Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][CH:9]2[O:13][C:12](=[O:14])[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[CH:15]#[C:16][CH:17]([OH:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(N(CC)CC)C.O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:26][CH:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16]#[C:15][C:2]1[N:7]=[C:6]([CH2:8][CH:9]2[O:13][C:12](=[O:14])[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(Cc2cccc(Br)n2)O1
Reactant: C#CC(O)CCCCCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCC(O)C#Cc1cccc(CC2CCC(=O)O2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.8 %

Procedure:
A solution of 500 mg of 5-[(6-bromo-2-pyridyl)-methyl]-tetrahydrofuran-2-one in 13 ml of triethylamine and 2 ml of tetrahydrofuran is mixed with 350 mg of (3RS)-1-undecin-3-ol, 37 mg of bis-(triphenylphosphine)-palladium(II) chloride and 5 mg of copper(I) iodide and the mixture is stirred for 3 days at room temperature. The reaction mixture is evaporated to dryness, distributed between water and ethyl acetate, dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/0-35% ethyl acetate. 294 mg of 5-(6-[(3RS)-3-hydroxy-1-undecinyl]-2-pyridyl-methyl}-tetrahydrofuran-2-one is obtained as oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([F:13])=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C(O)(=[O:16])C.OO>O1CCCC1>[F:13][C:5]1[C:6]([OH:16])=[CH:7][CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(B(O)O)c1F
Reactant: CC(=O)O
Agent: OO
Solvent: C1CCOC1
Product: CC(=O)c1cccc(O)c1F
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of (3-acetyl-2-fluorophenyl)boronic acid (10.0 g, 0.055 mol) in tetrahydrofuran (160 mL) was added glacial acetic acid (60 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 8 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 5 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 1-(2-fluoro-3-hydroxy-phenyl)-ethanone (8.50 g, 100%) as a white solid.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH2:16][N:17]([CH:21]([CH3:23])[CH3:22])[C:18](=[O:20])[CH3:19]>C(Cl)Cl>[CH:21]([N:17]([CH2:16][CH2:15][CH2:14][C:13](=[O:12])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18](=[O:20])[CH3:19])([CH3:23])[CH3:22]
Reactant: CC(=O)N(CCCC(O)c1ccccc1)C(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)N(CCCC(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
Pyridinium chlorochromate (20.35 g, 94.2 mmol) was added to a solution of N-(4-hydroxy-4-phenyl-butyl)-N-isopropyl-acetamide (15.69 g, 62.9 mmol), prepared in the previous step, in 350 ml of methylene chloride and the mixture stirred at room temperature for 2 hours. The entire reaction mixture was poured onto 750 g of silica gel (230-400 mesh) and the material eluted with 50% ethyl acetate-methylene chloride and then ethyl acetate. Isolation of the major fraction gave N-isopropyl-N-(4-oxo-4-phenyl-butyl)-acetamide (12.43 g, 80%) as a green solid, mp 36-39° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][C:6]=2[CH3:13].[CH2:15](Br)[CH:16]=[CH:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:3](=[O:14])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH2:15][CH:16]=[CH:17][CH3:18])[CH:8]=[CH:7][C:6]=2[CH3:13]
Reactant: CC=CCBr
Reactant: Cc1cc2c(O)ccc(C)c2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC=CCOc1ccc(C)c2[nH]c(=O)c(C)cc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
3,8-Dimethyl-5-hydroxycarbostyril (3 g, 15.86 mmol) was dissolved in dimethylformamide (30 ml). To the solution, crotyl bromide (2.06 ml, 20.45 mmol) and potassium carbonate (4.4g, 31.84 mmol) were added. The mixture was stirred at 70° C. for 2 hours. After spontaneous cooling, water (90 ml) was added to the mixture. Precipitated crystals were collected by filtration. The obtained crystals were dissolved in chloroform, washed with water and saturated aqueous NaCl solution in this order, and dried. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-n-hexane. As a result, 2.43 g of the title compound was obtained as colorless crystals (63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(N2Cc3cnc(S(C)=O)nc3NC2=O)c1
Reactant: CN1CCN(CCCCCN)CC1
Product: COc1cc(OC)cc(N2Cc3cnc(NCCCCCN4CCN(C)CC4)nc3NC2=O)c1
Yield: 24 %

Procedure:
Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.1475 g (0.805 mmol) of 5-(4-methyl-piperazin-1-yl)-pentylamine were reacted. The residue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v) then ethyl acetate/ethanol/triethylamine (9:3:2 v/v/v) to give 0.0322 g (24%) of the title compound: HPLC=97% pure.
