Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][O:16][CH2:17][CH2:18][NH2:19].[BH4-].[Na+]>CO>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][CH2:18][CH2:17][O:16][CH3:15])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-BOC-4-piperidone (2.00 g) and 2-methoxyethylamine (872 μl) were stirred together in methanol (20 ml) at room temperature for 12 hours. Sodium borohydride (760 mg) was added in several aliquots over 30 minutes and the reaction mixture stirred for a further 12 hours at ambient temperature. The solvents were removed in vacuo and the residue diluted with dichloromethane (50 ml) and washed with brine, dried (MgSO4). The solvents were removed in vacuo to give a residue which was purified by flash silica chromatography to give 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.69 g) as a colourless oil. To a solution of 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (425 mg) stirring in anhydrous acetonitrile (10 ml) was added benzyl bromide (215 μl), followed by potassium carbonate (340 mg) and the reaction mixture heated to reflux for 12 hours.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:17](C(OC(C)(C)C)=O)[NH:18]C(OC(C)(C)C)=O)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:33]1[N:34]=[CH:35][N:36]([C:38](C2C=CC=CC=2)(C2C=CC=CC=2)[C:39]2C=CC=C[CH:40]=2)[CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:57](#N)[CH:58]=C.[N:61]12CCCN=C1CCCCC2>CC#N>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:57]([CH3:58])=[N:18][N:17]=3)[C:11]=2[CH:10]=[C:9]1[C:33]1[N:34]=[CH:35][N:36]([CH2:38][CH2:39][C:40]#[N:61])[CH:37]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: C=CC#N
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)n2Cc2ccccc2)n1
Solvent: CC#N
Product: Cc1nnc2ccc3c(cc(-c4cn(CCC#N)cn4)n3Cc3ccccc3)n12
Reaction time: 0.25 h

