Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH:14]([O:17][CH3:18])[O:15][CH3:16])([CH3:13])[C@H:10]([OH:19])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][C:21]3=[S:29])[C:8]=2[CH:30]=1)([O-])=O.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH:14]([O:17][CH3:18])[O:15][CH3:16])([CH3:13])[C@H:10]([OH:19])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][C:21]3=[S:29])[C:8]=2[CH:30]=1
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COC(OC)[C@]1(C)Oc2ccc(N)cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Yield: 95.6 %

Procedure:
200 mg (0.46 mmol) of the compound obtained in Example 1 was dissolved in 10 ml of methanol, to which 100 mg of Raney-Ni was added. Reaction was continued for 14 hours at room temperature with 3 atmospheric pressure of hydrogen gas. The reaction solution was filtered to eliminate Ni, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), to give 177 mg (yield: 96%) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21]I)(=[O:16])[CH3:15].[H-].[Na+]>CN(C=O)C>[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[Br:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:16])[CH3:15]
Reactant: CC(=O)OCCCCI
Reactant: CCOC(=O)c1ccc(Br)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCCCCOC(C)=O)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Ethyl 4-bromo-3-hydroxybenzoate (200 mg) was dissolved in DMF (10 ml) and 4-iodo-butyl acetate (195 μl) and sodium hydride (56 mg, 60% dispersion in mineral oil) were added and the reaction stirred at 80° C. under nitrogen for 3 hours. The reaction was quenched with water (5 ml) and the solvents evaporated under vacuum. The residue was partitioned between ethyl acetate/chloroform (1:1) and water. The organic phase was dried using a hydrophobic filter and the solvent evaporated in vacuo to give ethyl 3-{[4-(acetyloxy)butyl]oxy}-4-bromobenzoate as a yellow gel (318 mg).
Reaction SMILES: Br.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[CH2:11][C:12]([CH3:15])([OH:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([O:9][CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: Nc1ccc(O)cn1
Reactant: CC(C)(O)CCl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)COc1ccc(N)nc1
Temperature: 140 °C

Procedure:
To a microwave flask containing 6-aminopyridin-3-ol hydrobromide (700 mg, 3.66 mmol) and 1-chloro-2-methyl-2-propanol (597 mg, 5.5 mmol) in anhydrous dimethylformamide (17 ml) was added cesium carbonate (3.7 g, 11.4 mmol) and the material was heated in a microwave oven at 140° C. for 3 hours. The vial was cooled to ambient and the solvent was concentrated in vacuo (rotary evaporator/mechanical pump). The residue was taken up in methylene chloride and filtered to remove insolubles, rinsing well with methylene chloride. The crude material was purified by HPLC on silica gel, eluting with a gradient of 2% to 10% methanol/methylene chloride to provide the desired product as a orange-brown viscous oil which solidified on standing (449 mg). MS (H+)=183 m/e.
Reaction SMILES: FC(F)(F)C(O)=O.[N+:8]([C:11]1[CH:30]=[CH:29][C:14]([CH2:15][NH:16][C:17]([N:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:20][CH2:21][CH3:22])=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH:31]([C@@H:33]1[C@@H:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:36][N:35]([C@H:44]([CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]2)[C:45]([O:47]CC2C=CC(OC)=CC=2)=[O:46])[CH2:34]1)=O>>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17]([N:19]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:31][C@@H:33]3[C@@H:37]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:36][N:35]([C@H:44]([CH:57]4[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]4)[C:45]([OH:47])=[O:46])[CH2:34]3)[CH2:25][CH2:24]2)[CH2:20][CH2:21][CH3:22])=[O:18])=[CH:29][CH:30]=1)([O-:10])=[O:9]
Reactant: CCCN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1
Yield: 63.4 %

