Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[NH2:12][C@@:13]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][C@H:14]1[CH2:28]O>ClCCl>[CH2:21]([O:20][CH2:19][C@@H:16]1[O:17][CH2:18][C@@:13]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])[C@H:14]([CH2:28][S:11][C:10]([NH2:9])=[N:12]2)[CH2:15]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N[C@@]1(c2ccccc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: NC1=N[C@@]2(c3ccccc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzoyl isothiocyanate (893 μl) was added dropwise to a solution of [(2R,4R,5S)-5-amino-2-benzyloxymethyl-5-(2-fluorophenyl)tetrahydropyran-4-yl]methanol (2.08 g) in dichloromethane (30 ml). The reaction solution was stirred at room temperature for three hours, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. Several drops of concentrated hydrochloric acid were added to a solution of the resulting intermediate in methanol (40 ml), and the mixture was heated under reflux for five hours. The reaction solution was returned to room temperature, and then the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (40 ml) and DBU (2 ml) was added, followed by heating under reflux for five hours. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography to obtain the title compound (1.61 g).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][OH:23])=[CH:16][C:15]=2[F:24])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6]>CCO.[Pd]>[F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][OH:23])=[CH:16][C:15]=2[F:24])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(F)c(F)c1Nc1ccc(C#CCO)cc1F
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(F)c(F)c1Nc1ccc(CCCO)cc1F
Yield: 93 %

Procedure:
Methyl 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]benzoate was dissolved in absolute EtOH and hydrogenated in the presence of 5% Pd/C by the general procedure of Example 1, Step D. Purification of the resulting oil was carried out by column chromatography on silica gel (20% EtOAc/PE as eluant) to give methyl 3,4-difluoro-2-[2-fluoro-4-(3-hydroxypropyl)anilino]benzoate as a waxy white solid (93%), used directly in the next step. 1H NMR [400 MHz, (CD3)2SO] δ 8.81 (s, 1 H), 7.78 (ddd, J=9.0, 6.1, 2.0 Hz, 1 H), 7.10–7.02 (m, 2 H), 6.98 (ddd, J=8.3, 8.3, 4.0 Hz, 1 H), 6.94 (dd, J=8.2, 1.9 Hz, 1 H), 4.46 (t, J=4.8 Hz, 1 H), 3.82 (s, 3 H), 3.43–3.37 (m, 2 H), 2.58 (t, J=7.7 Hz, 2 H), 1.74–1.66 (m, 2 H). LCMS (APCI−) 338 (M−H).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[S:14]1[C:18]2[CH:19]=[C:20]([C:23]([N:25]3[CH2:32][CH2:31][C:30]4([C:34]([NH2:36])=O)[CH2:33][CH:26]3[CH2:27][C:28]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][C:29]=34)=[O:24])[CH:21]=[CH:22][C:17]=2[N:16]=[CH:15]1.C(N(C(C)C)C(C)C)C>ClCCl>[S:14]1[C:18]2[CH:19]=[C:20]([C:23]([N:25]3[CH2:32][CH2:31][C:30]4([C:34]#[N:36])[CH2:33][CH:26]3[CH2:27][C:28]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][C:29]=34)=[O:24])[CH:21]=[CH:22][C:17]=2[N:16]=[CH:15]1
Reactant: NC(=O)C12CCN(C(=O)c3ccc4ncsc4c3)C(Cc3ccc(O)cc31)C2
