Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[C@H:6]([CH2:7][C@@H:8](OC2CCCCO2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[O:5][C:4]1=[O:33])[CH3:2].[CH2:34]([O:41][C:42]([NH:44][C@H:45]([C:50]([OH:52])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([C@@H:3]1[C:4](=[O:33])[O:5][C@H:6]1[CH2:7][C@@H:8]([O:51][C:50](=[O:52])[C@H:45]([CH2:46][CH:47]([CH3:49])[CH3:48])[NH:44][C:42]([O:41][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:43])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CC)OC1CCCCO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CC)OC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
from (3S,4S)-3-ethyl-4-[(S)-2-[(tetrahydro-2H-pyran-2-yl) oxy]nonadecyl]-2-oxetanone. 10.B.1) 796 mg of N-[(benzyloxy)carbonyl]-L-leucine were dissolved in 10 ml of methylene chloride the solution was cooled to 2°-3° C. and 309 mg of dicyclohexylcarbodiimide were added. After 15 minutes the white crystals were filtered off under suction and washed with methylene chloride. The filtrate was evaporated at room temperature in vacuo and the residue was dissolved in 7 ml of N,N-dimethylformamide (DMF). This solution was added to 574 mg of (3S,4S)-3-ethyl-4-[(S)-2-hydroxynonadecyl]-2-oxetanone and 22 mg of 4-dimethyl-amino-pyridine in 6 ml of DMF. The mixture was stirred for 30 minutes. The mixture was poured on to 100 ml of ice-water and extracted three times with 20 ml of diethyl ether. The combined organic phases were dried over sodium sulfate, filtered and evaporated. After chromatography on silica gel there was obtained N-[(benzyloxy)carbonyl]-L-leucine (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester as white crystals of m.p. 44°-47° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:24][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3ccc(F)cc3o2)c1
Reactant: CCCN
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2ccc(F)cc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-6-fluorobenzoxazole (552 mg, 2.0 mmol) and propylamine (492 μL, 6.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7](Cl)=[N:6][C:5]([C:9]#[N:10])=[C:4]([C:11]#[N:12])[N:3]=1.[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1.O>O1CCCC1>[NH2:1][C:2]1[C:7]([NH:18][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:6][C:5]([C:9]#[N:10])=[C:4]([C:11]#[N:12])[N:3]=1
Reactant: N#Cc1nc(N)c(Cl)nc1C#N
Reactant: NC1CCCC1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nc(N)c(NC2CCCC2)nc1C#N
Temperature: 40 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
4.2 g (0.023 mol) of 2-amino-3-chloro-5,6-dicyanopyrazine was dissolved in 50 ml of dry tetrahydrofuran, and 4.0 g (0.047 mol) of cyclopentylamine was dropwise added thereto at room temperature. After completion of the dropwise addition, the mixture was stirred at 40° C. for 1 hour, and the reaction solution was poured into 500 ml of water. The precipitated solid was collected by filtration and recrystallized from isobutyl alcohol to obtain 4.9 g of slightly yellow crystals (yield: 93.4%, decomposition point: 222° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16]O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16][N:29]4[C:25](=[O:35])[C:26]5=[CH:34][CH:33]=[CH:32][CH:31]=[C:27]5[C:28]4=[O:30])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:24]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 2, 8-bromo-1-(2-hydroxyethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dioxane is treated with phthalimide, triphenylphosphine and subsequently with diethyl azodicarboxylate to give 8-bromo-1-(2-phthalimidoethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21](O)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26].[NH2:27][C@@H:28]1[C@@H:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][CH2:31][N:30]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:29]1>>[CH2:34]([C@H:33]1[CH2:32][CH2:31][N:30]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:29][C@@H:28]1[NH:27][C:21]([C:14]1[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]2[O:10][C:9]([CH3:25])([CH3:24])[C:8](=[O:26])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=2[CH:13]=1)=[O:22])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Cc2ccccc2)[C@@H](N)C1
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)O)cc21
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N[C@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3Cc3ccccc3)cc21

