Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[C:41]3=[N:42][CH:43]=[CH:44][C:45](I)=[C:40]3[CH:39]=[N:38]2)=[CH:33][CH:32]=1.C(N(CC)CC)C.[CH3:54][C:55]1([CH3:62])[C:59]([CH3:61])([CH3:60])[O:58][BH:57][O:56]1>CC#N.CC#N.Cl[Pd]Cl>[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[C:41]3=[N:42][CH:43]=[CH:44][C:45]([B:57]4[O:58][C:59]([CH3:61])([CH3:60])[C:55]([CH3:62])([CH3:54])[O:56]4)=[C:40]3[CH:39]=[N:38]2)=[CH:33][CH:32]=1
Reactant: Fc1ccc(-n2ncc3c(I)ccnc32)cc1
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccnc3c2cnn3-c2ccc(F)cc2)OC1(C)C
Temperature: 110 °C
Reaction time: 14 h

Procedure:
A vial was charged with bis(acetonitrile)palladium(II) chloride (1.038 mg, 4.00 μmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (3.28 mg, 8.00 μmol), and Intermediate 2A (0.068 g, 0.200 mmol). The vial was capped with a rubber septum and then evacuated and backfilled with N2 (this sequence was carried out a total of 2 times). Dioxane (0.120 mL) was added via syringe, through the septum, followed by the addition of triethylamine (0.084 mL, 0.600 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.044 mL, 0.300 mmol) dropwise. The septum was then replaced with a Teflon screw valve, and the vial sealed. The reaction mixture was heated at 110° C. After 14 h, the reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered through a disposable fritted funnel and the filter cake washed with CH2Cl2. The filtrate was concentrated to afford the title compound as a yellow solid. Intermediate 105B: MS (ESI): m/z=340.2 [M+H]+ HPLC Peak ret. T=2.00 minutes was product. (HPLC conditions: Column:Luna C18 4.6×30 mm 3 u A:10:90 H2O:ACN NH4OAc/B:10:90 H2O:ACN NH4OAc; 0%-95% B in 2 min; 4 mL/min flow).
Reaction SMILES: [NH2:1][CH:2]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24].[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]=O)[CH:45]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C([O-])(O)=O.[Na+].CCOC(C)=O>[Si:27]([O:26][CH2:25][CH:2]([NH:1][CH2:50][C:46]1[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=1)[CH2:3][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24])([C:40]([CH3:43])([CH3:42])[CH3:41])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=Cc1cccnc1
Reactant: COc1ccc2c(=O)n(CC(N)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(C#N)c(-c3ccccc3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc2c(=O)n(CC(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)NCc3cccnc3)c(C#N)c(-c3ccccc3)c2c1
Reaction time: 8 h

Procedure:
To a solution of amine 94 (51 mg, 0.075 mmol) in dichloroethane (2 mL) was added pyridine 3-carboxaldehyde (0.017 mL, 180 mmol). After stirring at RT for 15 min NaBH(OAc)3 (48 mg, 0.23 mmol) was added. After stirring overnight, added 1.2 equiv aldehyde and 1.5 equiv NaBH(OAc)3. After stirring for 5 h, the reaction mixture was diluted with NaHCO3/EtOAc and stirred for 10 min. It was then partitioned between EtOAc and NaHCO3. The organic phase was washed once with brine then dried (Na2SO4) and concentrated. The product was purified by automated flash chromatography (70-100% EtOAc/hexane).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8](S(C)(=O)=O)=[N:7][C:6]=1[NH2:14])=[O:4].CO.C1COCC1.[BH4-].[Na+]>O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[NH2:14])=[O:4]
Reactant: COC(=O)c1sc(S(C)(=O)=O)nc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)c1scnc1N
Reaction time: 40 h
Yield: 60.8 %