Reaction SMILES: [H-].[Na+:2].[CH3:3][O-].[Na+].[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:18][OH:19])[C:15]([OH:17])=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7].CI>C1COCC1.CO>[CH3:6][O-:10].[Na+:2].[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:18][O:19][CH3:3])[C:15]([OH:17])=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CO
Product: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A sodium methanolate (NaOMe) solution was prepared by slowly adding MeOH (50 mL) to a suspension of sodium hydride (60% in mineral oil, 28 g, 0.71 mol) in dry THF (1.2 L) at 0° C. The resulting mixture was stirred at RT for 2 h. A portion of the NaOMe solution (320 mL) was added to (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (36 g, 175 mmol) in dry THF (1.6 L), and the mixture was stirred at RT for 1 h. Methyl iodine (16 mL) was then added and the mixture was stirred at RT for 1 h. Another aliquot of NaOMe solution (540 mL) was added and the reaction mixture stirred at RT for 1 h. Additional methyl iodine (38 mL) in THF (200 mL) was added and the reaction mixture was stirred at RT for 36 h. Following reaction, the mixture was concentrated and the residue was dissolved in water and washed with diethyl ether (2×100 mL). The aqueous layer was acidified to pH 2 by the addition of solid citric acid and was extracted with EtOAc (3×200 mL) and dried over Na2SO4. The organic phase was concentrated, and the residue was dissolved in water and extracted with DCM (4×150 mL). The organic layers were combined and concentrated to give the title compound as an oil, which was used without further purification (10.9 g, 28%).
Reaction SMILES: [C:1]1([C@H:7](/[N:9]=[CH:10]\[C:11]([O:13][CH3:14])=[O:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(CC(O)=O)(F)F.[CH:23]1[CH2:27][CH:26]=[CH:25][CH:24]=1>FC(F)(F)CO>[C:1]1([C@H:7]([N:9]2[C@H:10]([C:11]([O:13][CH3:14])=[O:12])[C@@H:25]3[CH2:26][C@H:27]2[CH:23]=[CH:24]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=CCC=C1
Reactant: COC(=O)/C=N\[C@H](C)c1ccccc1
Agent: O=C(O)CC(F)(F)F
Solvent: OCC(F)(F)F
Product: COC(=O)[C@@H]1[C@H]2C=C[C@H](C2)N1[C@H](C)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of methyl (2Z)-{[(1R)-1-phenylethyl]imino}acetate obtained in Example 42-1 (238 g) in 2,2,2-trifluoroethanol, was added trifluoromethylacetic acid (95.9 mL) at −10° C. The mixture was then stirred at the same temperature. After 1 hr, cyclopentadiene was added dropwise at −10° C. over 30 minutes.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([C:23](O)=[O:24])[CH2:6]1)(=[O:3])[CH3:2].[CH2:26]([O:29][C:30]([C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([NH2:41])[CH:40]=1)[C:35]([NH2:37])=[O:36])=[O:31])[CH:27]=[CH2:28]>>[C:1]([S:4][CH:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[CH:7]([C:23](=[O:24])[NH:41][C:39]2[CH:38]=[C:34]([C:35](=[O:36])[NH2:37])[CH:33]=[C:32]([C:30]([O:29][CH2:26][CH:27]=[CH2:28])=[O:31])[CH:40]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C=CCOC(=O)c1cc(N)cc(C(N)=O)c1
Product: C=CCOC(=O)c1cc(NC(=O)C2CC(SC(C)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc(C(N)=O)c1
Yield: 49.9 %

Procedure:
(2S,4S)-4-Acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-carboxypyrrolidine (0.75 g) was converted to the acid chloride and reacted with 3-allyloxycarbonyl-5-aminobenzamide (0.45 g) by a similar method to that described in example 12. The crude product was subjected to chromatography on silica gel, eluting with EtOAc and giving 4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonyl-5-carbamoylphenylcarbamoyl)pyrrolidine (0.58 g). Nmr (DMSO-d6): δ 1.92-2.06 (m, 1H); 2.3 (s, 3H); 2.79-2.83 (m, 1H); 3.38 (dd, 1H); 3.97-4.12 (m, 2H); 4.49 (dd, 1H); 4.83 (dt, 2H); 5.19 (dd, 2H); 5.25-5.43 (m, 2H); 5.97-6.11 (m, 1H); 7.31 (broad s, 2H); 7.54 (d, 2H); 8.04 (d, 2H); 8.12 (t, 1H); 8.26 (t, 1H); 8.31 (t, 1H); 10.0 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[CH2:6][N:7]1[CH2:31][CH2:30][C:10]2([N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:13](=[O:22])[N:12]=[C:11]2[NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:9][CH2:8]1)#[N:2]>CCO>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[CH2:6][N:7]1[CH2:31][CH2:30][C:10]2([N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:13](=[O:22])[N:12]=[C:11]2[NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:9][CH2:8]1
