Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:19][C:20]1([CH2:28][N:29]2[CH:33]=[C:32]([CH:34]=C)[N:31]=[C:30]2[N+:36]([O-:38])=[O:37])[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I([O-])(=O)=[O:40].[Na+]>[Os]=O.O.O1CCOCC1>[O:1]([CH2:19][C:20]1([CH2:28][N:29]2[CH:33]=[C:32]([CH:34]=[O:40])[N:31]=[C:30]2[N+:36]([O-:38])=[O:37])[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)[Si:2]([C:15]([CH3:16])([CH3:18])[CH3:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: C=Cc1cn(CC2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)COC(C)(C)OC2)c([N+](=O)[O-])n1
Agent: O=[Os]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(Cn2cc(C=O)nc2[N+](=O)[O-])CO1
Temperature: 25 °C
Reaction time: 120 h
Yield: 66.7 %

Procedure:
2.0 mL of a mixed solution of water/1,4-dioxane=3/1 was added to 163 mg (0.30 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(4-vinyl-2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane, 38 mg (microcapsules, Wako Pure Chemical Industries, Ltd., 0.015 mmol equivalents) of osmium oxide and 130 mg (0.60 mmol equivalents) of sodium iodate were added thereto, and the mixture was stirred at room temperature (25° C.) for 5 days. After completion of the reaction, the osmium oxide was taken out, and the reaction liquid was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate, and subsequently concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=5/1) to give 107 mg (0.20 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(4-formyl-2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([C:13]1[N:14]=[CH:15][N:16]2[C:21](=[O:22])[N:20]([CH2:23][S:24][CH3:25])[N:19]=[N:18][C:17]=12)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC(=NS([N+](CC)(CC)CC)(=O)=O)[O-]>C1COCC1>[CH3:25][S:24][CH2:23][N:20]1[C:21](=[O:22])[N:16]2[CH:15]=[N:14][C:13]([C:11]3[O:12][C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][N:10]=3)=[C:17]2[N:18]=[N:19]1
Reactant: CSCn1nnc2c(C(=O)NNC(=O)c3ccccc3)ncn2c1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CSCn1nnc2c(-c3nnc(-c4ccccc4)o3)ncn2c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
N′-benzoyl-3-(methylthiomethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbohydrazide (0.47 mmol, 170 mg, 1 eq.) and 1-methoxy-N-triethylammoniosulfonyl-methanimidate (Burgess Reagent) (1.61 mmol, 383 mg, 3.4 eq.) were dissolved in THF (8 mL). Microwave energy was applied to the solution for 5 minutes, keeping reaction temperature at 60° C. The reaction mixture was poured into ice/water and the formed solid was filtered and washed with water, acetonitrile and ether, and dried under vacuum to give the title compound. Yield 71%. δH (DMSO-d6) 8.90 (1H, bs), 7.92 (2H, bs), 7.49 (3H, bs), 5.29 (2H, bs), 2.09 (3H, bs).
Reaction SMILES: CC(CSC[C@H]1[O:11][C@@H:10](N2C3NC=NC(=O)C=3N=C2)[C@H](O)[C@@H]1O)C.Cl.[CH3:25][O:26][C:27](=[O:32])[C@H:28]([CH2:30][OH:31])[NH2:29].C(Cl)(Cl)=O>>[CH3:25][O:26][C:27]([CH:28]1[CH2:30][O:31][C:10](=[O:11])[NH:29]1)=[O:32]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC(C)CSC[C@H]1O[C@@H](n2cnc3c(=O)nc[nH]c32)[C@H](O)[C@@H]1O
Agent: Cl
Agent: O=C(Cl)Cl
Product: COC(=O)C1COC(=O)N1