Procedure:
To a 1 l solution of 37.6 g of 4-amino-2-methanesulfonylthiazole-5-carboxylic acid methyl ester in a methanol:THF=1:1 mixed solvent at room temperature, there was gradually added 15 g of sodium borohydride over a period of 10 hours. Stirring was continued for 40 hours at room temperature, and then the reaction mixture was poured into a mixture of 6 l of ethyl acetate and 3 l of water. The organic layer was washed with 3 l of water and 3 l of brine, and the aqueous layer was extracted again with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane system) to obtain the target compound (15.3 g) as an off-white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][N:14]=[C:15]([C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1)[C:16]([OH:18])=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Si](CC(N)=O)(C)C.[NH2:33][CH:34]1[C:54](=[O:55])[N:36]2[C:37]([C:51]([OH:53])=[O:52])=[C:38]([CH2:41][S:42][C:43]3[N:47]([CH2:48][CH:49]=[CH2:50])[N:46]=[N:45][N:44]=3)[CH2:39][S:40][C@H:35]12>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[CH2:6]([O:13][N:14]=[C:15]([C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1)[C:16]([NH:33][CH:34]1[C:54](=[O:55])[N:36]2[C:37]([C:51]([OH:53])=[O:52])=[C:38]([CH2:41][S:42][C:43]3[N:47]([CH2:48][CH:49]=[CH2:50])[N:46]=[N:45][N:44]=3)[CH2:39][S:40][C@H:35]12)=[O:18])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1nc(C(=NOCc2ccccc2)C(=O)O)cs1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCc3ccccc3)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.25 h
Yield: 27.4 %

Procedure:
Phosphorus oxychloride (1.0 g) was added at a time to a suspension of 2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer)(1.4 g) in dry tetrahydrofuran (14 ml) at 2° C. and the mixture was stirred for 15 minutes at 2° to 4° C. Trimethylsilylacetamide (1.0 g) was added dropwise thereto and the resulting mixture was stirred for 20 minutes at 2° to 6° C. Phosphorus oxychloride (1.0 g) was added thereto and the mixture was stirred for 20 minutes. Dry dimethylformamide (0.5 g) was added thereto at a time at 4° to 6° C. and the mixture was stirred for 1 hour to give a clear solution. On the other hand, trimethylsilylacetamide (5.3 g) was added to a stirred suspension of 7-amino-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g) in dry ethyl acetate (27 ml) and the solution was stirred for 30 minutes at 40° C. To this solution was added the above-obtained tetrahydrofuran solution at a time at -30° C., and the resulting mixture was stirred for 1 hour at -5° to -20° C. To the reaction mixture was added water (30 ml) and ethyl acetate (20 ml). An organic layer was separated and extracted with an aqueous solution of sodium bicarbonate. The extract was adjusted to pH 3.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water to give 7-[2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3--cephem-4-carboxylic acid (syn isomer)(0.85 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=[CH:23][C:17]=4[N:16]4[CH:27]=[CH:28][CH:29]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2].[CH3:34][N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:36].F[P-](F)(F)(F)(F)F.Cl.CNC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[C:21]([C:24]([N:35]([CH3:36])[CH3:34])=[O:25])[CH:22]=[CH:23][C:17]=4[N:16]4[CH:27]=[CH:28][CH:29]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)O)ccc2-n2cccc23)cc1OC
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)N(C)C)ccc2-n2cccc23)cc1OC