Procedure:
Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid, tert-butyl (rac.)-(3R,4S)-3-amino-4-benzylpiperidine-1-carboxylate (US 2005/182095), the title compound was obtained in a similar manner to Reference Example 197.
Reaction SMILES: O.[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].O1C=CC2C([O:17][CH2:18][C@@H:19]([OH:42])[CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[S:31][C:30]5[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=5[C:28]=4[CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH2:23][CH2:22]3)=CC=CC1=2.[O:43]1[CH2:45][C@H:44]1[CH2:46][O:47][C:48]1[C:53]2[O:54][CH:55]=[CH:56][C:52]=2[CH:51]=[CH:50][CH:49]=1>CO>[OH2:4].[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].[O:54]1[CH:55]=[CH:56][C:52]2[CH:51]=[CH:50][CH:49]=[C:48]([O:17][CH2:18][C@@H:19]([OH:42])[CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([C:27]4[S:31][C:30]5[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=5[C:28]=4[CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH2:25][CH2:26]3)[C:53]1=2.[O:54]1[CH:55]=[CH:56][C:52]2[CH:51]=[CH:50][CH:49]=[C:48]([O:47][CH2:46][C@@H:44]([OH:43])[CH2:45][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[S:31][C:30]5[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=5[C:28]=4[CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH2:23][CH2:22]3)[C:53]1=2.[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4]
Reactant: CN(C)CCCc1c(C2CCN(C[C@H](O)COc3cccc4occc34)CC2)sc2ccccc12
Reactant: c1cc(OC[C@@H]2CO2)c2occc2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: CN(C)CCCc1c(C2CCN(C[C@H](O)COc3cccc4ccoc34)CC2)sc2ccccc12
Yield: 39.9 %

Procedure:
A solution 4-(3-(3-dimethylaminopropyl)benzo[b]thiophen-2-yl)piperidine (0.075 g, 0.248 mmol, prepared in example 15) and (S)-(+)-7-(oxiranylmethoxy)benzo[b]furan (0.047 g, 0.248 mmol) in methanol (3 mL) was heated at reflux for 18 hours and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/10% methanol/1% ammonium hydroxide in dichloromethane gradient elution) to give the title compound as a yellow oil (0.039 g, 32%). The oxalate was prepared to give the title compound. FDMS m/e=493 (M++1 of free base). C29H36N2O3S.C2H2O4.0.5H2O
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]([OH:11])[CH2:10][C:4]=2[CH:3]=1.[Br:18][CH2:19][CH2:20]O.B(F)(F)F.CCOCC.O>C1C=CC=CC=1>[Br:18][CH2:19][CH2:20][O:11][CH:9]1[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][C:2]([CH3:1])=[CH:3][C:4]=2[CH2:10]1
Reactant: OCCBr
Reactant: Cc1ccc2c(c1)CC(O)c1ccccc1S2
Agent: FB(F)F
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: Cc1ccc2c(c1)CC(OCCBr)c1ccccc1S2
Temperature: 12.5 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of 2-methyl-10,11-dihydrodibenzo[b,f]thiepin-10-ol (3.63 g, 15 mmol, prepared as described in Ger. Offen. 2,336,130, 1974) and 2-bromoethanol (2.5 g, 20 mmol) in absolute benzene (25 ml), a solution of boron trifluoride etherate (2.25 g. 15.8 mmol) in absolute benzene (10 ml) was dropwise added at 10-15° C. over 15 minutes. The reaction mixture was stirred at 10-15° C. for 2 h and water (18 ml) was added. The organic layer was separated, washed with water (2×25 ml), dried (Na2SO4) and evaporated in vacuo to give 3.83 g (73%) crude 10-(2-bromoethoxy)-2-methyl-10,11-dihydrodibenzo[b,f]thiepine, which was used without further purification in the next step.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[S:15][CH:14]([CH2:16]O)[CH2:13][S:12]1.OCC1CSC[S:21]1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[S:15][CH:14]([CH2:16][SH:21])[CH2:13][S:12]1
Reactant: OCC1CSC(c2ccc3ccccc3c2)S1
Reactant: OCC1CSCS1
Product: SCC1CSC(c2ccc3ccccc3c2)S1

Procedure:
The same method was followed as in Example 1 except that 2-(β-naphtyl)-4-hydroxymethyl-1,3-dithiolane produced in Example 4 was used in stead of 4-hydroxymethyl-1,3-dithiolane synthesized in Manufacturing Example 1 to obtain 2-(β-naphtyl)-4-mercaptomethyl-1,3-dithiolane represented by the following formula (2-8).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]([C:24]4[S:25][C:26]([C:30]([O:32]CC)=[O:31])=[C:27]([CH3:29])[N:28]=4)[C:20](=[O:35])[CH:19]=3)[CH2:14][C@H:13]2[O:36][CH2:37][CH3:38])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Na+].Cl>O1CCOCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]([C:24]4[S:25][C:26]([C:30]([OH:32])=[O:31])=[C:27]([CH3:29])[N:28]=4)[C:20](=[O:35])[CH:19]=3)[CH2:14][C@H:13]2[O:36][CH2:37][CH3:38])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(-n2ccc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](OCC)C3)cc2=O)nc1C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCO[C@@H]1CN(c2ccn(-c3nc(C)c(C(=O)O)s3)c(=O)c2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
Ethyl cis(±)-2-[4-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-2-oxopyridin-1(2H)-yl]-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (140b) (10.8 mg, 0.0192 mmol) was dissolved in dioxane (0.5 mL). A 1 N aqueous sodium hydroxide solution (0.5 ml, 0.5 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was neutralized with 1 N hydrochloric acid and brine was added, followed by extraction with chloroform three times. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Thereafter, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane/methanol=9/1) to obtain 4.5 mg of the title compound as a colorless solid (44%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[O:5])[CH3:2]>C1(C)C=CC=CC=1>[CH2:1]([O:3][P:4]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C@H:6]1[C@H:7]([C:8]([O:10][CH3:11])=[O:9])[CH2:15][CH:14]=[CH:13][CH2:12]1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(/C=C/C(=O)OC)CCCCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOP(=O)(CCCCc1ccccc1)[C@@H]1CC=CC[C@H]1C(=O)OC
Temperature: -78 °C
Yield: 118.9 %

