Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=2)[C@@H:15]([C@H:17]2CCCC[N:18]2[CH:23](C2C=CC=CC=2)[C:24]2[CH:29]=CC=CC=2)[OH:16])=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2].FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@@H]([O:73][C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][N:75]=3)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@H](O)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.OC1C=CC=CN=1>C1COCC1>[C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:38]=[C:39]([F:44])[CH:40]=[C:41]([F:43])[CH:42]=2)[C@H:15]([OH:16])[C@H:17]2[CH2:29][C@@H:24]([O:73][C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][N:75]=3)[CH2:23][NH:18]2)=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2]
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](Oc3ccccn3)CN2C(c2ccccc2)c2ccccc2)O1
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Agent: Oc1ccccn1
Solvent: C1CCOC1
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@@H](Oc3ccccn3)CN2)C1=O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
Step 12 (A): (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4R)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)oxazolidin-2-one. To a solution of triphenylphosphine (54 mg, 0.206 mmol) in THF (2.5 mL) at rt was added DEAD (0.0324 mL, 0.206 mmol). After 1 min, a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4S)-1-benzhydryl-4-hydroxypyrrolidin-2-yl)oxazolidin-2-one (Preparation K, 80 mg, 0.172 mmol) in THF (2.5 mL) was added. After 2 min, 2-hydroxypyridine (16.4 mg, 0.172 mmol) was added and the mixture was stirred at rt for 3.5 h. pH 7 buffer was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 0-100% ethyl acetate/hexane) gave 39.7 mg of the title compound as an opaque oil: 1H NMR (CDCl3, 300 MHz) δ 2.17-2.22 (1H, m), 2.32-2.42 (2H, m), 2.74 (1H, dd, J=3, 12 Hz), 3.20 (2H, m), 3.50 (1H, m), 3.78 (1H, m), 4.80 (1H, m), 4.97 (1H, s), 5.02 (1H, s), 5.38 (1H, m), 6.51 (2H, m), 6.66 (1H, m), 6.72 (1H, d, J=9 Hz), 6.81 (1H, t, J=6 Hz), 7.18-7.36 (10H, m), 7.52 (1H, m), 8.04 (1H, m). HPLC retention time: 1.52 min (method A). MS (ESI) (M+H)+ 542.15.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.O=[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(Cl)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(Cl)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 45.6 %

Procedure:
4-[4-Chloro-2-(2-ethoxycarbonyl-vinyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (12.4 g, 30.4 mmol) in EtOAc (150 mL) containing PtO2 (1 g) was placed on a Parr hydrogenator at 60 psi H2. After 18 h the mixture was filtered through celite and evaporated to give a clear brown liquid. The liquid was purified by column chromatography (silica, 20-50% EtOAc/hexanes) to obtain 5.7 g (46%) of the title compound. TLC (silica, 25% EtOAc/hexanes): Rf=0.5. MS (electrospray): exact mass calculated for C21H31ClN2O4, 410.2. m/z found, 411.2 [M++H]. 1H NMR (400 MHz, CDCl3): 7.05 (dd, J=6.06 Hz, 2.54 Hz, 1H), 6.99 (d, J=2.35 Hz, 1H), 6.55 (d, J=8.61 Hz, 1H), 4.13 (dd, J=7.04 Hz, 3.13 Hz, 2H), 4.11-3.98 (m, 2H), 3.81 (br s, 1H), 3.72 (t, J=6.26 Hz, 2H), 3.46-3.36 (m, 1H), 2.75 (t, J=7.43 Hz, 2H), 2.60 (t, J=7.04, 2H), 2.04-1.95 (m, 2H), 1.46 (s, 9H), 1.42-1.33 (m, 2H), 1.26 (t, J=7.24 Hz, 3H).