Procedure:
A mixture of 6-benzyl-7-(1H-imidazol-4-yl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (4.3 mg, 0.013 mmol, from Example 74) and 2-propenenitrile (2.6 μL, 0.039 mmol, Aldrich) in MeCN (0.17 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (2.0 μL, 0.013 mmol, Aldrich). The reaction was allowed to proceed for 15 minutes, then was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (3.3 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH:15]=2)O)=[CH:4][CH:3]=1.Cl.[CH3:31][OH:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH:15]2[O:32][CH3:31])=[CH:4][CH:3]=1
Reactant: OC(C1=CCN(Cc2ccccc2)CC1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CO
Agent: Cl
Product: COC1CN(Cc2ccccc2)CCC1=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A mixture of 50.9 parts of α,α-bis(4-fluorophenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinemethanol, 320 parts of methanol and 800 parts of a hydrochloric acid solution 1N was stirred first for 3 hours at reflux temperature and then for 56 hours at room temperature. The whole was evaporated till all traces of methanol were removed. The free base was liberated with ammonium hydroxide. The product was extracted with 1040 parts of dichloromethane. The extract was washed with 100 parts of water, dried, filtered and evaporated. The residue was dissolved in 270 parts of N,N-dimethylformamide. The whole was heated to 60° C. 2.5 Parts of a sodium hydride dispersion 50% were added at 80° C. After stirring for 1 hour at 80° C., the mixture was cooled to room temperature. 9 Parts of iodomethane were added dropwise. Upon completion, the whole was stirred and heated for 30 minutes at 40° C. After cooling, the reaction mixture was poured onto 2000 parts of ice-water. The product was extracted twice with 450 parts of methylbenzene. The combined extracts were dried, filtered and evaporated. The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 29.6 parts (57%) of 4-[bis(4-fluorophenyl)methylene]-3-methoxy-1-(phenylmethyl)piperidine as a residue (intermediate 29).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:24][O:23][CH2:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[O:23]1[CH2:24][CH:21]([CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2COC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CC(C2COC2)CCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-hydroxy-1-(hydroxymethyl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (7.62 g, 0.029 mol) in anhydrous THF (100 mL) at 0° C., a solution of n-BuLi (1.6 M in hexanes, 18.4 mL, 0.029 mol) was added dropwise. The resulting mixture was stirred at 0° C. for 30 min, then a solution of toluenesulfonyl chloride (5.26 g, 0.028 mol) in anhydrous THF (50 mL) was added by canula. The thick reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. A solution of n-BuLi (1.6 M in hexanes, 18.4 mL, 0.029 mol) was added dropwise and the reaction mixture heated at 60° C. for 2 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, pentane:EtOAc; gradient from 100:0 to 20:80) to afford 4-oxetan-3-ylpiperidine-1-carboxylic acid tert-butyl ester as a white solid (5.33 g, 75%). TFA (10 mL) was added to a solution of 4-oxetan-3-yl-piperidine-1-carboxylic acid tert-butyl ester (7.1 g, 0.029 mol) in DCM (100 mL) and the mixture stirred at ambient temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (50 g), the cartridge was washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: 2 M NH3 in MeOH 100:0 to 98:2 to 95:5 to 90:10 to 85:15 to 80:20) to afford 4-Oxetan-3-ylpiperidine as a colourless oil which solidified on standing (2.05 g, 49%). 1H NMR (CDCl3, 300 MHz) δ 4.75 (dd, J=7.9, 6.0 Hz, 2 H); 4.52-4.42 (m, 2 H); 3.14-3.04 (m, 2 H); 2.81-2.67 (m, 1 H); 2.61 (td, J=12.2, 2.6 Hz, 2 H); 1.85-1.68 (m, 1 H); 1.60 (m, 2 H) and 1.02 (qd, J=12.2, 4.0 Hz, 2 H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.Cl[CH2:18][C:19]1[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[O:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.CO>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:30]=[CH:31][C:26](/[CH:25]=[CH:24]/[C:21]2[O:22][CH:23]=[C:19]([CH2:18][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)[N:20]=2)=[CH:27][CH:28]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (400 mg, 1.84 mmol) and 4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (529 mg, 1.84 mmol) were dissolved in dimethylformamide (3 ml), potassium carbonate (279 mg, 2.02 mmol) was added and the mixture was stirred at 65-75° C. for 4 hours. 4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (40 mg, 0.184 mmol) was added and the mixture was stirred at 65-75° C. for 3 more hours. After cooling to room temperature, water (5 ml) and methanol (3 ml) were added in this order, and the mixture was stirred at room temperature for 40 min. The precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give 1-[4-[4-[[2-[(E)-2-[-4-(trifiuoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole (799 mg, yield 93%).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:16]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([OH:22])(=[O:21])[CH2:19][SH:20].B(F)(F)F.[CH3:27][CH2:28]OCC.Cl>ClCCCl.O>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:16][S:20][CH2:19][C:18]([O:22][CH2:27][CH3:28])=[O:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOCC
Reactant: O=C(O)CS
Reactant: OCc1[nH]c2ccccc2c1-c1ccccc1
Agent: Cl
Agent: FB(F)F
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)CSCc1[nH]c2ccccc2c1-c1ccccc1
Reaction time: 0.25 h

Procedure:
A 250 mL round-bottom flask containing a magnetic stirring bar equipped with a reflux condenser was charged with 1.6 g (0.00717 mol) of compound 62, 0.8 mL (0.00717 mol) of thioglycolic acid and 50 mL of 1,2-dichloroethane. At 0° C., 1.4 mL (0.0107 mol) of BF3.Et2O dissolved in 10 mL of 1,2-dichloroethane was added slowly. The resulting mixture was stirred for 15 minutes and then 100 mL of water and 10 mL of HCl (1N) were added. The product was extracted with 2×50 mL of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was used for the next step (preparation of Example 18).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1.[C:14]([O-])(=[O:16])[CH3:15].[Na+].C(C1C(=O)CC(C2C=CC(F)=CC=2)CC1=O)(=O)C>>[C:14]([CH:9]1[C:10](=[O:12])[CH2:11][CH:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:7][C:8]1=[O:13])(=[O:16])[CH3:15]
Reactant: O=C1CC(=O)CC(c2cccs2)C1
Reactant: CC(=O)[O-]
Agent: CC(=O)C1C(=O)CC(c2ccc(F)cc2)CC1=O
Agent: [Na+]
Product: CC(=O)C1C(=O)CC(c2cccs2)CC1=O