Procedure:
A solution of the title compound from Example 1A (3.72 g, 12.0 mmols) in a minimum amount of toluene (ca 5 ml) was transferred to a 25×150 mm glass tube which served as a liner of a stainless steel Parr pressure bomb. The bomb and its contained tube were cooled to -78° C. and a stream of butadiene was bubbled through the mixture until the glass tube was nearly full. The pressure bomb was then quickly sealed and allowed to warm to room temperature. The bomb and its contents were then heated to 100° C. and maintained at that temperature for 24 hours, after which they were cooled to room temperature. The pressure was released from the bomb and methanol was added to the contents, resulting in a gelatinous precipitate. The precipitate was removed by filtration and the filtrate was concentrated to a clear oil (3.52 g) The oil was chromatographed on LPS-1 silica gel, eluting with ethyl acetate, to give the title compound (2.6 g, 59%, Rf 0.2).
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2)(=[O:17])=[O:16])([O-])=O>CCO>[NH2:6][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2)(=[O:17])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 100.2 %

Procedure:
Tin (II) chloride dihydrate (4.11 g, 18.2 mmol) was added to a solution of 2-nitro-N-quinolin-8-yl-benzenesulfonamide (Example Compound 6) (2.0 g, 6.07 mmol) in EtOH (50 ml) and the mixture was heated under reflux for 2 h. After cooling, the mixture was concentrated in vacuo. The crude residue was dissolved in EtOAc (40 ml) and cooled in an ice bath, the mixture was basified with aqueous ammonia. The resulting white precipitate was collected by filtration, washed with EtOAc and discarded. The organic combined organic filtrates were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (1.82 g, 53%).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].Br[CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C=O)C>[CH2:17]([N:4]([CH3:3])[C:5](=[O:10])[C:6]([F:9])([F:8])[F:7])[CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12]
Reactant: CCCCC=CBr
Reactant: CNC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Sodium hydride (1.05 eq) was slowly added at 0° C. to a solution of N-methyltrifluoro-acetamide (25 g) in DMF (140 mL). The mixture was stirred for 1 h at room temperature under nitrogen. Then, a solution of bromohexene (32.1 g) in DMF (25 mL) was added dropwise and the mixture was heated to 70° C. for 12 hours. The reaction mixture was poured on water (200 mL) and extracted with ether (4×50 mL), dried (MgSO4), filtered and evaporated to give 35 g of the target product 18 as a yellowish oil which was used without further purification in the next step.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:22][CH2:23][CH3:24])[N:3]=1.N(OCCC(C)C)=O.[ClH:33]>C(#N)C.[Cu](Cl)Cl>[Cl:33][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:22][CH2:23][CH3:24])[N:3]=1
Reactant: CCOc1nc(N)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOc1nc(Cl)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 60 °C
Reaction time: 3 h

Procedure:
14.8 g (45.631 mmol) of 2-amino-6-ethoxy-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile are initially charged in 830 ml of acetonitrile, 32.07 g (273.785 mmol) of isoamyl nitrite and 36.81 g (273.785 mmol) of copper(II) chloride are added and the mixture is stirred at 60° C. for 3 hours. 800 ml of 1N hydrochloric acid are added, and the reaction mixture is extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The residue is triturated with ethanol, and the solid is filtered off, washed with ethanol and dried under high vacuum. As the mother liquor still contains product, it is adsorbed onto 35 g of silica gel and purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 2:1→1:1). This gives a total of 11.9 g (72% of theory) of the target compound.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C1COCC1.CN(C=O)C>[F:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:3])=[CH:15][CH:14]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1cccoc1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Reaction time: 2.5 h