Reaction SMILES: C(OC(=O)CCC[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](I)[CH:25]=[C:24]([C:29]3[CH:37]=[CH:36][C:32]4[O:33][CH2:34][O:35][C:31]=4[CH:30]=3)[CH:23]=2)[C:10]=1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])C.[N:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1>>[CH2:43]([O:42][C:40](=[O:41])[CH:39]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:49]3[CH:50]=[CH:51][N:46]=[CH:47][CH:48]=3)[CH:25]=[C:24]([C:29]3[CH:37]=[CH:36][C:32]4[O:33][CH2:34][O:35][C:31]=4[CH:30]=3)[CH:23]=2)[C:10]=1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:38][CH3:10])[CH3:44]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccncc1
Product: CCOC(=O)CCc1c(CCCCCCOc2cc(-c3ccncc3)cc(-c3ccc4c(c3)OCO4)c2)cccc1OC(CC)C(=O)OCC
Yield: 124.7 %

Procedure:
A similar procedure as described in Example 12, step 8 was used, starting from 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-iodo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (87 mg, 0.12 mmol) and pyridin-4-ylboronic acid (45 mg, 0.36 mmol) to afford 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-pyridin-4-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy-butyric acid ethyl ester (51 mg, 63%) as a light yellow oil: ES(+)-HRMS m/e calculated for C41H47NO8 (M+H)+ 682.3375, found 682.3369.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:8]=[C:7]([C:20]2[S:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](=[O:26])[N:25]=2)[N:6]=1)(=[O:4])=[O:3].C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:8]=[C:7]([C:20]2[S:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](=[O:26])[N:25]=2)[N:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)CCc1cc(-c2nc(=O)c3ccccc3s2)nc(S(C)(=O)=O)c1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1cc(CCC(=O)O)cc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
tert-Butyl 3-[2-(methylsulfonyl)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.20 g, 0.45 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 0.5 hr. Diisopropyl ether was combined with the reaction mixture to give precipitates, which were recrystallized from ethanol to give the titled compound (0.11 g, 63%) as pale yellow crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[NH:13][C:12](=[O:17])[C:11]3[S:18][CH:19]=[CH:20][C:10]=3[C:9]=2[C:8]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:23][CH:22]=1)(=O)=O.[CH3:38][N:39](C=O)C>[Cl-].[Zn+2].[Cl-].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:38]([C:7]1[CH:16]=[CH:15][C:14]2[NH:13][C:12](=[O:17])[C:11]3[S:18][CH:19]=[CH:20][C:10]=3[C:9]=2[C:8]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:29](=[O:30])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:23][CH:22]=1)#[N:39]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2c(OS(=O)(=O)C(F)(F)F)ccc3[nH]c(=O)c4sccc4c23)cc1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2c(C#N)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 87 %

Procedure:
A solution of 9-{4-[(tert-butoxycarbonylamino)methyl]phenyl}-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-8-yl trifluoromethanesulfonate (176 mg, 0.320 mmol), zinc chloride (75 mg, 0.640 mmol), 1,1′-bis(diphenylphosphino)ferrocene (18 mg, 0.032 mmol), and tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.016 mmol) in anhydrous DMF (4 mL) was heated at 130° C. for 3 h. The reaction mixture was cooled, quenched with water and the resulting precipitate was filtered and purified by column chromatography (silica, methanol/methylene chloride gradient) to afford the desired product (120 mg, 87%) as a brown solid: ESI MS m/z 432 [C24H21N3O3S+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=1>C1COCC1>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[CH:23]=[CH:22][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(C2CCCCN2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(C2CCCCN2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
To a suspension of LiAlH4 (72 mg, 1.8 mmol) in 2 ml of anhydrous THF is added dropwise a solution of methyl 4-(piperidin-2-yl)benzoate hydrochloride (250 mg, 0.98 mmol) in THF at 0° C. The reaction mixture is stirred at room temperature for 4 hours, and is then carefully quenched with water at 0° C. After filtration, the filtrate is evaporated to dryness to give 187 mg of crude product as white solids, which is used for the next reaction without further purification. MS (ESI) m/z 192.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[O:5][C:4](=[O:19])[C:3]=1[S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:27]OC(=O)COC1C=CC(C(=O)C)=CC=1.C(N(CC)CC)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.S1C=CC=C1C(C(OCC)=O)C(OCC)=O>ClCCl>[OH:1][C:2]1[C:7]([CH3:27])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:17][CH:18]=2)[O:5][C:4](=[O:19])[C:3]=1[S:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)COc1ccc(-c2cc(O)c(Sc3ccccc3)c(=O)o2)cc1
