Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([O:24]CC)=[O:23])=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.[OH-].[Li+:29].Cl>O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([O-:24])=[O:23])=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Li+:29]
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C(C)C)CC3)ccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)N1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 101.6 %

Procedure:
To ethyl 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (5.68 g, 15.8 mmol) in water (30 mL) was added lithium hydroxide hydrate (0.67 g, 16.0 mmol). The reaction was heated to 95° C. for 4 hours. The reaction was cooled to ambient temperature and hydrogen chloride (0.0394 mL, 4M in dioxane) was added to the reaction mixture, which was stirred for 10 minutes. Water was removed under vacuum for overnight to give the title compound (5.43 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[N:31][N:30]=[N:29]1)[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:27]([N:28]4[CH:32]=[N:31][N:30]=[N:29]4)=[C:19]([F:18])[CH:20]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: O=C(O)c1ccc(-n2cnnn2)c(F)c1
Product: O=C(c1ccc(-n2cnnn2)c(F)c1)N(C1CC1)C1CCN(c2ncc(Cl)cn2)CC1

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 3-fluoro-4-tetrazol-1-yl-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.18 min; Mass spectrum (ESI+): m/z=443 [M+H]+.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#Cc1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(-c2c(-c3ccccc3)c(-c3ccccc3)c(-c3ccccc3)c(-c3ccccc3)c2-c2ccccc2)cc1
Yield: 8 %

