96 (2H, m), 4.10 (3H, s), 5.08 (1H, d, J 4.7 Hz), 5.19 (1H, m), 5.83-5.92 (3H, m), 6.32 (2H, br. s, exch), 7.02 (1H, s), 7.63 (1H, br. d, exch., J 8.6 Hz). [Mass spectrum: +ve ion (thioglycerol) MH+ (568)].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[O:51]1[CH:55]=[CH:54][CH:53]=[C:52]1[C:56]([NH:58][NH2:59])=[O:57]>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([NH:59][NH:58][C:56]([C:52]1[O:51][CH:55]=[CH:54][CH:53]=1)=[O:57])=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NNC(=O)c1ccco1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)NNC(=O)c1ccco1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
2-Carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) was added to [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] (3.13 g) in dimethylformamide (10 ml) containing diisopropylethylamine (3.2 g) and the mixture stirred for 15 min. 2-Furoic acid hydrazide (1.04 g) was then added and stirring continued for 16 h. The reaction mixture was diluted with water and extracted with diethyl ether. The combined ether extracts were washed with water, dried and solvent removed at reduced pressure. the residue was column chromatographed (silica gel, 20-50% ethyl acetate/hexane) to give the title compound (2.05 g).
Reaction SMILES: [CH2:1]([N:8]([C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]2[N:20]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=3[Cl:33])[N:21]=[C:22]([S:23][CH3:24])[C:14]=12)[CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][C:35](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:36].C(N(CC)CC)C>C(Cl)Cl>[C:35]([O:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]2[N:20]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=3[Cl:33])[N:21]=[C:22]([S:23][CH3:24])[C:14]=12)(=[O:36])[CH3:34]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(N(CCCO)Cc3ccccc3)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(N(CCCOC(C)=O)Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 3-{benzyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-propanol (80 mg, 0.148 mmol) in 1 ml of methylene chloride was treated with acetic anhydrous (38 mg, 0.37 mmol) and triethyl amine (38 mg, 0.37 mmol) and stirred at room temperature for 15 hours. The mixture was quenched with water and a few drops of dilute HCl and extracted with ethyl acetate. The organic layer was neutralized with aqueous sodium bicarbonate and washed with brine, separated, dried and concentrated to give the title compound as an oil. The oil was purified through silica gel column chromatography using chloroform as eluent to give 57 mg of the title compound as a white glass form. 1H NMR (CDCl3): 2.0(s,3H, 2.03(m,2H), 2.45(s,3H), 2.60(s,3H), 3.74(t,2H), 4.10(t,2H), 5.1(s,2H), 7.2-7.4(m,5H), 7.50(s,2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:13])[C:10](O)=[O:11])=[CH:6][CH:5]=[C:4]([Cl:14])[N:3]=1.CN(C)C=O.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:13])[C:10]([Cl:22])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:14])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1ccc(Cl)nc1Cl)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Cl)nc1Cl)C(=O)Cl

Procedure:
23.6 g (0.1 mole) of 2-[(2,6-dichloro-3-pyridyl)oxy]propionic acid, 150 ml of chloroform and 1.5 ml of dimethylformamide were heated with stirring at 55°, and an addition was then made dropwise in the course of 1 hour of a solution of 18 g (0.15 mole) of thionyl chloride in 40 ml of chloroform. The reaction mixture was subsequently refluxed for 16 hours and afterwards concentrated in vacuo. The resulting product was used directly for further reactions.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([O:25][CH3:26])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.[BH4-].[Na+]>C1COCC1.CO.O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:25][CH3:26])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1
Reactant: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1N
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
A solution of 1-(2-fluoroethyl)-4-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (15.94 g, 43.50 mmol) in THF (200 mL) and MeOH (300 mL) was cooled to 0° C. Nickel(II) chloride hexahydrate (5.18 g, 21.80 mmol) was added in one portion. The solution was stirred for 30 min followed by portion-wise addition of NaBH4 (3.29 g, 87.00 mmol). Prior to warming the reaction to rt additional nickel(II) chloride hexahydrate (5.18 g, 21.80 mmol) and NaBH4 (3.29 g, 87.00 mmol) was added to the reaction. The solvent was removed in vacuo and the residue was taken up in DCM, filtered through Celite®, and washed with EtOAc. Purification by flash chromatography provided the title compound of step E (13.46 g, 40.10 mmol, 92%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (qd, J=11.9, 3.6 Hz, 2H), 1.76 (d, J=12.1 Hz, 2H), 2.12-2.20 (m, 1H), 2.35-2.45 (m, 10H), 2.53 (dt, JHF=28.6 Hz, J=4.9 Hz, 2H), 3.37 (d, J=12.1 Hz, 2H), 3.68 (s, 3H), 4.14 (br. s., 2H), 4.47 (dt, JHF=47.9 Hz, J=4.94 Hz, 2H), 6.24 (dd, J=8.2, 2.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 6.45 (d, J=8.4 Hz, 1H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[OH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[CH2:13][CH2:14][C:15](O)=O>Cl>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:15]=1[CH2:14][CH2:13][C:12]1[CH:11]=[C:10]([OH:9])[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)CCc1cccc(O)c1
Agent: Cl
Product: Oc1cccc(CCc2nc3ccccc3[nH]2)c1
Temperature: 135 °C
Reaction time: 8 h
Yield: 803.5 %