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CC12CCN(C(=O)c3ccc4ncsc4c3)C(Cc3ccc(O)cc31)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic anhydride (43 μL) is added to a solution of 3-(benzothiazole-6-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-carboxylic acid amide (40 mg) and ethyldiisopropylamine (50 μL) in dichloromethane (0.5 mL) chilled in an ice bath. The ice bath is removed and the solution is stirred at ambient temperature for 4 h. Then, another portion of trifluoroacetic anhydride (43 μL) and ethyldiisopropylamine (50 μL) are added and the solution is stirred overnight. Methanol (1 mL) is added and the solution is stirred for another 10 min. The solution is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (water/MeCN) to give the title compound.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:11][C@:10]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:6]1[CH2:7][CH2:8][C@H:9]2[O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)(=O)[CH3:2].[N-:42]=[N+:43]=[N-:44].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH2:13]([N:12]1[C@@H:6]2[C@H:5]([N:4]3[C:1]([CH3:2])=[N:44][N:43]=[N:42]3)[CH2:11][C@@:10]1([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:9]([O:26][CH2:27][C:28]1[CH:29]=[C:30]([C:38]([F:40])([F:41])[F:39])[CH:31]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:33]=1)[CH2:8][CH2:7]2)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)N[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nnnn1[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
(1R*,2R*,5S*,6R*)-6-Acetamido-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 109; 384 mg, 0.67 mmol) and sodium azide in dichloromethane (10 ml) were cooled to 0° C. and trifluoromethanesulphonic anhydride (0.11 ml, 0.67 mmol) added. The reaction was warmed to room temperature and stirred for 3 hours then quenched with saturated sodium hydrogen carbonate solution and extracted with dichloromethane (×3). The organics were dried (MgSO4) and concentrated in vacuo to give a brown solid. This was purified by flash column chromatography [2.5% methanol in dichloromethane] to give the title compound as a cream-coloured solid (134 mg, 34%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[N:16]=[CH:15]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc2[nH]ncc2c1)OCc1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(cnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1)OCc1ccccc1

Procedure:
5-Benzyloxycarbonylaminoindazole (0.534 g, 2 mmol) was stirred with trityl chloride (0.556 g, 2 mmol) and tetrabutylammonium iodide (0.074 g, 0.2 mmol) in tetrahydrofuran (5 ml) and triethylamine (0.42 ml, 3 mmol) for 3 days at room temperature. Solvent was removed under vacuum, and the solid residue was triturated with methanol (3 ml). The solid was washed with a mixture of methanol-water (5:1, ca. 15 ml) and dried under vacuum to afford the desired product. Yield 0.73 g (72%). 1H NMR.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].OC1C=CC=[C:22]2C=1C[CH2:20][C:21]2=[O:26].C(C1OC1)Cl.[OH-].[Na+]>>[O:26]1[CH2:22][CH:21]1[CH2:20][O:1][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[CH2:5][CH2:4][C:2]2=[O:3]
Reactant: O=C1CCc2c(O)cccc21
Reactant: O=C1CCc2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCC1CO1
Product: O=C1CCc2c(OCC3CO3)cccc21

Procedure:
3,4-Dihydrocumarine is allowed to react with anhydrous aluminum chloride at 200° C. and the resulting 4-hydroxyindanone is allowed to react with epichlorohydrin in an aqueous solution of sodium hydroxide to give 4-(2,3-epoxypropoxy)-1-indanone (cf. Japanese Patent No. Sho-48-817).