Procedure:
The title compound was prepared from 4-(N-(N-(4-nitrobenzyl)carbamoyl)-N-(prop-1-yl)amino)-piperidine trifluoroacetate (21 mg, 0.048 mmol, from Step A) and 2-(R)-(3-(R)-formyl-4-(S)-phenyl-pyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (14 mg, 0.028 mmol, Aldehyde 5) according to the method described in Example 1, Step C to give 11 mg (63%) of the title compound. ESI-MS: 620.4 (M+H); HPLC A: 2.33 min.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:11](Cl)[C:12]#[CH:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:11]#[C:12][CH2:13][NH:1][C@H:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: C#CCCl
Reactant: NC1CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCN[C@@H]1CCc2ccccc21

Procedure:
EP436492 discloses process for preparation of R-(+)-Rasagiline hydrochloride which involves reaction of racemic 1-aminoindan (2) with propargyl chloride (6) in presence of potassium carbonate in acetonitrile (ACN) at 60° C. for 16 hours to obtain racemic Rasagiline base (4) which is purified using column chromatography. The ethereal solution of purified racemic base is then treated with HCl gas followed by recrystallization using isopropanol (IPA) to obtain racemic Rasagiline hydrochloride (7). R-(+)-Rasagiline is separated from the obtained racemic Rasagiline base (4) by preparative HPLC chromatography and further converted to its hydrochloride salt.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.C(N(CC)CC)C.Cl[Si](C)(C)C.[Cl:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>ClCCl>[Cl:27][CH2:28][CH2:29][CH2:30][C:31]([N:10]([C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1)[CH2:11][C:12]([OH:14])=[O:13])=[O:32]
Reactant: O=C(Cl)CCCCl
Reactant: O=C(O)CNc1csc2ccccc12
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CN(C(=O)CCCCl)c1csc2ccccc12
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 621 mg (3 mM) of 3-benzothienylglycine in 15 ml of dichloromethane containing 0.92 ml (6.6 mM) of triethylamine and 717 mg of chlorotrimethylsilane was heated at 50° C. and stirred for thirty minutes and then cooled to 5° C. A solution of 0.336 ml (3 mM) of 4-chlorobutyryl chloride in 5 ml of dichloromethane was added dropwise to the reaction mixture and stirring was continued at 5° C. for one hour following the addition. The reaction mixture was warmed to 25° C. and stirred for an additional hour. The reaction mixture was next washed twice with 10 ml portions of water, dried, and the solvent was removed by evaporation to give an oil. The oil was crystallized from 0.7 ml of acetone and 2.7 ml of water, and recrystallized from ethyl acetate to afford 150 mg of N-(3-chloropropylcarbonyl)-3-benzothienylglycine. m.p. 167°-168° C.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:28]=[CH:27][C:21]2[N:22]=[C:23]([S:25][CH3:26])[S:24][C:20]=2[CH:19]=1.O>CN(C=O)C>[CH3:26][S:25][C:23]1[S:24][C:20]2[CH:19]=[C:18]([CH2:17][N:3]3[C:4]4=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[C:9]4[N:1]=[CH:2]3)[CH:28]=[CH:27][C:21]=2[N:22]=1
Reactant: COC(=O)c1cnc2[nH]cnc2c1
Reactant: CSc1nc2ccc(CCl)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(SC)sc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a stirred solution of methyl 3H-imidazo[4,5-b]pyridine-6-carboxylate (1.34 g, 7.56 mmol) from Step 2 of this Example in anhydrous DMF (25 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 333 mg, 8.32 mmol) and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (1.3 g, 5.66 mmol) from Step 4 of Example 36 in DMF (5 mL). The mixture was allowed to warm to rt then stirred for a further 15 h. To the reaction mixture was added water (300 mL) and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM followed by 1% MeOH in DCM to afford methyl 3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (1.3 g, 46%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.95 (d, J=1.9 Hz, 1H), 8.81 (s, 1H), 8.56 (d, J=1.7 Hz, 1H), 8.00 (d, J=1.1 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.47 (dd, J=1.6, 8.4 Hz, 1H), 5.66 (s, 2H), 3.90 (s, 3H), 2.76 (s, 3H). LCMS (ESI) m/z 371 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][C:7]([C:10]#[N:11])([CH3:9])[CH2:6][C:4](=O)[CH2:3]1.[NH3:13]>CO>[CH3:1][C:2]1([CH3:12])[CH2:8][C:7]([CH2:10][NH2:11])([CH3:9])[CH2:6][CH:4]([NH2:13])[CH2:3]1
Reactant: N
Reactant: CC1(C)CC(=O)CC(C)(C#N)C1
Solvent: CO
Product: CC1(C)CC(N)CC(C)(CN)C1
Yield: 92.1 %