Reactant: N#Cc1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Solvent: CCO
Product: NCc1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Reaction time: 8 h

Procedure:
A 50 mL EtOH suspension of 0.470 g (1.02 mmol) 8-[3-cyanobenzyl]-4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one (Example (7-12)) and a small amount of Raney Nickel (in water) was first evacuated and flushed with N2 3 times then put under a H2 balloon and allowed to stir overnight. The catalyst was filtered and the filtrate concentrated in vacuo to pure product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:29])[CH:23]2[CH2:26][CH:25]([CH2:27][OH:28])[CH2:24]2)[O:12]1.CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39].O>C(Cl)Cl>[CH3:37][S:38]([O:28][CH2:27][CH:25]1[CH2:24][CH:23]([N:22]([CH2:21][C@@H:13]2[C@@H:14]3[C@@H:15]([O:16][C:17]([CH3:19])([CH3:20])[O:18]3)[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH2:1])[O:12]2)[CH3:29])[CH2:26]1)(=[O:40])=[O:39]
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(COS(C)(=O)=O)C1
Reaction time: 2 h
Yield: 35 %

Procedure:
To a solution of (3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)methanol taken directly from the previous step in DCM (25 ml) was added Et3N (467 mg, 4.62 mmol) and MsCl (264 mg, 2.31 mmol) as a solution in DCM (5 ml). The mixture was stirred for 2 h. Water (20 ml) and DCM (30 ml×2) was added. The organic layer was dried over Na2SO4 and concentrated, purified with Prep-TLC (DCM:MeOH=10:1) to give the title compound (390 mg, Yield 35% for two steps). 1H NMR (500 MHz, MeOD): δH 8.27 (s, 1H), 8.21 (s, 1H), 6.203-6.200 (m, 1H), 5.529 (dd, J=2.0, 7.0 Hz, 1H), 5.010 (dd, J=3.0, 6.0 Hz, 1H), 4.354 (dd, J=3.5, 8.0 Hz, 1H), 4.197-4.182 (m, 2H), 3.585 (brs, 1H), 3.073-2.948 (m, 5H), 2.595-2.513 (m, 2H), 2.394 (brs, 1H), 2.207 (brs, 1H), 2.107 (s, 3H), 2.030-1.989 (m, 1H), 1.840-1.811 (m, 2H), 1.586 (s, 3H), 1.390 (brs, 1H), 1.329-1.280 (m, 6H), 0.905-0.878 (m, 1H) ppm; ESI-MS (m/z): 483.3[M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].Cl[CH2:18][C:19]1[C:20]([CH2:36][CH2:37][O:38][CH3:39])=[N:21][C:22]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:18][C:19]3[C:20]([CH2:36][CH2:37][O:38][CH3:39])=[N:21][C:22]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)=[N:23][C:24]=3[CH3:25])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CCl
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)Cn1ccc2ccc(OCc3c(C)nc(-c4ccc(C(F)(F)F)cc4)nc3CCOC)cc21

Procedure:
In analogy to the procedure described in example 7 a], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with 5-chloromethyl-4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine in the presence of cesium carbonate and potassium iodide, using acetonitrile as solvent, to obtain the title compound as colorless crystals.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][OH:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl:14][C:15]1[N:20]=[C:19]([C:21]2[C:22](F)=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=2)[C:18]2[N:29]([CH2:41][C@H:42]3[CH2:47][CH2:46][C@H:45]([CH3:48])[CH2:44][CH2:43]3)[C:30]([N:32]3[CH2:37][CH2:36][O:35][C@@H:34]4[CH2:38][CH2:39][CH2:40][C@@H:33]34)=[N:31][C:17]=2[CH:16]=1>CN(C=O)C>[Si:3]([O:10][CH2:11][CH2:12][O:13][C:22]1[C:21]([C:19]2[C:18]3[N:29]([CH2:41][C@H:42]4[CH2:47][CH2:46][C@H:45]([CH3:48])[CH2:44][CH2:43]4)[C:30]([N:32]4[CH2:37][CH2:36][O:35][C@@H:34]5[CH2:38][CH2:39][CH2:40][C@@H:33]45)=[N:31][C:17]=3[CH:16]=[C:15]([Cl:14])[N:20]=2)=[CH:26][C:25]([Cl:27])=[CH:24][N:23]=1)([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:5])[CH3:4]