Reaction SMILES: [C:1]1([C:7]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:12]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[O:11][C:10](=[O:23])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:30].[Na+]>CN(C=O)C.O.Cl>[C:24]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([O:8][CH2:9][C:10]([OH:23])=[O:30])[C@H:12]([OH:11])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [OH-]
Reactant: O=C1COC(c2ccccc2)(c2ccccc2)[C@@H](C(=O)OCc2ccccc2)O1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COC(c1ccccc1)(c1ccccc1)[C@H](O)C(=O)OCc1ccccc1

Procedure:
14 g (36 mmol) of benzyl (S)-5,5-diphenyl-2-oxo-1,4-dioxane-6-carboxylate were dissolved in 50 ml of DMF and, with ice-cooling, 43 ml of 1 N NaOH solution were added. After ten minutes, the mixture was diluted with 300 ml of water and neutralized with 43 ml of 1 N hydrochloric acid and the aqueous phase was extracted with ether. The ether phase was dried, the solvent was distilled off and the residue (8.8 g, 21 mmol of an oil) was directly reacted further.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.C1O[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15]C1.[Cl-].[NH4+]>CCCCCC.CCOCC.O1CCCC1>[OH:22][C:19]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH2:20][CH2:21][C:16](=[O:15])[CH2:17][CH2:18]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C1CCC(O)(c2ccncc2)CC1
Yield: 82.6 %

Procedure:
35 ml of ether was cooled to -78° C. and 20 ml of a 1.6 M solution of n-butyllithium in hexane was added thereto. To the obtained mixture, 5 g of 4-bromopyridine dissolved in 30 ml of ether was added. Then 5 g of 1,4-cyclohexanedione monoethylene acetal dissolved in 30 ml of tetrahydrofuran was further added thereto. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and purified by extracting with chloroform to give 5 g of 4-hydroxy-4-(4-pyridyl)cyclohexanone
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:8]([F:23])=[CH:9][C:10]([F:22])=[C:11]([CH:21]=1)[CH2:12][NH:13][C:14](=[O:20])[CH:15](OC)OC.[OH-].[Na+]>>[Cl:6][C:7]1[C:8]([F:23])=[CH:9][C:10]([F:22])=[C:11]2[C:21]=1[CH:15]=[C:14]([OH:20])[N:13]=[CH:12]2
Reactant: COC(OC)C(=O)NCc1cc(Cl)c(F)cc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc2c(Cl)c(F)cc(F)c2cn1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Sulfuric acid (18 M; 2.0 mL, 36 mmol.) was added to N-(5-chloro-2,4-difluorobenzyl)-2,2-dimethoxyacetamide (708 mg, 2.53 mmol) at rt. The solution was stirred at 90° C. overnight. After that time, the mixture was poured into ice and basified with NaOH (10 N) until pH=6-7 forming a solid. The solid was filtered off, washed with water, and dried in vacuo to give the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=6.94 (t, J=9.2 Hz, 1H), 7.48 (s, 1H), 9.04 (s, 1H). MS(ES+): m/z=215.47/217.76 (45/100) [MH+]. HPLC: tR=2.67 min (polar—5 min, ZQ3).
Reaction SMILES: [OH:1][CH:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:5]=2[CH2:4][CH2:3]1.[ClH:24]>C(Cl)Cl.O1CCOCC1>[ClH:24].[ClH:24].[N:11]1([C:10]2[C:5]3[CH2:4][CH2:3][CH:2]([OH:1])[C:6]=3[N:7]=[CH:8][N:9]=2)[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2CCC3O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: OC1CCc2c1ncnc2N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of tert-butyl 4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.37 g, 1.2 mmol) in DCM (20 mL) was added HCl in dioxane (4M, 5 mL). The mixture was stirred at room temperature overnight. The solvent was removed to afford the 4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.25 g, 98%). MS (APCI+) [M+H] +221.
Reaction SMILES: CN(C)N=N[C:5]1[C:13]2[S:12][CH:11]=[C:10]([CH3:14])[C:9]=2[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1.[FH:19]>>[CH3:14][C:10]1[C:9]2[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=[C:5]([F:19])[C:13]=2[S:12][CH:11]=1
Reactant: F
Reactant: Cc1csc2c(N=NN(C)C)cc([N+](=O)[O-])cc12
Product: Cc1csc2c(F)cc([N+](=O)[O-])cc12
Temperature: 100 °C

Procedure:
0.5 mole of 1,1-dimethyl-3-(3-methyl-5-nitrobenzothiophen-7-yl)-triazene is introduced in portions into 10 moles of hydrofluoric acid. The apparatus is then closed, 5 bar of nitrogen are forced in and the mixture is warmed to 100° C. The nitrogen formed is let down continuously under 9 bar. When the reaction had ended (about 1 hour), the mixture is cooled to room temperature, the residual pressure is let down and excess HF is distilled off in vacuo. The residue is stirred in methylene chloride and the mixture is washed neutral with water and finally with NaHCO3 solution, dried and concentrated. The product is purified by recrystallisation from light petroleum.