Procedure:
The preparation of 1-1 was carried out according to the literature procedure (see: Sibi, M. P. et al, J. Chem. Soc. Perkin Trans. 1 1994, 1675). Thus, 39.5 grams of serine methyl ester hydrochloride was reacted with phosgene (20% solution in toluene, 175 mL) to give 42 grams of desired product. 1H NMR (400 MHz, acetone-d6): δ 7.1 (br s, 1H, NH), 4.64–4.56 (m, 2H), 4.44 (dd, 1H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:24]=[CH:23][C:11]([C:12]([NH:14][NH:15][C:16]3[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][N:17]=3)=O)=[CH:10][CH:9]=2)[C@H:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(O)=O>>[I:22][C:20]1[CH:19]=[CH:18][N:17]2[C:12]([C:11]3[CH:23]=[CH:24][C:8]([N:4]4[C@@H:3]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:2]([CH3:1])([CH3:31])[O:6][C:5]4=[O:7])=[CH:9][CH:10]=3)=[N:14][N:15]=[C:16]2[CH:21]=1
Reactant: CC1(C)OC(=O)N(c2ccc(C(=O)NNc3cc(I)ccn3)cc2)[C@H]1c1ccccc1
Solvent: CC(=O)O
Product: CC1(C)OC(=O)N(c2ccc(-c3nnc4cc(I)ccn34)cc2)[C@H]1c1ccccc1
Temperature: 180 °C

Procedure:
A heterogeneous mixture of (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-N′-(4-iodopyridin-2-yl)benzohydrazide (1.53 g, 2.90 mmol) in glacial AcOH (11.70 mL, 203 mmol) was heated at 180° C. for 1 hour. LC-MS indicated clean and complete conversion to the desired product. The reaction mixture was concentrated under vacuum to give the product as a yellow solid. The material was carried on to next step without purification. m/z (ESI) 511.0 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:12]2[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][CH:16]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH:3]=[CH:2]1.C[N+](C)=CCl.[Cl-].[NH2:26][CH:27]1[C:38](=[O:39])[N:29]2[C:30]([C:35]([OH:37])=[O:36])=[CH:31][CH:32]([CH3:34])[S:33][C@H:28]12.C[Si](CC(N)=O)(C)C>O1CCCC1.C(OCC)(=O)C.O>[CH:1]1([O:6][N:7]=[C:8]([C:12]2[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][CH:16]=2)[C:9]([NH:26][CH:27]2[C:38](=[O:39])[N:29]3[C:30]([C:35]([OH:37])=[O:36])=[CH:31][CH:32]([CH3:34])[S:33][C@H:28]23)=[O:11])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=CNc1nc(C(=NOC2C=CCC2)C(=O)O)cs1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(N)[C@H]2S1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC3C=CCC3)c3csc(NC=O)n3)[C@H]2S1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A solution of 2-(2-cyclopenten-1-yl)oxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.5 g) in dry tetrahydrofuran (12 ml) was added to the stirred suspension of the solution of Vilsmeier reagent under ice-cooling. The resulting mixture was added to a solution of 7-amino-2-methyl-3-cephem-4-carboxylic acid (1.37 g) and trimethylsilylacetamide (5.04 g) in ethyl acetate (14 ml) at -30° to -20° C. and the mixture was stirred at -5°~-10° C. for 2 hours. After the addition of water and ethyl acetate to the reaction mixture, the ethyl acetate layer was separated and adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated and thereto was added ethyl acetate. The mixture was adjusted to pH 2.5 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated. The residue was pulverized in diisopropyl ether to give 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer) (1.98 g).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cnc2[nH]ccc2n1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(Br)cnc32)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (78.0 g, 394 mmol, Ark Pharm) in anhydrous DMF (272 mL) was added drop-wise over about 60 min to a stirred suspension of NaH (60% dispersion in mineral oil, 12.8 g, 532 mmol) in anhydrous DMF (543 mL) at about 0-5° C. The brown reaction solution was stirred for about 30 min at about 0-5° C. then a solution of p-toluenesulfonyl chloride (94.0 g, 492 mmol) in anhydrous DMF (272 mL) was added drop-wise over about 60 min at about 0-5° C. The reaction mixture was stirred at about 0-5° C. for about 1 h then allowed to warm to ambient temperature and stirred for about 18 h at ambient temperature. The reaction mixture was poured slowly into ice water (6 L), followed by the addition of aqueous 2.5 N NaOH (50.0 mL, 125 mmol). The precipitate was collected by filtration and stirred with cold water (3×200 mL). The solid was collected by filtration and dried to constant weight in a vacuum oven at about 55° C. to yield 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine: (134.6 g, 97%) as a pale beige solid: LC/MS (Table 2, Method d) Rt=1.58 min; MS m/z: 352/354 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]2[C:23]=1[CH:24]=[N:25][C:26]([CH3:34])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:32][C:30]1[C:29]([F:33])=[C:28]2[C:23]([CH:24]=[N:25][C:26]([CH3:34])=[N:27]2)=[C:22]([N:21]=[CH:11][C@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[O:19][CH3:20])[CH3:18])[CH:31]=1
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Reactant: Cc1ncc2c(N)cc(F)c(F)c2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1cc(F)c(F)c2nc(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 150 mg (0.5 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 100 mg (0.51 mmol) of 5-amino-7,8-difluoro-2-methylquinazoline and 0.2 ml of titanium tetraethoxide are reacted to give (2R*,4R*)-1-[(7,8-difluoro-2-methylquinazolin-5-yl)imino]-4-(3-fluoro-2-methoxyphenyl)-2-(trifluoromethyl)pentan-2-ol. 240 mg of resultant crude imine are cyclized in the same way as in Example 1 at −30° C. using 4 ml (4 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) yields 30 mg of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([N:51]=[S:52]([CH3:58])([NH:54][CH:55]([CH3:57])[CH3:56])=[O:53])=[CH:47][CH:46]=1>>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:5]4=[N:6][C:7]([C:8]5[CH:9]=[CH:10][C:11]([C:45]6[CH:46]=[CH:47][C:48]([N:51]=[S:52]([CH3:58])([NH:54][CH:55]([CH3:56])[CH3:57])=[O:53])=[CH:49][CH:50]=6)=[CH:12][CH:13]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CC(C)NS(C)(=O)=Nc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Product: CC(C)NS(C)(=O)=Nc1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N′-(4-bromophenyl)-N-(propan-2-yl)-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.12 min; Mass spectrum (ESI+): m/z=714 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:32])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)[C:20]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].C(OC)(OC)OC.CC(O)=O.[O:52]1[CH2:55][C:54](=O)[CH2:53]1>CO.CCOC(C)=O.C1COCC1>[Si:34]([O:33][C@H:3]1[C@H:2]([NH:1][CH:54]2[CH2:55][O:52][CH2:53]2)[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:32])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH:24]4[CH2:25][CH2:26]4)[C:20]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36]
Reactant: O=C1COC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1NC1COC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
(+/−) 2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 171C) (60 mg, 0.104 mmol) was taken up in MeOH (1 mL) and THF (1 mL) and trimethyl orthoformate (0.859 mL, 7.77 mmol), AcOH (0.024 mL, 0.414 mmol), and oxetan-3-one (0.066 mL, 1.036 mmol) were added. The reaction was stirred at rt for 2 h, then NaCNBH4 (65.1 mg, 1.036 mmol) was added and the reaction was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3, then brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography, eluting with 0-3% MeOH/DCM. (+/−)-2-((3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-(oxetan-3-ylamino)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30 mg) was obtained as a white foam.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([N+:14]([O-])=O)[CH:6]=1)[CH2:3][OH:4]>CO.[Pd]>[OH:1][CH:2]([C:5]1[CH:6]=[C:7]([NH2:14])[CH:8]=[C:9]([NH2:11])[CH:10]=1)[CH2:3][OH:4]
Reactant: O=[N+]([O-])c1cc(C(O)CO)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(N)cc(C(O)CO)c1