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(-c4cc(Cl)cnc4F)c32)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ncc(Cl)cc1-c1nc(Cl)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
NaH (24 mg, 0.6 mmol) was added to solution of 2-((tert-butyldimethylsilyl)oxy)ethanol (70 mg, 0.4 mmol) in DMF (1.0 mL) at 0° C., and the reaction was stirred at 0° C. for 30 minutes. A solution of 6-chloro-4-(5-chloro-2-fluoropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic, Example 18.1, Step 1; 100 mg, 0.2 mmol) was added, and the reaction was stirred at 0° C. for 30 minutes. The reaction was quenched by adding saturated aqueous NH4Cl solution and extracted using EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Purification of the residue on a silica gel column with 0 to 50% EtOAc/hexane afforded 4-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-5-chloropyridin-3-yl]-6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic). MS APCI calc'd. for C34H49Cl2N5O3Si [M+H]+ 674. found 674.
Reaction SMILES: COC[O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([O:12][CH2:13][O:14][CH3:15])[C:6]=1[C:16]1([C:19]#N)[CH2:18][CH2:17]1.O.ClC[O:24]C.[H-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1>CO>[OH:24][CH2:19][C:16]1([C:6]2[C:7]([O:12][CH2:13][O:14][CH3:15])=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[OH:4])[CH2:17][CH2:18]1
Reactant: COCOc1ccc(C)c(OCOC)c1C1(C#N)CC1
Reactant: COCCl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCOc1ccc(C)c(O)c1C1(CO)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 72.9 %

Procedure:
To a solution of 1-[2,6-bis(methoxymethoxy)-3-methyl-phenyl]cyclopropanecarbonitrile (Intermediate 35, 26.2 g, 94.476 mmol) in Methanol (260 mL) hydrogen chloride 6N in water (31.5 ml, 188.95 mmol) was added and the reaction mixture was stirred for 5 hours at 70° C. Volatiles were removed under reduced pressure and the residue was suspended in Toluene (50 ml) and the solvent evaporated. Additional Toluene (50 ml) was added and then re-evaporated. The residue (yellow pale solid) was dissolved in THF (200 mL) and the reaction mixture was cooled to 0° C. chloro(methoxy)methane (7.89 ml, 103.92 mmol) was added followed by a portionwise addition of sodium hydride 60% dispersion in mineral oil (4.1569 g, 103.92 mmol). The reaction mixture was stirred for 1 hour at the same temperature and then lithium aluminum hydride 1M in THF (47.24 ml, 47.24 mmol) was slowly added. The reaction mixture was stirred for 1 hour at 0° C. and then it was quenched with ice cold aqueous 2N HCl (100 ml), diluted with water (200 ml) and extracted with ethyl acetate (2×200 ml). The organic layer was dried (Na2SO4), filtered and evaporated and The residue was purified by flash chromatography on silica gel using a silica pad ˜300 g of silica and cyclohexane/ethyl acetate from 100:0 to 70:30 as eluent affording the title compound (16.4 g) as colourless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:6][CH2:7][CH3:8].CS[C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:19][N:18]=1>N1C=CC=CC=1>[CH2:6]([N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[CH:19][N:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:7][CH3:8]
Reactant: CCCN(CCCN)c1ccccn1
Reactant: CSc1ncc(CC2CCCCC2)c(=O)[nH]1
Solvent: c1ccncc1