Procedure:
By far the most studied and useful cyclotrimerization catalysts have been of the η5 -cyclopentadienyl cobalt (CpCo) family. In 1967, Yamazaki and Hagihara isolated the first cobalt cyclopentadiene triphenylphosphine complex (CpCoP(Ph)3), which when treated with a stoichiometric amount of diphenylacetylene in refluxing toluene produced hexaphenylbenzene in 8% yield after one hour. (Yamazaki and Hagihara (1967) J. Organomet. Chem. 7:22). Cobalt cyclopentadiene dicarbonyl (CpCo(CO)2) (5), a commercially available catalyst, reacts catalytically with bis-alkynes (6) in refluxing n-octane to form several bicyclic systems (7), including benzocyclobutenes (n=2) in 45% yield. (Vollhardt and Bergman (1974) J. Am. Chem. Soc 96:4996). ##STR4##
Reaction SMILES: C([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:34]=[C:33]([F:35])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24][C@@H:23]1[OH:36])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[Cl:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[C:42]([F:48])[CH:41]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][O:36][C@@H:23]2[C@@H:22]([CH2:21][OH:20])[O:26][C@@H:25]([N:27]3[CH:34]=[C:33]([F:35])[C:31](=[O:32])[NH:30][C:28]3=[O:29])[CH2:24]2)=[C:42]([F:48])[CH:41]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Reactant: Fc1cc(Cl)ccc1CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccc(Cl)cc3F)[C@@H](CO)O2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
The title compound was prepared according to the process disclosed in Japanese Unexamined Patent Publication No. 106593/1986. The process was carried out as follows. A 5.0 g quantity of 2'-deoxy-5'-O-trityl-5-fluorouridine was dissolved in 40 ml of tetrahydrofuran. To the solution was added 856 mg of 60% sodium hydride, followed by 1 hour of stirring at room temperature. After addition of 2.58 g of 4-chloro-2-fluorobenzyl bromide, the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C. and saturated ammonium chloride was added in excess. The tetrahydrofuran layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off at reduced pressure, and the residue was purified by silica gel column chromatography (eluate: n-hexane-ethyl acetate (3:2)), giving 5.03 g of the title compound (yield 78%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[Na+].[Na+].O.[C:18]1(B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21][CH2:20][CH:19]=1>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.O1CCOCC1>[C:18]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1C1=CCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a mixture of 1-chloro-2-nitrobenzene (0.5 g, 3.2 mmol) and sodium carbonate (0.34 g, 3.2 mmol) in a 100 mL roundbottom flask equipped with a magnetic stir bar and nitrogen inlet were added water (3.2 mL), dioxane (13 mL) and 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.77 mL, 3.8 mmol). The reaction flask was evacuated and purged with nitrogen (2×) prior to the addition of bis(triphenylphosphine)palladium(II) chloride (0.18 g, 0.25 mmol), and then evacuated and purged (3×) following the addition of the catalyst. The reaction was heated to 80° C. and stirred overnight. The reaction was cooled and filtered through a pad of Celite® which was subsequently washed with water and ethyl acetate. The phases were separated and the organic phase was dried by passing it through a phase separator cartridge and concentrated. The residue was purified by flash column chromatography providing the title compound (0.56 g, 3.0 mmol, 93% yield) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.78-7.71 (m, 1H), 7.54-7.47 (m, 1H), 7.40-7.32 (m, 2H), 5.86-5.82 (m, 1H), 2.63-2.55 (m, 2H), 2.55-2.47 (m, 2H), 2.09-1.98 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 148.77, 139.96, 133.58, 132.08, 130.87, 130.52, 127.55, 123.70, 35.31, 33.49, 24.05; ESIMS m/z 190 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.[Li]CCCC.C(O[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)(C)C.[NH4+].[Cl-].[Na+].[Cl-]>O1CCCC1.C(OCC)(=O)C>[CH3:28][C:23]1([CH3:29])[C:24]([CH3:27])([CH3:26])[O:25][B:21]([C:2]2[CH:11]=[CH:10][C:5]3[O:6][CH:7]([CH3:9])[O:8][C:4]=3[CH:3]=2)[O:22]1
Reactant: CC1Oc2ccc(Br)cc2O1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2O1
Temperature: -70 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
5-Bromo-2-methylbenzo[d][1,3]dioxole (1.0 g, 4.7 mmol, prepared as described in Matyus, Peter; Magyar, Kalman; Pihlavista, Marjo; Gyires, Klara; Haider, Norbert; Wang, Yinghua; Woda, Patrick; Dunkel, Petra; Toth-Sarudy, Eva; Turos, Gyoergy, WO2010029379) was dissolved in dry tetrahydrofuran (10 mL), cooled to −70° C. and treated with n-BuLi (2.5 M; 2.1 mL, 4.7 mmol) over 5 min. After 1 h, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 g, 6.0 mmol) was added and the mixture was stirred for 90 min at −70 to −30° C. After addition of saturated NH4Cl (5 mL), the mixture was shaken with ethyl acetate (40 mL) and saturated NaCl (10 mL), dried (Na2SO4) and evaporated. The material was purified by chromatography on silica with a 0-30% ethyl acetate-hexane gradient to give the title compound (730 mg, 59%): 1H NMR (400 MHz, CDCl3) δ 7.33 (dd, J=7.7, 1.1 Hz, 1H), 7.18 (d, J=0.9 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.25 (q, J=5.0 Hz, 1H), 1.66 (d, J=4.9 Hz, 3H), 1.32 (s, 12H); EIMS m/z 262.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([NH:35]C(C1N(C)C(CNS(C2C=CC=CC=2)(=O)=O)=CC(=O)C=1OCC1C=CC=CC=1)=O)([CH3:34])[CH3:33]>>[CH:32]([NH:35][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:31])([CH3:34])[CH3:33]
Reactant: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2)n1C
Reactant: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)n2C)cc1
Product: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)NC(C)C)n2C)cc1
Yield: 38.08 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-06) (250.0 mg, 38.08%) was synthesized as a brown solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-06) (600.0 mg, 1.36 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-01).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[C:25]([C:29]([OH:31])=O)[NH:26]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[CH3:32][NH:33][CH3:34].O1CCCC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[C:25]([C:29]([N:33]([CH3:34])[CH3:32])=[O:31])[NH:26]3)=[CH:22][CH:21]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc2ccc(CC3c4ccc(O)cc4CCN3c3ccc(F)cc3)cc2[nH]1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2ccc(CC3c4ccc(O)cc4CCN3c3ccc(F)cc3)cc2[nH]1
Yield: 48 %