Procedure:
A 100 mL flask fitted with a stir-bar and a condenser was charged with 1,2-phenylenediamine (3.42 g, 31.6 mmol), 3-hydroxyhydrocinnamic acid (5.25 g, 3.16 mmol), and 4M HCl (50 mL). The mixture was heated in a 135° C. bath overnight. The mixture was cooled in an ice bath, and the precipitate was filtered and rinsed with H2O (5 mL). The solid was suspended in saturated NaHCO3 (75 mL). 50% aq NaOH was added until pH 11 was attained, and then another portion of saturated NaHCO3 (75 mL) was added. The suspension was stirred overnight. The solid was filtered, pressed with rubber dam, and rinsed with H2O (2×10 mL). The resultant material was dried to give 6.05 g of 69 as a white solid (80%). 1H NMR (60 MHz, CDCl3): δ 7.6-7.4 (m, 2H), 7.4-7.0 (m, 3H), 6.9-6.6 (m, 3H), 5.2 (s, 2H), 3.1 (s, 4H) ppm. HPLC analysis (35:10:55 H2O:A1:MeOH) showed a purity of greater than 99% with a retention time of 3.1 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([B:14]2[O:18][C:17]([CH3:20])(C)C(C)(C)[O:15]2)=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])C=O)[CH3:2].[N+:23](C)([O-:25])=[O:24]>C1COCC1.[OH-].[Na+]>[CH2:1]([O:3][C:4]1[C:5]2[B:14]([OH:15])[O:18][CH:17]([CH2:20][N+:23]([O-:25])=[O:24])[C:6]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: CCOc1c(OC)ccc(C=O)c1B1OC(C)(C)C(C)(C)O1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1c(OC)ccc2c1B(O)OC2C[N+](=O)[O-]
Yield: 58.5 %

Procedure:
Synthesized according to the methods of general procedure 9 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: [3-ethoxy-4-methoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (1.47 g, 4.80 mmol), nitromethane (0.92 g, 14.4 mmol), CATBr (88 mg, 0.24 mmol) in dry THF (20 mL) and NaOH (0.025 M aqueous solution). Purification by silica gel column chromatography (eluant: 10% EtOAc/hexane to 30% EtOAc/hexane) to obtain the title compound as a yellow solid (0.75 g, 59%). 1H NMR {400 MHz, DMSO-d6+D2O (0.01 ml)} δ (ppm) 9.34 (s, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 5.68 (dd, J=9.2, 2.0 Hz, 1H), 5.29 (dd, J=13.2, 2.8 Hz, 1H), 4.55-4.50 (m, 1H), 4.20 (q, J=7.0 Hz, 2H), 3.77 (s, 3H), 1.27 (t, J=7.0 Hz, 3H); MS (ESI) m/z=261 (M−1, negative).
Reaction SMILES: CC1[O:3][CH2:4][C:5]([CH2:26][OH:27])([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:11][CH:10]=2)[N:6]=1.[ClH:28]>C(O)C>[ClH:28].[NH2:6][C:5]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:11][CH:10]=1)([CH2:26][OH:27])[CH2:4][OH:3]
Reactant: CC1=NC(CO)(CCc2ccc(OCCCOc3ccccc3)cc2)CO1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCOc2ccccc2)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[2-(4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenol (300 mg, 1.27 mmol) in DMF (5 ml) was added Cs2CO3 (1.2 g, 3.83 mmol) and (3-bromo-propoxy)-benzene (273 mg, 1.27 mmol). The reaction mixture was stirred at 85° C. for 4 hours. AcOEt and water were then added, the organic layer was separated and the aqueous phase was extracted with AcOEt (3×50 ml). The combined organic extracts were washed with brine, dried over MgSO4, and evaporated to dryness. Purification by flash chromatography (AcOEt/Hexane 9:1) affords (2-methyl-4-{2-[4-(3-phenoxy-propoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl)-methanol as colorless oil. To a solution of (2-methyl-4-{2-[4-(3-phenoxy-propoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl)-methanol (50 mg, 0.135 mmol) in ethanol (2 ml) was added conc. HCl (2 ml). The reaction mixture was stirred at 85° C. for 2 hours, then concentrated to dryness. The residue was re-dissolved in AcOEt and precipitated with hexanes. The solid was filtered off, washed with dry ether and dried in vacuo to afford 2-amino-2-{2-[4-(3-phenoxy-propoxy)-phenyl]-ethyl}-propane-1,3-diol hydro-chloride as a colorless powder. ESI+ MS: m/z=370.4 (M+H)+.