Reaction SMILES: B(Br)(Br)Br.CCCCCCC.C[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)=[CH:16][CH:15]=1>C(Cl)Cl>[OH:29][C@H:26]1[CH2:27][CH2:28][C@H:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([OH:13])=[CH:19][CH:18]=2)[CH2:24][CH2:25]1
Reactant: COc1ccc(CCN[C@H]2CC[C@H](O)CC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCCCCCC
Product: Oc1ccc(CCN[C@H]2CC[C@H](O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add dropwise 1.0 M BBr3 in heptane (1.35 mL, 1.35 mmol) to a suspension of (±)-(trans)-4-[2-(4-methoxyphenyl)ethylamino]cyclohexanol (Part A, 153.2 mg, 0.61 mmol) in anhydrous CH2C12 (5.0 mL) at 0° C. Add another 1.0 mL of CH2Cl2 when the compound precipitates out. Stir the mixture at 0° C. for 30 minutes and at room temperature for 2 hours. Quench the reaction with 5 drops of H2O and concentrate. Purify the residue on an SCX column, washing with MeOH and then eluting with 2.0 M NH3 in MeOH to yield (±)-(trans)-4-[2-(4-hydroxycyclohexylamino)ethyl]phenol (121.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19]2.[NH2:29][CH2:30][C:31]1[CH:46]=[CH:45][C:34]([C:35]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[NH2:44])=[O:36])=[CH:33][CH:32]=1>>[NH2:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[NH:37][C:35]([C:34]1[CH:33]=[CH:32][C:31]([CH2:30][NH:29][C:26]([C:22]2[C:23]3[C:18](=[CH:17][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)=[CH:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=2)=[O:27])=[CH:46][CH:45]=1)=[O:36]
Reactant: NCc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)NCc5ccc(C(=O)Nc6ccccc6N)cc5)cccc4c3)c2cc1OC
Yield: 71.9 %

Procedure:
The title compound (43.1 mg, 72% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-aminophenyl)benzamide (28.9 mg, 0.12 mmol) by an analogous procedure to that described in example 16. LC-MS (m/z) 600 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[C:21]([C:28]#[N:29])[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[C:31]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C.ClCCCl.[Pd]>[C:1]([O:5][C:6](=[O:30])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH2:28][NH:29][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCCC1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc([N+](=O)[O-])c(C#N)n2)c(OC)c1
Agent: [Pd]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CNC3CCCCC3)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (6-cyano-5-nitro-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester Example 20 (Step 2) (1.10 g, 2.65 mmol, 1 equiv) and cyclohexanone (320 μL, 3.20 mmol, 1.2 equiv) in THF (10 mL) and acetic acid (20 mL), was added Pd/C (10%, 200 mg) and the reaction mixture was hydrogenated overnight. The catalyst was removed by filtration and the filtrate evaporated to give an oil. The oil was dissolved in DCE (15 mL) and treated with cyclohexanone (100 μL, 1.0 mmol) followed by sodium triacetoxyborohydride (954 mg, 4.5 mmol, 1.7 equiv). The reaction mixture was stirred at ambient temperature for 2 h, saturated NaHCO3 was added and the product was extracted with dichloromethane. The organic phase was dried (MgSO4), filtered and the solvent evaporated. The crude material was purified by column chromatography (SiO2, eluted with dichloromethane—MeOH 0-10%) to afford (5-amino-6-cyclohexylaminomethyl-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (390 mg). MS: [M+H]+=471.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][NH:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])C>C(O)=O.ClCCl>[CH2:1]([CH:8]([CH2:12][N:13]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:22]=[O:24])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(CNOCc1ccccc1)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O=CO
Product: O=CN(CC(Cc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of 2-(R,S)-benzyl-3-benzyloxyamino-propionic acid (7.8 g, 27.4 mmol) in formic acid (40 mL) was cooled in an ice-water bath and treated dropwise with acetic anhydride (15 mL). The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was diluted with dichloromethane (150 mL) and partitioned with water (100 mL). The organic layer was separated, washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to yield 2-(R,S)-benzyl-3-(benzyloxy-formyl-amino)-propionic acid as a colourless oil (7.8 g, 91%). 1H-NMR; δ (CDCl3), 7.87-7.16 (10H, m), 4.924.66 (2H, m), 4.03-3.90 (2H, m), 3.17-2.93 (2H, m), 2.78-2.70 (1H, m).