Reactant: COC(=O)COc1ccc(C(C)=O)cc1
Agent: CCOC(=O)C(C(=O)OCC)c1cccs1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(-c2ccc(OCC(=O)O)cc2)oc(=O)c(Sc2ccccc2)c1O

Procedure:
The title compound (0.691 g, m.p. 194 - 197° C.) was prepared in a similar manner to that demonstrated in the preparation of [4-[4-hydroxy-2-oxo-3- (phenylthio) -2H-pyran-6-yl]phenoxy]-acetic acid using the following: Methyl-[4-(1-oxoethyl)phenoxy]-acetate (2.00 g, 8.81 mmol), triethylamine (3.68 mL, 26.4 mmol), trimethylsilyltriflate (2.38 mL, 12.3 mmol), dichoromethane (20.0 mL), diethyl 2-(thiophenyl)propane-1,3-dioate (1.34 g, 5.00 mmol.), 1H NMR (400 MHz, DMSO-d6) δ7.585 (d, 2 H, J=9 Hz), 7.325-7.286 (m, 2 H), 7.178 (d, 3 H, J=7.5 Hz), 7.063 (d, 2 H, J=9 Hz), 4.784 (s, 2 H), 2.042 (s, 3 H).
Reaction SMILES: [Br:1]Br.[N:3]1[NH:4][C:5](=[O:10])[NH:6][C:7](=[O:9])[CH:8]=1>O>[Br:1][C:8]1[C:7](=[O:9])[NH:6][C:5](=[O:10])[NH:4][N:3]=1
Reactant: O=c1cn[nH]c(=O)[nH]1
Reactant: BrBr
Solvent: O
Product: O=c1[nH]nc(Br)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 26 h
Yield: 46.4 %

Procedure:
Bromine (2.506 mL, 48.6 mmol) was added to a suspension of 1,2,4-triazine-3,5(2H,4H)-dione (commercially available from Aldrich, 2.5 g, 22.11 mmol) in Water (40 mL). The mixture was stirred at room temperature for 26 hours. A white precipitate was formed. The solid was recovered by filtration and recrystallized from water (15 mL at reflux temperature) affording the title compound 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (1.97 g, 10.26 mmol, 46.4% yield) as a white crystalline solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C(OC([NH:20][C@H:21]([CH3:24])[CH2:22][OH:23])=O)(C)(C)C.O[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.O>[NH2:20][C@H:21]([CH3:24])[CH2:22][O:23][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=1
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OC[C@@H](C)N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
16.6 g of diethyl azodicarboxylate were added, whilst ice-cooling, to a solution of 16.8 g of (R)-2-t-butoxycarbonylamino-1-propanol, 10.0 g of methyl 4-hydroxyphenylacetate and 24.0 g of triphenylphosphine in 50 ml of dry benzene, and the resulting mixture was stirred at room temperature for 2 days. At the end of this time, the benzene solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in 100 ml of methanol, and 200 ml of a 4N solution of hydrogen chloride in dioxane were added to the solution thus obtained, whilst ice-cooling, after which the mixture was allowed to stand at room temperature for 3 hours. The reaction mixture was then poured into water, and the pH of the aqueous mixture was adjusted to a value of 8 to 9 by the addition of an aqueous solution of potassium carbonate, and then the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the ethyl acetate solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give the title compound. [α]D23 -13.2° (c=1.048, chloroform)
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:19][C:20]([OH:22])=[O:21].[N+:23]([O-])([OH:25])=[O:24]>>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Product: O=C(O)COc1ccc2c(-c3cc([N+](=O)[O-])ccc3F)noc2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10.9 g of {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid in 70 ml of ice-cold sulfuric acid, 2.2 ml of 16N nitric acid is added. The reaction mixture is stirred in the cold for 2 hr, allowed to warm to room temperature over 1 hr and poured into ice-water. The precipitate is collected to afford {[7-chloro-3-(2-fluoro-5-nitrophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid. The fluoro-compound is treated with excess sodium methoxide in refluxing methanol for a total of 48 hr. The reaction mixture is acidified and the product is collected by filtration. Recrystallization from acetonitrile affords {[7-Chloro-3-(2-methoxy-5-nitrophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp 260°-262° C. (dec.)