Product: CCCN(CCCNc1ncc(CC2CCCCC2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-propylamino]pyridine (1.09 g) and 2-methylthio-5-cyclohexylmethylpyrimid-4-one (0.9 g) were heated together under reflux in pyridine (2.5 ml) for 28 hr. After stripping, the residue was triturated with ether and crystallized twice from ethanol/water to give 2-[3-(N-propyl-N-pyrid-2-ylamino)propylamino]-5-cyclohexylmethylpyrimid-4-one 0.5 H2O, 1.14 g (78%) m.p. 103°-106° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([N:1]([CH2:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A stirred suspension of 13A.HCl (5.12 g, 24.65 mmol) in acetonitrile (75 mL) was treated with K2CO3 (13.63 g, 99 mmol) and (bromomethyl)benzene (7.32 mL, 61.6 mmol). The resulting suspension was stirred at 80° C. overnight. Upon cooling, the solid was filtered off and filtrate was concentrated. The residue was purified by Isco silica column (80 g) eluted with ethyl acetate-hexane: 0%-20%. Concentration of the appropriate fractions provided 13B (7.92 g, 91% yield) as a colorless oil. MS (ES): m/z=352.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.08-7.34 (m, 10H); 4.01 (q, 2H, J=7.1 Hz); 3.55 (s, 4H); 2.40-2.49 (m, 1H); 2.06-2.14 (m, 1H); 1.86-2.00 (m, 2H); 1.24-1.38 (m, 2H); 1.18 (t, 3H, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([OH:34])[CH:28]=2)(=[O:26])=[O:25])=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:37][O:38][C:39]([CH3:55])([CH3:54])[C:40]([NH:42][NH:43][C:44](=[O:53])[C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[C:47]([OH:52])[CH:46]=1)=[O:41]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:37]/[O:38][C:39]([C:40](=[O:41])[NH:42][NH:43][C:44](=[O:53])[C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[C:47]([OH:52])[CH:46]=2)([CH3:54])[CH3:55])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([OH:34])[CH:28]=2)(=[O:26])=[O:25])=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CS(=O)(=O)c4ccc(O)c(O)c4)CS[C@H]23)cs1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CS(=O)(=O)c3ccc(O)c(O)c3)CS[C@H]12)c1csc(N)n1)C(=O)NNC(=O)c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.2 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[(3,4-dihydroxyphenyl)sulphonyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (160 mg) (0.30 mmol) are dissolved in 2.0 ml of dimethylacetamide, treated with 130 mg (0.39 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride and stirred at room temperature for 20 hours. The dimethylacetamide is evaporated under a high vacuum and the product is precipitated by the addition of water. The purification is effected by chromatography on silica gel with water/acetonitrile as the eluent. After lyophilization there are obtained 200 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[(3,4-dihydroxyphenyl)sulphonyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:9]=[C:10]([C:14](=[O:22])[CH:15]=[C:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH3:21])[CH:11]=[CH:12][CH:13]=1.O.C1(C([O-])=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+]([O-])=O>O1CCCC1>[CH3:7][C:8]1[CH:9]=[C:10]([C:14](=[O:22])[CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH3:21])[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccc(C(=O)C=C2CCCN2C)c1
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)CC2CCCN2C)c1

Procedure:
5.8 g of lithium aluminum hydride are added portionwise at 0° to 66 g of 1-(3-methylphenyl)-2-(1-methyl-2-pyrrolidinyliden)ethanone dissolved in 550 ml of tetrahydrofuran. 20 minutes after completion of the addition, water is added dropwise until no evolution of gas is any longer observed. The light-yellow organic phase is decanted from the formed precipitate, the latter is extracted with diethyl ether, the united organic phases are dried over sodium sulfate and concentration to an oil is effected. After distillation under vacuum, 61.7 g (92% of theory) of the title compound (b.p. 116° at 0.01 mm Hg) are obtained. Picrate (from ethanol): m.p. 146° to 149°.