Reaction SMILES: [N:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:19]=C)[CH:17]=3)[NH:12][C:11]=2[C:21]([NH2:23])=[O:22])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:25].[Na+].O.C([O-])(O)=O.[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[CH:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:21]([NH2:23])=[O:22])=[C:10]2[S:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)(=[O:8])=[O:9])=[O:25]
Reactant: C=Cc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)c1[nH]c2ccc(C=O)cc2c1S(=O)(=O)N1CCOCC1

Procedure:
3-(Morpholin-4-ylsulfonyl)-5-vinyl-1H-indole-2-carboxamide (207 mg, 0.617 mmol, 1.0 equiv), sodium periodate (660 mg, 3.09 mmol, 5.0 equiv) and osmium tetraoxide (16 mg, 0.062 mmol, 0.1 equiv) were dissolved in 18 mL of a 5:1 solution of acetone:water and stirred for 18 hours. The mixture was poured into aqueous saturated NaHCO3 and extracted three times with dichloromethane. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The title compound was obtained by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 338.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1)[CH:6]=O.[C:17](=O)([O-])[O-].[K+].[K+].P(=O)([O-])OC(=[N+]=[N-])C(=O)C(C)C>CO>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[C:3]([O:2][CH3:1])[CH:4]=1)#[CH:17]
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: O=C([O-])[O-]
Agent: CC(C)C(=O)C(=[N+]=[N-])O[PH](=O)[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
3-Methoxy-4-(4-methyl-imidazol-1-yl)-benzaldehyde (2.00 g, 9.25 mmol) and anhydrous potassium carbonate (2.56 g, 18.5 mmol) were placed in a 250-mL flask and placed on high vacuum for 10 minutes. Under nitrogen, anhydrous MeOH (60 ml) was added via syringe. To the yellowish suspension was added dimethyl(1-diazo-2-oxopropyl) phosphonate (2.132 g, 11.10 mmol). The reaction was stirred at room temperature for 22 h. The reaction was quenched with aqueous sodium hydrogen carbonate (5%, 100 mL), and the mixture was diluted with diethyl ether (250 mL). The combined organic fractions were washed with brine (saturated, 2×100 mL), dried over MgSO4, filtered and evaporated. The residue was dried on high vacuum to give the title compound as a yellow solid (1.71 g, 87%). The product was pure enough by LCMS and NMR and not further purified.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[C:38]2=[CH:39][N:40]=[N:41][C:42](=O)[C:37]2=[N:36][CH2:35]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)[Cl:56]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Cl:56][C:42]1[N:41]=[N:40][CH:39]=[C:38]2[N:34]([C@@H:11]3[O:12][C@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:14]([O:15][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C@H:10]3[O:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:35]=[N:36][C:37]=12
Reactant: O=C1N=NC=C2C1=NCN2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: ClP(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCN(CC)c1ccccc1
Solvent: CC#N
Product: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nncc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
A solution containing the compound from Step B (1.32 g, 2.27 mmol), the N,N-diethylaniline (365 μL), tetrabutylammonium chloride (1.2 g), freshly distilled phosphorus chloride (1.3 μL) and anhydrous acetonitrile (17 mL) was stirred at 90° C. for 1 hour. The reaction mixture was poured over cracked ice/water. The aqueous layer was extracted with dichloromethane (3×60 mL). The organic layer was washed with sodium hydrogenocarbonate 5%, water and was evaporated to dryness. The crude product was purified on silica gel using n-hexane/ethyl acetate (3/1) as eluant to give the title compound (404 mg) as a yellow powder.