Procedure:
1-(1,2-Dihydroxyethyl)-3,5-dinitrobenzene (0.10 g, 0.44 mmol) was dissolved in methanol (35 ml) and hydrogenation was carried out at 60 psi using a Pd/C catalyst (10%, 50 mg). The catalyst was filtered off and the solution was evaporated. Yield: 0.074 g (100%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=C[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].O.NN>C(O)C>[NH2:8][C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[SH:10]
Reactant: O=[N+]([O-])c1ccc2ncsc2c1
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])cc1S
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
A solution of 6-nitrobenzothiazole (5 g, 27.7 mmol) in ethanol (50 mL) was treated with mono hydrazine hydrate (19 g, 388 mmol). The reaction mixture was stirred for 3 h at 25° C. and concentrated in vacuo. The resulting red oil was taken up in ethyl acetate, carefully acidified with 0.1 M aqueous hydrochloric acid solution until the solution turned light yellow. The reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting orange solid was triturated with diethyl ether and dried in vacuo to afford the desired product, 2-amino-5-nitro-benzenethiol (4.1 g, 23.9 mmol, 86% yield) as a yellow solid. 1H NMR (400 MHz, Acetone-d6) δ 6.43 (bs, 2H), 6.82 (d, 1H, J=8.7 Hz), 7.65 (d, 1H, J=2.2 Hz), 7.88 (dd, 1H, J1=8.9 Hz, J2=2.7 Hz). LC-MS (ESI) calcd for C6H6N2O2S [M+H+] 171.01. found 193.20 [M+Na+].
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25])[CH:16]=1)[CH3:2].[C:29](Cl)(=[O:31])[CH3:30]>>[C:29]([N:3]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:27])([F:28])[C:24]([OH:26])=[O:25])[CH:16]=1)[CH2:1][CH3:2])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)C(=O)O)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)C(=O)O)ccc1OC)C(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-difluoro-acetic acid and acetyl chloride.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12>CO.O=[Pt]=O.[Pd]>[N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12
Reactant: c1cn2cnnc2cn1
Agent: O=[Pt]=O
Agent: [Pd]
Solvent: CO
Product: c1nnc2n1CCNC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.6 %