Procedure:
The title compound was prepared from 5-thien-2-yl-cyclohexane-1,3-dione (600 mg, 3.09 mmol) and sodium acetate (253 mg, 3.09 mmol), following the procedure describing the synthesis of 2-acetyl-5-(4-fluoro-phenyl)-cyclohexane-1,3-dione (example 3/a stage 1).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:21][NH2:22])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:21][NH:22][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[CH3:1])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(CN)N2CCOCC2)cc1
Reactant: Cc1cccc(C(=O)O)c1C
Product: COc1ccc(C(CNC(=O)c2cccc(C)c2C)N2CCOCC2)cc1

Procedure:
From 2,3-dimethylbenzoic acid and 2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@@H:5]([CH:13]([CH3:15])[CH3:14])[N:6]=[C:7]([O:10][CH2:11][CH3:12])[CH2:8][N:9]=1)[CH3:2].[Li]CCCC.Br[CH2:22][C@@H:23]([CH:33]([CH3:35])[CH3:34])[CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH2:26]([O:25][CH2:24][C@H:23]([CH:33]([CH3:35])[CH3:34])[CH2:22][C@H:8]1[C:7]([O:10][CH2:11][CH3:12])=[N:6][C@H:5]([CH:13]([CH3:15])[CH3:14])[C:4]([O:3][CH2:1][CH3:2])=[N:9]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC1=N[C@H](C(C)C)C(OCC)=NC1
Reactant: CC(C)[C@H](CBr)COCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC1=N[C@H](C(C)C)C(OCC)=N[C@H]1C[C@H](COCc1ccccc1)C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of (R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine (15.4 g, 0.084 mol) in anhydrous THF (250 mL) at −78° C. was added dropwise 2.5 M n-BuLi in hexanes (34 mL, 0.085 mol) over 45 min. After stirring for 30 min at −78° C., a solution of (S)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene (15.6 g, 0.056 mol) in THF (100 L) was added dropwise over 30 min. The mixture was stirred for 2 h at −78° C. and then at −20° C. for 18 h. After evaporation, the residue was partitioned between H2O (200 mL) and EtOAc (3×200 mL). The combined organic layers were washed with brine (0.5 L), dried over MgSO4, evaporated, and purified by flash chromatography on silica gel eluting with 1:25 EtOAc/hexane to give (2S,5R)-2-((S)-2-(benzyloxymethyl)-3-methylbutyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine (18.5 g, 80%). 1H NMR (400 MHz, CDCl3): δ8.00 (s, 1H), 7.34-7.24 (m, 5H), 4.50 (s, 2H), 4.03 (m, 1H), 3.93 (m, 1H), 3.72 (s, 3H), 3.62 (s, 3H), 3.54-3.42 (m, 2H), 2.27 (m, 1H), 1.94-1.88 (m, 1H), 1.80-1.61 (m, 1H), 1.47-1.42 (m, 1H), 1.05 (d, J=6.4 Hz, 3H), 0.88 (d, J=6.4 Hz, 3H), 0.80 (d, J=6.4 Hz, 3H), 0.68 (d, J=6.4 Hz, 3H); MS: 403 (M++1).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.O.[CH2:9]=O.[C:11]([BH3-])#[N:12].[Na+]>C(#N)C.C(O)(=O)C>[CH3:9][N:12]([CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: Nc1ccccn1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(C)c1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To an ice-cold solution of 2-aminopyridine (5.0 g, 53.12 mmol) in acetonitrile (150.0 mL) was added sequentially water (33.0 mL) followed by formaldehyde (37% aq. solution, 50.0 mL) and sodium cyanoborohydride (10.0 g, 159.13 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min followed by drop wise addition of acetic acid (12.0 mL). The reaction mixture was then allowed to stir at room temperature for 15 h. After the completion of the reaction (TLC monitoring), the solvent was evaporated and the residue was treated with aqueous NaOH (2N, 50.0 mL) and extrated with hexane (3×50.0 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified over silica gel (100-200 M, 2% EtOAc-Hexane) to get the desired compound (3.50 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br-:10].[Na+].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: Cc1ccc(Cl)cc1Cl
Reactant: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(CBr)c(Cl)c1
Temperature: 80 °C