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].Cl.[CH3:11][C:12]1([CH3:19])[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1>>[CH3:11][C:12]1([CH3:19])[CH2:17][CH2:16][CH:15]([N:18]2[CH2:8][CH2:7][CH:2]2[C:3]([O:5][CH3:6])=[O:4])[CH2:14][CH2:13]1
Reactant: COC(=O)C(Br)CCBr
Reactant: CC1(C)CCC(N)CC1
Agent: Cl
Product: COC(=O)C1CCN1C1CCC(C)(C)CC1
Yield: 52 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with 4,4-dimethylcyclohexylamine hydrochloride 18C yielded methyl 1-(4,4-dimethylcyclohexyl)azetidine-2-carboxylate as a brown oil (52%). MS ISP (m/e): 226.3 (100) [(M+H)]+.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[CH2:12][C:13]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[C:17]([OH:19])[CH:18]=3)[C:9]3[C:10]2=[C:5]([CH:6]=[C:7]([OH:24])[C:8]=3[O:22][CH3:23])[CH2:4][CH2:3]1.[CH2:25](Br)[CH:26]=[CH2:27]>>[CH3:1][N:2]([CH2:27][CH:26]=[CH2:25])[CH2:3][CH2:4][C:5]1[C:10]2[CH:11]=[CH:12][C:13]3[C:14]([C:9]=2[C:8]([O:22][CH3:23])=[C:7]([OH:24])[CH:6]=1)=[CH:15][C:16]([O:20][CH3:21])=[C:17]([OH:19])[CH:18]=3
Reactant: C=CCBr
Reactant: COc1cc2c(cc1O)C[C@H]1c3c(cc(O)c(OC)c3-2)CCN1C
Product: C=CCN(C)CCc1cc(O)c(OC)c2c1ccc1cc(O)c(OC)cc12

Procedure:
1 g of boldine was dissolved in 30 ml of N,N-dimethylformamide(DMF), the mixture was reacted with 1.2 ml of allyl bromide at 100°-110° C. for 2 hours. The residue obtained after evaporation under reduced pressure was purified to give the pure compound (1) N-allylsecoboldine.