Procedure:
To a solution of [1,2,4]triazolo[4,3-a]pyrazine (1.50 g) in MeOH (150 mL) was added PtO2 (1.10 g) and 10% Pd/C (0.46 g) at rt. The suspension was stirred under H2 at room temperature for 16 h and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column to give the title compound (0.18 g, 11.54%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 125.1 (M+1).
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][NH:7][CH2:8][CH2:9][N:4]2[C:3](=[O:10])[O:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[CH:15]=[N:14][N:13]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[C:12]([N:7]1[CH2:8][CH2:9][N:4]3[C:3](=[O:10])[O:2][CH2:1][C@H:5]3[CH2:6]1)=[N:13][N:14]=[CH:15]2
Reactant: O=C1OC[C@H]2CNCCN12
Reactant: Clc1ccc2c(Cl)nncc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C1OC[C@H]2CN(c3nncc4cc(Cl)ccc34)CCN12
Temperature: 140 °C

Procedure:
The title compound was prepared by a method analogous to that described in Example 8 (Method A). A mixture of (R)-tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (0.800 g, 5.63 mmol), 1,6-dichlorophthalazine (0.516 g, 2.59 mmol) and N,N-diisopropylethylamine(1.40 mL, 8.04 mmol) in 3 mL 1-methyl-2-pyrolidone was heated at 140° C. After 4.5 h the reaction was cooled to RT, quenched with H2O and extracted with ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered, evaporated onto silica gel and purified by flash chromatography eluting with 2 M NH3 in MeOH/CH2Cl2 (0:1→1:39) to give 1.18 g of a brown liquid. MS m/z: 305.1 [M+1].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[CH2:8]([O:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: Clc1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(COc2ccccn2)cc1
Temperature: 110 °C
Yield: 22.7 %

Procedure:
2-Chloro-pyridine (5 g, 44 mmol) was added to a stirred solution of benzylalcohol (6.1 g, 57.2 mmol), KOH (2.9 g, 52.8 mmol) and 18 crown[6] (50 mg) in toluene (20 mL) and the resulting mixture was heated to reflux at 110° C. for 6 hours. The reaction mixture was then cooled to room temperature and concentrated. The residue was diluted with waster and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 1.85 g (22%) of 2-benzyloxy-pyridine.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=O.N1CCCN[C:8]1=[O:13].[O:14]=[C:15]1[C:20](=[O:21])[NH:19][CH2:18][CH2:17][NH:16]1>>[C:15](=[C:20]1[NH:1][CH2:5][CH2:4][NH:3][C:2]1=[C:8]=[O:13])=[O:14].[NH:19]1[CH2:18][CH2:17][NH:16][C:20]1=[O:21]
Reactant: O=C1NCCCN1
Reactant: O=C1NCCNC1=O
Agent: O=C1NCCN1
Product: O=C=C1NCCNC1=C=O