Procedure:
To a 500 mL round bottom flask fitted with a Teflon magnetic stirrer was added 2,4-dichlorotoluene (Aldrich) (14.4 g, 90 mmol) in 300 mL glacial acetic acid. To this was added sodium bromide (9.4 g, 92 mmol) and anhydrous ceric ammonium nitrate (100 g, 182 mmol) and the reaction mixture was heated at 80° C. for 2.5 h. The reaction mixture was then poured into 1000 g of ice and water. The slurry was extracted with ether (3×200 mL) and the combined ether layers were washed with saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude product was chromatographed by flash column chromatography on silica gel (eluted with 100% hexanes) and the desired product obtained. 1H-NMR 500 MHz (CDCl3): δ 4.58 (s, 2H), 7.28 (m, 1H), 7.43 (m, 2H),
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH2:10][S:9][C@H:8]2[N:5]([C:6](=[O:23])[C@H:7]2[NH:11][C:12](=[S:22])[CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:24]([O-:26])=[O:25].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH2:10][S:9][C@H:8]2[N:5]([C:6](=[O:23])[C@H:7]2[NH:11][C:12](=[S:22])[CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:24]([OH:26])=[O:25]
Reactant: O=C([O-])C1=C(CCl)CS[C@@H]2[C@H](NC(=S)Cc3cc(Cl)ccc3Cl)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: O=C(O)C1=C(CCl)CS[C@@H]2[C@H](NC(=S)Cc3cc(Cl)ccc3Cl)C(=O)N12
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A slurry of (6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, diphenylmethyl ester (10.0 g, 15.8 mmol) in CH2Cl2 (200 mL) at 0° C. was treated with anisole (24 mL) and then trifluoroacetic acid (80 mL). The resulting solution was stirred for 1 h at 0° C. and then concentrated under reduced pressure. The residue was stirred with Et2O, and the resulting solid was collected by filtration to give 5.20 g of (6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a white solid (70% yield), m.p. 125° C. 1H NMR (300 MHz, DMSO-d6) δ 3.51 (d, J=18 Hz, 1 H), 3.70 (d, J=18 Hz, 1 H), 3.91 (s, 2 H), 4.52 (d, J=11 Hz, 1 H), 4.58 (d, J=11 Hz, 1 H), 5.13 (d, J=5 Hz, 1 H), 5.70 (dd, J=5, 8 Hz, 1 H), 7.24 (dd, J=2, 8 Hz, 1 H), 7.47 (dd, J=2.8 Hz, 1 H), 9.28 (d, J=8 Hz, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)#[N:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([NH:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)=[O:12])#[N:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: N#Cc1cccc(OCCCC(=O)O)c1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(NC(=O)CCCOc2cccc(C#N)c2)cc1
Reaction time: 0.03 h