Reaction SMILES: I[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:28]=2)[C:26]#[N:27])O1.N>>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:28]=2)[C:26]#[N:27])[O:6][N:5]=1
Reactant: Ic1cc(-c2ccccn2)no1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Agent: N
Product: N#Cc1cncc(-c2cc(-c3ccccn3)no2)c1

Procedure:
The titled compound was prepared as the bishydrochloride salt according to Method CC using 5-iodo-3-(pyridin-2-yl)isoxazole (136 mg, 0.5 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (Frontier, 173 mg, 0.750 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.60 (ddd, J=7.3, 4.8, 1.4 Hz, 1H), 7.93 (s, 1H), 8.04 (td, J=7.6, 1.8 Hz, 1H), 8.11 (dt, J=7.9, 1.2 Hz, 1H), 8.78 (ddd, J=2.9, 1.8 Hz, 1H), 8.96 (t, J=2.2 Hz, 1H), 9.16 (d, J=1.6 Hz, 1H), 9.47 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C@@H:12]([OH:15])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl.Cl[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C@@H:12]([O:15][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: ClCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2cccnc2)C1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
55% of NaH in mineral oil (160 mg, 6.68 mmol) is added to a solution of (R)-3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.67 mmol) in THF (8 mL) at 0° C. After 15 min, 3-chloromethyl-pyridine HCl salt (526 mg, 3.20 mmol) is added, and the reaction mixture is stirred at 40° C. After completion, the reaction mixture is quenched by H2O, EtOAc is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a white powder; ES-MS: M+=279.2: AtRet=2.80.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1.[BH4-].[Na+]>CCO>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCC(=O)CC4)c3)cc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCC(O)CC4)c3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
4-oxo-piperidine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (50 mg, 0.1 mmol) in absolute EtOH, at 4° C. was treated with sodium borohydride (4 mg, 0.1 mmol). The reaction was warmed to rt and stirred for 1 hour before the reaction was partitioned between EtOAc and water. The organic phase was washed with brine, dried, filtered and concentrated in vacuo to give 4-hydroxy-piperidine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (39 mg, 78%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.14 (1H, s), 9.07 (1H, s), 8.26 (1H, s), 8.14 (1H, d), 8.10 (1H, s), 7.94 (1H, t), 7.79 (1H, s), 7.71-7.73 (1H, m), 7.64 (1H, d), 7.30-7.33 (1H, m), 7.23-7.28 (1H, m), 6.92-6.94 (1H, m), 6.66 (1H, t), 6.54 (1H, d), 4.68 (1H, d), 4.43 (2H, d), 4.13 (3H, s), 3.79-3.84 (2H, m), 3.60-3.67 (1H, m), 3.00-3.08 (2H, m), 1.70-1.73 (2H, m), 1.23-1.35 (2H, m); m/z (ES+) 500 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:14])[N:11]=[N:12][CH:13]=2)=[C:4]([O:15][CH3:16])[CH:3]=1.CC(C)([O-])C.[Na+].C(=[NH:36])(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])=O.[Na+].[NH4+].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:16][O:15][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[C:8]1[CH:9]=[C:10]([CH3:14])[N:11]=[N:12][CH:13]=1)[NH2:36]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COc1cc(Br)ccc1-c1cnnc(C)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1cc(N)ccc1-c1cnnc(C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
5-(4-Bromo-2-methoxyphenyl)-3-methylpyridazine (1.72 g, 6.20 mmol), Pd2(dba)3 (57 mg, 0.062 mmol), BINAP (116 mg, 0.19 mmol), sodium tert-butoxide (833 mg, 8.68 mmol), benzophenone imine (1.25 mL, 7.44 mmol) and toluene (30 mL) were added into a sealed tube. The flask was purged with N2 three times. The reaction was stirred at 80° C. overnight and then cooled down, filtered through a pad of diatomaceous earth and the filter was washed with MTBE. The filtrate was concentrated. The residue was dissolved in MeOH (60 mL). NaOAc (1.22 g, 14.90 mmol) and ammonium hyxroxide hydrochloride (776 mg, 11.2 mmol) was added. The mixture was stirred at room temperature for 1 hour. Sodium carbonate (1.23 g, 11.60 mmol) was added, and the mixture was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. The residue was taken up in dichloromethane. The organic phase was washed with water, brine, dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 0% to 1% methanol in ethyl acetate to afford the title compound 1.24 g (93%) as a solid.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[S:33]([NH2:36])(=[O:35])=[O:34]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:36][S:33]([C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)(=[O:35])=[O:34])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1cccs1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccs2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2-thiophenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method A described hereinabove. Yield (27%); 1H NMR (d6-DMSO) δ 12.34 (br s, 1H), 7.99 (m, 1H), 7.76 (m, 1H), 7.39-7.08 (m, 14H), 6.85 (d, J=8.4 Hz, 2H), 6.41 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 500 (M+H+).