Procedure:
An analogous product is obtained when, instead of imidazolidin-2-one there is used either hexahydropyrimidin-2-one or 2,3-diketopiperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=S)[C:6]3([F:16])[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.[NH3:17]>>[NH2:17][C:7]1[C:6]2([F:16])[CH2:13][CH2:14][CH2:15][CH:5]2[C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: FC12CCCC1c1cc(Cl)ccc1NC2=S
Reactant: N
Product: NC1=Nc2ccc(Cl)cc2C2CCCC12F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
90 mg (0.35 mmol) of 8-chloro-3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione is dissolved in 20 ml of 7 M methanolic ammonia solution. After 2 hours of stirring at room temperature, the batch is concentrated by evaporation in a vacuum, and the residue is purified by column chromatography on silica gel with ethyl acetate: 73 mg of product, melting point 223° C.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C([Li])CCC.[N+:32]([C:35]1[CH:36]=[C:37]([C:41](OS(C(F)(F)F)(=O)=O)=[CH2:42])[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33]>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:32]([C:35]1[CH:36]=[C:37]([C:41]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH:19]=[CH:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)=[CH2:42])[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33]
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Reactant: C=C(OS(=O)(=O)C(F)(F)F)c1cccc([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1cccc([N+](=O)[O-])c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Temperature: 23 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a solution of 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole, prepared in Example 14, step (i), (330 mg, 0.693 mmol) in THF (3.0 mL) at −78° C. was added n-butyllithium (0.56 mL, 1.5 M, 1.2 equiv). After 20 min, this solution was then added to anhydrous zinc chloride (170 mg) and the mixture was warmed to 23° C. and stirred for 15 min. To this mixture was added 1-(3-nitro-phenyl)vinyltriflate (146 μL, 1.05 equiv) and Pd(PPh3)4 (40 mg, 0.05 equiv). This mixture was stirred for 30 min, was partitioned between ethyl acetate and saturated sodium bicarbonate and the organic layer was separated. The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (1:9 ethyl acetate-hexane) then a second column (1% ethyl acetate/benzene) gave 6-(1-(3-nitrophenyl)-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as an oil (180 mg, 52%): FTIR (thin film) 2951, 1616, 1530, 1477, 1448, 1348, 1305, 1248, 1217, 1077, 961, 913, 859 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.26 (t, 1H, J=1.9 Hz), 8.21 (m, 1H), 8.00 (d, 1H, J=8.5 Hz), 7.69 (dt, 1H, J=1.4, 7.8), 7.62-7.28 (m, 9H), 7.19 (dd, 1H, J=1.4, 8.4 Hz), 5.72 (s, 3H), 5.69 (s, 1H), 3.60 (t, 2H, J=8.2 Hz), 0.89 (t, 2H, J=8.2 Hz), 0.05 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 149.9, 149.6, 144.7, 144.5, 142.8, 140.7, 138.6, 135.6, 133.1, 130.7, 130.2, 129.4, 128.0, 124.4, 124.2, 124.1, 123.8, 122.6, 121.2, 118.9, 111.0, 79.2, 68.0, 19.2, 0.0; HRMS (FAB) [M+Na]/z Calc'd 520.2031, found 520.2046.
Reaction SMILES: [CH2:1]([N:3](CC1C=CC(OC)=CC=1)[C:4]1[CH:5]=[C:6]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[C:7]([F:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])[CH3:2]>CCO.[Pd]>[CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[C:7]([F:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])[CH3:2]
Reactant: CCN(Cc1ccc(OC)cc1)c1cc(C(=O)OC)c(F)c(N2CCCC2=O)c1
Agent: [Pd]
Solvent: CCO
Product: CCNc1cc(C(=O)OC)c(F)c(N2CCCC2=O)c1
Reaction time: 3 h
Yield: 97.9 %

Procedure:
To a solution of methyl 5-(ethyl{[4-(methyloxy)phenyl]methyl}amino)-2-fluoro-3-(2-oxo-1-pyrrolidinyl)benzoate (D155) (7 g, 17.5 mmol, 1 equiv) in EtOH (150 ml) was added 10% palladium on charcoal (50% wet, 1.4 g, 10% w/w) and the resulting mixture was stirred under an atmosphere of hydrogen (1 atm) for 3 h. The catalyst was filtered off through a pad of celite and the solution concentrated in vacuo. The residue was triturated with AcOEt/iso-hexane to give methyl 5-(ethylamino)-2-fluoro-3-(2-oxo-1-pyrrolidinyl)benzoate (B118) (4.8 g, 98%) as a pale greenish solid which was used in the next step without further purification. [M+H]+=281.2, RT=2.35 min.