Procedure:
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (2.31 g, 15 mmol, Aldrich) in THF (40 mL) and DMF (10 mL) at rt was added 4-fluoroaniline (1.67 g, 15 mmol), and the reaction mixture was stirred for 2.5 h. To the 4-fluoroaniline intermediate formed via a Michael addition was added EDCI.HCl (3.85 g, 20 mmol) and DMAP (120 mg) at rt. The reaction mixture was stirred at rt overnight. To the reaction mixture were added 1 N aq. HCl (50 mL) and EtOAc (150 mL). The EtOAc layer was separated, and the aqueous layer was washed with EtOAc (150 mL). The combined EtOAc layers were dried over MgSO4 and concentrated in vacuo to obtain a semi-solid material (˜4.4 g). The crude product was dissolved in ether (100 mL) and methanol (15 mL), and the solid which formed after stirring was filtered off. The filtrate was concentrated in vacuo to afford the desired product (2.95 g, 80%) as a semi-solid, which was sufficiently pure to use in the next step without further purification. 1H NMR (DMSO-d6) δ 8.23 (dd, 1H, J=7.2, 2.2 Hz), 7.57 (dd, 1H, J=6.6, 1.7 Hz), 7.32-7.34 (m, 2H), 7.17 (t, 2H, J=8.8 Hz), 6.32 (t, 1H, J=7.1 Hz), 3.89 (s, 3H); MS(ESI+) m/z 248.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:30](O)C>C(OCC)C>[CH2:1]([O:2][C:3]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:21][CH:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:15][CH:16]=2)=[CH:5][CH:4]=1)[CH3:30]
Reactant: COc1ccc(-c2ccc(N3CC(CNC(C)=O)OC3=O)cc2)ccc1=O
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOc1ccc(-c2ccc(N3CC(CNC(C)=O)OC3=O)cc2)ccc1=O
Temperature: 25 °C
Yield: 85 %

Procedure:
A slurry of (±)-N-[[3-[4-(4-methoxy-5-oxo-1,3,6-cycloheptatrien-1-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (0.100 g, 0.27 mmol) in absolute ethanol (10 mL) was treated with a catalytic quantity of sodium hydride (5 mg of a 60% dispersion in mineral oil). The mixture was heated to reflux under nitrogen, during which time the mixture became a homogeneous solution. After 15 min of reflux the solution was cooled to ambient temperature and a solid precipitate noted. The reaction mixture was diluted with diethyl ether and the solids collected by filtration. After drying in vacuo, 0.088 g (85%) of the title compound was obtained as a light yellow solid with the following characteristics:
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.C1(C2C3C=CC=CC=3N(CC(N3CCN(C)CC3)=O)C(=O)N(CC(O)=O)N=2)CCCCC1.[C:72]([O:76][C:77](=[O:87])[N:78](C1C=CC=C(N)C=1)[CH3:79])([CH3:75])([CH3:74])[CH3:73].C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[C:72]([O:76][C:77](=[O:87])[N:78]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:79])([CH3:75])([CH3:74])[CH3:73]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CN1CCN(C(=O)CN2C(=O)N(CC(=O)O)N=C(C3CCCCC3)c3ccccc32)CC1
Agent: COC(=O)c1cccc(N)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1, step e) except that {5-cyclohexyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-acetic acid (Example 72, step b) and (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) were used instead of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.12 (1H, s), 7.46 (2H, m), 7.27 (2H, m), 7.03 (1H, t), 6.91 (1H, t), 6.46 (1H, dd), 6.30 (1H, dd), 4.52 (2H, m), 4.37 (1H, d), 4.14 (1H, d), 3.62 (2H, m), 3.49 (2H, m), 2.79 (5H, m), 2.40 (4H, m), 2.30 (3H, s), 2.00-1.75 (6H, m), 1.26 (4H, m). The compound was further characterised as the di-hydrochloride salt. Found: C, 53.60; H, 7.08; N, 14.50%; C30H39N7O3.2.0HCl.3.0H2O requires: C, 53.54; H, 7.05; N, 14.57%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:17]([O:24][CH2:16][CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[OH:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Reactant: OCc1ccccc1
Solvent: CCO
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 5-(4-Bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole and benzyl alcohol. After the reaction the material was submitted to chiral preparatory HPLC (Chiralcel AS Column, 2% EtOH in hexanes, 65 minute run). The first enantiomer off of the column is Enantiomer A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[N:10][C:3]=12.ClC1C=CC=C(C(OO)=[O:19])C=1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:19])=[C:4]2[NH:8][CH:9]=[N:10][C:3]=12
Reactant: Clc1ccnc2[nH]cnc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Product: [O-][n+]1ccc(Cl)c2nc[nH]c21

Procedure:
7-Chloro-3H-imidazo[4,5-b]pyridine (15 g, 97.7 mMol) was dissolved in 150 mL of glacial acetic acid and m-chloroperbenzoic acid (23 g, 131 mMol) was added in portions to the stirred solution. After 12 hours the solid was isolated and washed with ether. The solid was suspended in 400 mL of hot ethanol, stirred, and isolated. The product, 7-chloro-3H-imidazo[4,5-b]pyridine-4-oxide, was dried in vacuo. Yield 14.98 g (8.83 mMol, 90.4%); m.p. 200° C. (dec).