Procedure:
A solution containing 15 wt. % of IPN, 30 wt. % of ammonia and 55 wt. % of methanol was produced and stirred in a pressure vessel under the pressure obtained for 24 h at 25° C.; in this case isophorone nitrile (IPN) was converted largely into isophorone imino nitrile (IPIN). This solution was then pumped at 400 ml/h, corresponding to an LHSV value of 2 h-1, through the reactor, which was filled with 160 ml of hydrogenation catalyst according to the invention (as in Example 1) and 40 ml of inert steel balls. According to the analysis of the product mixture a yield of 92.1% of IPDA was obtained. After distillation of the product mixture a product purity of 99.78% IPDA was obtained.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[O:12][CH3:13].[CH2:15]([N:17]([CH2:28][CH3:29])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[N:26]=1)[C:21](O)=O)[CH3:16]>>[CH3:13][O:12][C:5]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[N:14]=[C:21]([C:20]2[CH:24]=[C:25]([CH3:27])[N:26]=[C:18]([N:17]([CH2:28][CH3:29])[CH2:15][CH3:16])[CH:19]=2)[O:1][N:2]=1
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Reactant: COc1cccc(C(=N)NO)c1OC
Product: CCN(CC)c1cc(-c2nc(-c3cccc(OC)c3OC)no2)cc(C)n1

Procedure:
The title compound is prepared in analogy to Example 5 starting from N-hydroxy-2,3-dimethoxy-benzamidine and 2-diethylamino-6-methyl-isonicotinic acid; LC-MS: tR=1.16*min; [M+1]+=369.03.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[O:11][C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([OH:21])=[C:16]([CH3:22])[CH:15]=3)=[N:13][C:8]2=[CH:7][CH:6]=1.O[CH2:28][C:29]([CH3:41])([CH3:40])[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[O:11][C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:28][C:29]([CH3:41])([CH3:40])[C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])=[C:16]([CH3:22])[CH:15]=3)=[N:13][C:8]2=[CH:7][CH:6]=1
Reactant: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1O
Reactant: CC(C)(CO)C(=O)OCc1ccccc1
Product: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(C)(C)C(=O)OCc1ccccc1
Yield: 41.5 %

Procedure:
Analogously to Example 3 (step (a)), the reaction of 250 mg of 4-[5-(2-fluorophenoxy)oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenol with 178 mg of benzyl 3-hydroxy-2,2-dimethylpropionate gave 160 mg (41%) of benzyl 3-{4-[5-(2-fluorophenoxy)oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenoxy}-2,2-dimethylpropionate.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:4]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH2:12])[N:6]=1.[O:32]=[C:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]1[CH2:43][C:44](O)=[O:45]>>[CH3:1][C:2]1[N:3]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:4]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:44](=[O:45])[CH2:43][N:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:41][CH2:42][C:33]2=[O:32])[N:6]=1
Reactant: Cc1nc(-c2sccc2N)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CN1C(=O)CCc2ccccc21
Product: Cc1nc(-c2sccc2NC(=O)CN2C(=O)CCc3ccccc32)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from 2-(2-methyl-1-trityl-1H-imidazol-4-yl)thiophen-3-amine and 2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid using protocol B (125 mg). Method [7] Retention time 7.33 min by HPLC (MH+ 609).
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].[CH3:7][Si:8]([CH3:14])([CH3:13])[O:9][CH2:10][CH2:11]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:7][Si:8]([CH3:14])([CH3:13])[O:9][CH2:10][CH2:11][C:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cc[cH-]c1
Reactant: C[Si](C)(C)OCCBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCC1=CC=CC1
Reaction time: 12 h
Yield: 64 %