Procedure:
A solution of 1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylic acid (40 mg, 0.09 mmol), HATU (34 mg, 0.090 mmol), N,N-dimethylamine hydrochloride (7.3 mg, 0.090 mmol) and iPr2NEt (62 μL, 0.36 mmol) in DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was filtered and purified by reverse phase LC-MS (10-99% CH3CN/H2O). Pure fractions were combined and evaporated to yield 1′-(4-ethyl-3-methoxybenzoyl)-N,N-dimethylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxamide. ESI-MS m/z calc. 473.6, found 474.5 (M+1)+; Retention time: 1.80 minutes (3 min run).
Reaction SMILES: CN1CC[N:5]([C:8](=[O:25])[CH2:9][C:10]2([CH3:24])[C:15]3=[C:16]([CH3:23])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[N:14]3[CH2:13][CH2:12][O:11]2)[CH2:4][CH2:3]1.CNC(=O)CC1(C)C2=C(C)C3C=CC=CC=3N2CCO1>>[CH3:24][C:10]1([CH2:9][C:8]([NH:5][CH2:4][CH3:3])=[O:25])[C:15]2=[C:16]([CH3:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[N:14]2[CH2:13][CH2:12][O:11]1
Reactant: Cc1c2n(c3ccccc13)CCOC2(C)CC(=O)N1CCN(C)CC1
Agent: CNC(=O)CC1(C)OCCn2c1c(C)c1ccccc12
Product: CCNC(=O)CC1(C)OCCn2c1c(C)c1ccccc12

Procedure:
By following the procedure of Example 284 but using as starting material an equivalent amount of one of the amide compounds of formula V, described in Examples 108 to 283 instead of N,1,10-trimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-acetamide, then the corresponding compounds of formula I are obtained. Examples of such compounds of formula I are listed as products in Tables VII and VIII together with the appropriate starting material. In each case the starting material is noted by the example in which it is prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].I[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:17]
Reactant: OCCc1ccccc1Cl
Reactant: CCOC(=O)CI
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)COCCc1ccccc1Cl

Procedure:
In analogy to the procedure described in example 78.1, 2-(2-chloro-phenyl)-ethanol was reacted with ethyl iodoacetate in the presence of silver trifluoromethanesulfonate and 2,6-di-tert-butylpyridin to give [2-(2-chloro-phenyl)-ethoxy]-acetic acid ethyl ester as yellow liquid. 1H NMR (CDCl3): 1.28 (t, J=7.3 Hz, 3H), 3.09 (t, J=7.1 Hz, 2H), 3.78 (t, J=7.1 Hz, 2H), 4.09 (s, 2H), 4.21 (q, J=7.3 Hz, 2H), 7.13-7.23 (m, 2H), 7.29-7.37 (m, 2H).
Reaction SMILES: [NH2:1]C1C=NC2C(C=1NCC(C)(O)C)=CC=C(OCC1C=CC=CC=1)C=2.C(OCC)(OCC)OCC.C(OC)(OC)(OC)CCC.[CH2:46]([O:53][C:54]1[CH:55]=[CH:56][C:57]2[C:58]3[N:66]([CH2:67][C:68]([CH3:71])([OH:70])[CH3:69])[CH:65]=[N:64][C:59]=3[CH:60]=[N:61][C:62]=2[CH:63]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[NH2:1][C:60]1[C:59]2[N:64]=[CH:65][N:66]([CH2:67][C:68]([CH3:71])([OH:70])[CH3:69])[C:58]=2[C:57]2[CH:56]=[CH:55][C:54]([O:53][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[CH:63][C:62]=2[N:61]=1
Reactant: CC(C)(O)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: CC(C)(O)Cn1cnc2cnc3cc(OCc4ccccc4)ccc3c21
Agent: CCCC(OC)(OC)OC
Solvent: CCOC(OCC)OCC
Product: CC(C)(O)Cn1cnc2c(N)nc3cc(OCc4ccccc4)ccc3c21

Procedure:
1-{[3-Amino-7-(benzyloxy)quinolin-4-yl]amino}-2-methylpropan-2-ol, prepared as described in Parts A and B of Example 54, was treated according to the general method of Part G of Example 1 with triethyl orthoformate used in lieu of trimethyl orthobutyrate. The product, (7-benzyloxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol, was treated according to the general methods of Parts H and I of Example 1 to provide (4-amino-7-benzyloxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white powder, mp 254-257° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[O-]CC.[Na+]>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ncccn1
Reactant: NCCCN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCCNc1ncccn1