Procedure:
100 mg (0.49 mmol) of 4-(3-cyanophenoxy)butyric acid and 50 mg (0.49 mmol) of triethylamine were stirred in dimethylformamide under cooling with ice. 53 mg (0.49 mmol) of ethyl chloroformate was added to the resultant mixture. After stirring for 2 minutes, 58 mg (0.49 mmol) of p-aminobenzonitrile was added to the reaction mixture. The temperature was elevated to room temperature, and they were stirred overnight. 1 N hydrochloric acid was added to the reaction mixture. After the extraction with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the crude title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[H-].[Na+].[NH:30]1[CH:34]=[CH:33][CH:32]=[N:31]1>CN(C)C=O>[N:30]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[C:4]([C:24]([F:27])([F:25])[F:26])[CH:3]=2)[CH:34]=[CH:33][CH:32]=[N:31]1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2cccn2)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Yield: 54.9 %

Procedure:
In the manner of Example 2, employing (4-fluoro-2-trifluoromethyl-phenyl)-(5H, 11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.20 g), pyrazole (0.25 g) and dimethylformamide (35 ml). The product (0.62 g) was obtained as a colorless amorphous solid, MS, m/z: 423.2 (M+H)+, 445.2 (M+Na)+, 845.3 (2M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][C:8]1[C:9]([CH2:14]O)=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:6]>C(Cl)(Cl)Cl>[ClH:3].[Cl:3][CH2:14][C:9]1[C:8]([O:7][CH2:5][CH3:6])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: CCOc1cccnc1CO
Solvent: ClC(Cl)Cl
Product: CCOc1cccnc1CCl
Product: Cl

Procedure:
Thionyl chloride (8 cc) was added over 8 minutes to a stirred solution of 3-ethoxy-2-hydroxymethylpyridine (5.6 g) in chloroform (60 cc) at room temperature. After 11/2 hrs the mixture was evaporated to dryness and the residue was recrystallised from 0.16 M ethanolic hydrogen chloride/diethyl ether (1:1) to give 2-chloromethyl-3-ethoxypyridine hydrochloride (6.5 g) m.p. 176°-179.5°. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[N:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1>[Ni].CCO.C1COCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:13][CH2:14]1
Reactant: Cc1cccc(N2CCN(CCCC=Cc3ccc4c(n3)NC(=O)CC4)CC2)c1Cl
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cccc(N2CCN(CCCCCc3ccc4c(n3)NC(=O)CC4)CC2)c1Cl
Yield: 87.1 %

Procedure:
7-{5-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.322 g, 0.758 mmol) was hydrogenated using Ra—Ni (0.5 g) in 1:1 EtOH/THF (50 mL) for 21 h. The reaction was filtered and concentrated. Purification by liquid chromatography (SiO2, 5% MeOH/CH2Cl2 to 7% MeOH/CH2Cl2) gave the title compound as a light yellow foam (282 mg, 0.660 mmol, 87%). MS: APCI: M+1: 427.3 (Exact Mass: 426.22).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][N:44]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:43]1=[O:56]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:10])[NH:41][C@H:42]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][N:44]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:43]1=[O:56])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCCCCN(c2ccccc2)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCCN(c4ccccc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S)-2-oxo-1-phenylazocan-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 64 (5.7 mg, 0.022 mmol) to give a white solid (6.6 mg, 46% yield). Anal. Calcd. for C44H54N4O6S m/z 766.5. found: 767.5 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.41-7.34 (2H, m), 7.31-7.03 (14H, m), 6.84 (1H, d, J=7.7 Hz), 5.32 (1H, t, J=4.7 Hz), 5.14-5.09 (1H, m), 5.06-4.98 (1H, m), 4.97-4.90 (1H, m), 4.19 (1H, t, J=14.0 Hz), 3.67 (3H, s), 3.53 (1H, d, J=14.3 Hz), 3.07 (1H, ddd, J=14.2, 11.1, 2.7 Hz), 2.87-2.67 (5H, m), 2.43-2.26 (3H, m), 2.04-1.95 (2H, m), 1.82-1.45 (16H, m), 1.34-1.24 (1H, m).