Procedure:
150 ml of a 2.3 M sodium cyclopentadienide solution in tetrahydrofurane (346 mmol) is slowly added to a solution of 68.2 g (346 mmol) 2-trimethylsiloxy-1-bromo-ethane in tetrahydrofurane. The immediate formation of a pinkish solid is observed. The reaction is maintained under stirring for 12 hours. Then, an ammonium chloride aqueous solution is added. The organic phase is extracted, dried with magnesium sulphate and the volatile part is distilled under vacuum, obtaining an orange oil. This oil is distilled in order to obtain a colourless oil. (Tb.: 63–65° C., 0.02 bar (15 mmHg.)). (40.3 g, 221 mmol. Yield:64%). 1H-NMR (CDCl3): 6.50–6.00 (m,3H), 3.75 (m, 2H), 2.95 (m, 2H), 2.65 (m, 2H), 0.15 (s, 9H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.[CH2:25]([N:27]([CH2:30][CH2:31][CH2:32][C:33](=O)[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][CH3:29])[CH3:26]>C(O)C>[CH2:25]([N:27]([CH2:30][CH2:31][CH2:32][C:33]1[C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[C:4]2[C:3](=[CH:20][C:19]([O:21][CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=2)[N:2]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCOC(=O)CC(=O)CCCN(CC)CC
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(CCCN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 13.6 %

Procedure:
A mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone hydrochloride (7.7 g), ethyl 6-(N,N-diethylamino)-3-oxohexanoate (5.0 g) and ethanol (100 ml) was stirred under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform. The chloroform layer was washed with an aqueous saturated solution of sodium bicarbonate and water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-methanol (20:1, v/v) gave ethyl 2-[3-(N,N-diethylamino)propyl]-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (1.51 g, 14%). This compound was recrystallized from ethanol-hexane. Colorless prisms, mp. 96°-98° C.
Reaction SMILES: C([N:8]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH2:10][CH:9]1[CH2:22][OH:23])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[Si:15]([O:14][CH2:13][CH:12]1[NH:8][CH:9]([CH2:22][OH:23])[CH2:10][CH2:11]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(CO)N1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC1CCC(CO)N1
Yield: 86.8 %