Procedure:
The title compound was prepared as described in Example 34. B using 6-{[2-(4-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinolyl]methyl}indole-2-carboxylic acid (0.25 g, 0.6 mmol) and 2.0 M solution of dimethylamine in tetrahydrofuran (1.0 mL, 2.0 mmol) to provide the title compound (0.127 g, 48% yield): 1H NMR (CDCl3) 9.05 (br, 1H), 7.52 (d, 1H), 7.26-6.76 (m, 7H), 6.61 (d, 1H), 6.57 (d, 1H), 6.50 (dd, 1H), 4.80 (t, 1H), 3.58 (m, 1H), 3.47 (m and s, 4H), 3.27 (dd 1H), 3.20 (s, 3H), 3.03 (dd, 1H), 2.89 (m, 1H), 2.67 (dt, 1H); ES-MS m/z 444 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[CH:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][C:41]=1[C:50](Cl)=[O:51]>>[CH:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][C:41]=1[C:50]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:51]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc4ccccc4c3)CN2C1=O
Yield: 26.1 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 2-naphthoyl chloride (66 mg, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 33 mg (26%) of 18-(2-naphthoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.5% pure (HPLC), MS m/z 721 (M−H)−, HRMS: calcd. 740.3329 and found 740.3321 (M+NH4)+, mp 156-158° C.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][N:18]=2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][NH:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(COc2ccc(C3=NCCc4ccccc43)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(COc2ccc(C3NCCc4ccccc43)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
Sodium borohydride (0.34 g, 0.89 mmol) was added in small portions to a solution of 1-(4-benzyloxyphenyl)-3,4-dihydroisoquinoline (0.139 g, 0.44 mmol) in MeOH (10 ml) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, stirred at rt for 1 hr, then quenched by the dropwise addition of H2O (1.0 ml). The resulting mixture was concentrated in vacuo to remove the methanol, and the remaining aqueous layer was extracted with CHCl3 (4×10 ml). The combined extracts were dried over MgSO4 and concentrated in vacuo to give 0.138 g (99% yield) of colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.S(=O)(=O)(O)O.[Br:17]N1C(=O)CCC1=O.O>FC(F)(F)C(O)=O>[Br:17][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[CH3:8]
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-fluoro-2-nitrotoluene (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 mL) was added concentrated sulfuric acid (12.5 mL) followed by N-bromosuccinimide (17.2 g, 96.6 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was then poured onto ice and water and stirred for 15 min. The product was then extracted into EtOAc and the organic layer washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a pale oil which crystallised out on standing (11.76 g, 77%). NMR δH (300 MHz, CDCl3) 2.59 (s, 3H), 7.50 (dd, J=2.8, 7.6, 1H) and 7.58 (dd, J=2.9, 7.4, 1H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[N:11]([C:16]1[CH:21]=[C:20]([NH:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[N:19]=[C:18]([CH3:28])[N:17]=1)[CH2:10][CH2:9]2.[CH:29]([O:32]C)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[N:11]([C:16]1[C:21]([CH:29]=[O:32])=[C:20]([NH:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[N:19]=[C:18]([CH3:28])[N:17]=1)[CH2:10][CH2:9]2
Reactant: CCC(CC)Nc1cc(N2CCc3cc(Cl)cc(Cl)c32)nc(C)n1
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCC(CC)Nc1nc(C)nc(N2CCc3cc(Cl)cc(Cl)c32)c1C=O
Temperature: 20 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
To a suspension of AlCl3 (736 mg, 5.44 mmol) in CHCl3 (5 mL) a solution of 4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine (1.46 g, 4 mmol) in CHCl3 was added at 0° C., followed by Cl2CHOMe (0.4 mL, 4.4 mmol). The reaction was stirred at 0° C. for 2 h and at 20° C. for 16 h. Then an additional amount of Cl2CHOMe was added (0.2 mL, 2.2 mmol) and the reaction was continued for 26 h. The mixture was poured into ice/water (50 mL) and after quenching it was basified with 1 N NaOH, extracted with EtOAc (2×100 mL each) and the combined organic extracts were washed with water, brine, dried over (MgSO4) and stripped in vacuo. The residue was chromatographed on silica gel using 10% EtOAc/hexanes as eluent to give the product 4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-formyl-2-methylpyrimidine (470 mg, 30% yield).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[O:46][C:47]([CH3:50])=[N:48][N:49]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[O:46][C:47]([CH3:50])=[N:48][N:49]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nnc(CCl)o1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1nnc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)o1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole and isolated as colorless gum. MS (m/e): 379.3 (MH+).
Reaction SMILES: [ClH:1].[CH:2]1[CH:11]=[CH:10][C:9]2[CH2:12][CH2:13][CH2:14][N:7]3[C:8]=2[C:3]=1[C@@H:4]1[CH2:18][NH:17][CH2:16][C@H:5]1[C:6]3=[O:15].C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl.C(O)C.CCOCC>[ClH:1].[CH3:21][N:17]1[CH2:18][C@@H:4]2[C@H:5]([C:6](=[O:15])[N:7]3[CH2:14][CH2:13][CH2:12][C:9]4[CH:10]=[CH:11][CH:2]=[C:3]2[C:8]3=4)[CH2:16]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1[C@@H]2CNC[C@H]2c2cccc3c2N1CCC3
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: ClCCCl
Product: CN1C[C@H]2C(=O)N3CCCc4cccc(c43)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
To a solution of (±)-trans-5,6,9,10,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinolin-8(8aH)-one, hydrochloride salt from EXAMPLE 3 (200 mg, 0.76 mmol) in 5 mL of 1,2-dichloroethane was added 37% aqueous formaldehyde (0.065 mL, 0.76 mmol) and sodium triacetoxyborohydride (260 mg, 1.22 mmol). The resulting mixture was stirred at ambient temperature for 1 h and then the reaction was quenched with water. The mixture was partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo. A portion of the residue (50 mg, 0.21 mmol) was dissolved in 1 mL ethanol and 5 mL of ether and then there was added 2M HCl in ether (0.105 mL, 0.21 mmol). A solid precipitated out of solution. The solvents were decanted and the solid was triturated twice with ether and dried in vacuo to afford 25 mg (43%) of the title compound of EXAMPLE 5 as an off white powder. 1H NMR (d6-dmso): δ 7.12 (d, 1H, J=7.4 Hz), 6.99 (t, 1H, J=7.3 Hz), 6.97-6.90 (m, 1H), 4.25-4.12 (m, 2H), 3.75-3.65 (m, 2H), 3.40-3.20 (m, 3H), 2.97-2.90 (m, 3H), 22.81-2.70 (m, 3H), 1.88-1.80 (m, 2H). LRMS (ES)+: 243.4 (M+H)+.
Reaction SMILES: [Si](O[C@@H]1[C@@](C=O)(CO)O[C@@H]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])C1)(C(C)(C)C)(C)C.NO.Cl>N1C=CC=CC=1>[NH:18]1[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]1=[O:20]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@](C=O)(CO)O2)c(=O)[nH]c1=O
Agent: Cl
Agent: NO
Solvent: c1ccncc1
Product: Cc1c[nH]c(=O)[nH]c1=O
Temperature: 24 °C
Reaction time: 16 h