Procedure:
To a solution of 1-benzyl-5-t-butyldimethylsilyloxymethyl-2-hydroxymethylpyrrolidine (6.3 g) in methanol (63 ml) was added palladium hydroxide on carbon (630 mg) under nitrogen atmosphere. The apparatus was evacuated to remove nitrogen, then filled with hydrogen, and the mixture was stirred under hydrogen atmosphere until 19 mmol of hydrogen was absorbed. The palladium hydroxide on carbon was filtered off and the solvent was removed under reduced pressure to give 5-t-butyldimethylsilyloxymethyl-2-hydroxymethylpyrrolidine (4.0 g). To a solution of this residue in tetrahydrofuran (60 ml) and water (30 ml) were added sodium bicarbonate (4.10 g) and then allyl chloroformate (1.42 ml) at room temperature. After stirring for 2 hours, sodium bicarbonate (2.1 g) and allyloxycarbonyl chloride (1.42 ml) was added. After stirring for an hour, ethyl acetate (100 ml) and water (50 ml) were added and the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine successively, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (eluent: hexane/ethyl acetate, 9:1-4:1 V/V) to give 1-allyloxycarbonyl-5-t- butyldimethylsilyloxymethyl-2-hydroxymethylpyrrolidine (4.91 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16](=[O:19])[CH2:17][CH3:18])=[C:4]([O:20][CH3:21])[CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](O)=[O:30])(=[O:25])=[O:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][C:16](=[O:19])[CH2:17][CH3:18])[C:29](=[O:30])[C:28]2[CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=[C:26]([S:23]([CH3:22])(=[O:25])=[O:24])[CH:27]=2)=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CCC(=O)CNc1cnccc1-c1ccc(F)cc1OC
Product: CCC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to Example 90, from 1-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-ylamino]-butan-2-one (example 203, intermediate a) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 24 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100), followed by a second chromatography using preparative HPLC (Gemini NX column) and a gradient of methanol:water (with 0.05% formic acid) (80:20 to 98:2). Light red foam (13%). MS (ESI): m/z=539.126 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[O:12][C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].Cl[CH:22]([O:24]C)Cl>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[O:12][C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([CH:22]=[O:24])[C:14]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: CCOC(=O)N1CCc2oc3c(OC)cccc3c2C1
Solvent: ClCCl
Product: CCOC(=O)N1CCc2oc3c(OC)ccc(C=O)c3c2C1
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
2-ethyoxycarbonyl-6-methoxy-1,2,3,4-tetrahydro[1]benzofuro[3,2-c]pyridine (from step 7) (0.420 g, 1.52 mmol) was dissolved in dichloromethane (25 ml). To this stannic chloride (0.675 g, 2.59 mmol) was added followed by addition of dichloromethylmethylether (0.17 g, 1.52 mmol) at −10° C. and stirred for 30 min. Reaction was quenched by pouring on crushed ice and extracted with ethyl acetate. Ethyl acetate layer was washed with water (10 ml×2), brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography using 100-200 mesh silica gel and eluted in 10% ethyl acetate in petroleum ether to get 170 mg of the product as white solid.
Reaction SMILES: C([C:3]1([CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:8][CH2:7][CH2:6][C:5](=O)[CH2:4]1)C.[CH3:15][NH:16][NH2:17]>C(O)CC>[CH:3]1([C:10]2[CH2:11][C:12](=[O:14])[N:16]([CH3:15])[N:17]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CNN
Reactant: CCC1(CCC(=O)O)CCCC(=O)C1
Solvent: CCCO
Product: CN1N=C(C2CCCCC2)CC1=O

Procedure:
To ethyl 3-oxo-cyclohexanepropionic acid (4.4 g, 0.234 mole) in n-propanol (500 ml) is added dropwise with stirring under nitrogen at 80°C. methylhydrazine (13.8 g, 0.3 mole). After heating at reflux during 5 hours, the reaction is cooled and evaporated to a residual oil. Crystallization from ethylacetate gives a white powder mp 170.5°C. to 172°C.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:10][C:9]=1[C:19]([O:21]C)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:10][C:9]=1[C:19]([NH2:2])=[O:21])[CH3:5]
Reactant: [NH4+]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N=NN(C)C
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)N=Nc1cc(-c2ccccc2)sc1C(N)=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 8 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (80 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]-5-phenylthiophene-2-carboxylate (2.2 g) in THF (15 mL) for 5 min followed by catalytic amount of PEG-400 and the mixture was stirred at rt for 36 h. The solution was poured into ice cooled water and extracted with chloroform. The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (94:6) as eluents to give the product. The crude product was recrystallized from chloroform-hexane to give the product as a yellow color solid (170 mg, 8%), mp 220-222° C. IR (neat) νmax, 3343, 2922, 2855, 1642, 1595, 1221, 1023, 880, 841 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.30 (1H, br s), 7.64-7.66 (2H, m), 7.53 (1H, s), 7.30-7.41 (3H, m), 6.34 (1H, br s), 3.59 (3H, s), 3.20 (3H, s); 13C NMR (100 MHz, CDCl3): δ 164.7, 151.1, 146.7, 133.9, 128.9, 128.5, 125.8, 125.4, 114.7, 43.6, 36.5; LC-MS (positive ion mode): m/z 297 (M+Na)+.