Procedure:
A solution of the 4'-α and 4'-β isomers 3'-O-t-butyldimethylsilyl-4'-formylthymidine (380 mg, 1 mM), the compound of Formula 12, prepared, e.g., as described in Preparation 8, with H2NOH HCl (110 mg, 1.6 mM) in pyridine (1.5 ml) was stirred at 24° C. for 16 hours. The solvent was removed by evaporation. The residue was partitioned between H2O (5 ml) and EtOAc (15 ml). The aqueous layer was extracted with EtOAc (10 ml), and the EtOAc fractions were combined. The solvent was removed by evaporation and the residue was purified on a thick silica gel plate (60% EtOAc/hexane), 3'-O-t-butyldimethylsilyl-4'-hydroxyiminomethylthymidine (148 mg, 0.37 mM). MS (399 M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>>[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][N:24]1[C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]([Cl:1])[CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: O=C(N(CCc1ccccc1)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](N(CCc2ccccc2)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 60.4 %

Procedure:
189 mg (0.992 mmol) of 3,5-dichlorobenzoic acid are reacted in analogy to Example 2a first with 0.108 ml (1.49 mmol) of thionyl chloride and subsequently with 155 mg (0.397 mmol) of (2R*,4S*)-2-benzyl-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamine and 166 μl (1.19 mmol) of triethylamine to give the title compound (135 mg, 60%). TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.70, FD-MS: M+ =562, 564.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:40])[C@@H:22]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C@H:23](O)[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>FC(F)(F)C(O)=O>[CH2:8]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:40])[C@@H:22]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(O[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](O)c2ccc(O)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(O[C@@H](Cc2ccc(O)cc2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reaction time: 18 h
Yield: 85.3 %

Procedure:
Triethylsilane (24.0 ml) was added at room temperature to a solution of (S)-4-benzyl-3-[(2S,3R)-3-hydroxy-3-(4-hydroxyphenyl)-2-(4-methylphenoxy)propionyl]oxazolidin-2-one (8.15 g) obtained from Reference example 20(c) in trifluoroacetic acid (90 ml), then the mixture was stirred for 18 hours and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed successively with a saturated aqueous sodium hydrogencarbonate solution, a 1N aqueous solution of hydrochloric acid and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were filtered off and washed with a mixed solvent of isopropyl ether and hexane to give the target compound (6.70 g) as colorless crystals.