Procedure:
Reaction of 2-bromopyrimidine with 1,3-diaminopropane in ethanol containing sodium ethoxide gives 2-(3-aminopropylamino)pyrimidine which on reaction with methyl isothiocyanate results in the production of N-methyl-N'-[3-(2-pyrimidylamino)propyl]thiourea.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][CH2:6][CH2:7][N:8]1[C:25](=[N:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=2[CH:36]([CH3:38])[CH3:37])[CH:24]=[C:11]2[C:12]3[C:17]([CH2:18][CH2:19][N:10]2[C:9]1=[O:39])=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3.[OH-].[Na+]>O.Cl>[C:2]([NH:5][CH2:6][CH2:7][N:8]1[C:25](=[N:26][C:27]2[C:28]([CH:36]([CH3:37])[CH3:38])=[CH:29][CH:30]=[CH:31][C:32]=2[CH:33]([CH3:35])[CH3:34])[CH:24]=[C:11]2[C:12]3[C:17]([CH2:18][CH2:19][N:10]2[C:9]1=[O:39])=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)(=[O:1])[NH2:3]
Reactant: N#C[O-]
Reactant: COc1cc2c(cc1OC)-c1cc(=Nc3c(C(C)C)cccc3C(C)C)n(CCN)c(=O)n1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3c(C(C)C)cccc3C(C)C)n(CCNC(N)=O)c(=O)n1CC2
Temperature: 80 °C
Reaction time: 4 h
Yield: 17.2 %

Procedure:
Sodium cyanate (0.87 g, 13.4 mmol) in water (20 ml) was added dropwise to a stirred solution of amine 3 (3.2 g, 6.7 mmol) in water (100 ml) and 1M HCl (13.4 ml) at 80° C. After stirring for 4 h at 80° C. the mixture was cooled and basified with 2M NaOH. The mixture was extracted with CH2Cl2 until no more product remained in the organic phase. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography [dichloromethane/methanol (97:3)] and the isolated product taken up in a mixture of dichloromethane and ether which on concentration afforded the title compound (0.6 g, 17%) as a pale yellow foam.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].Cl.[O:10]1[CH2:14][CH:13]([OH:15])[CH2:12][NH:11]1>CN(C=O)C>[C:1]([Si:5]([CH3:8])([CH3:7])[O:15][CH:13]1[CH2:14][O:10][NH:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CNOC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CNOC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.9 %

Procedure:
tert-Butyl-dimethyl-chlorosilane (0.5 g, 3.21 mmol) was added to a stirred solution of isoxazolidin-4-ol hydrochloride (0.40 g, 3.18 mmol) in DMF (3 mL). The mixture was left to stir at ambient temperature for 2.5 hours before the solvent was evaporated and the resultant residue partitioned between ethyl acetate (50 mL) and water (20 mL). The organic phase was separated and washed with water (3×20 mL) then brine (20 mL), dried (MgSO4), filtered and evaporated to provide the desired product as a colourless oil (0.62 g, 96%). 1H NMR (CDCl3, 400 MHz) 5.52 (s, 1H), 4.60-4.65 (m, 1H), 3.45-3.62 (m, 1H), 3.80-4.05 (m, 1H), 2.80-3.05 (m, 2H), 0.80 (s, 9H), 0.08 (s, 6H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].F[C:33](F)(F)C(O)=O.C(N(CC)CC)C.C(OC(OC(CC)(C)C)=O)(OC(CC)(C)C)=O>ClCCl.O1CCCC1.O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH2:29][CH3:33])=[O:24])[CH2:21][CH2:22]3)=[CH:13][N:12]=2)=[CH:30][CH:31]=1)(=[O:3])=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(S(C)(=O)=O)cc3)nc2)CC1
Agent: CCC(C)(C)OC(=O)OC(=O)OC(C)(C)CC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of tert-butyl 4-[2-(4-methanesulfonyl-phenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 1) (30 mg, 0.067 mmol) in dry dichloromethane (0.35 mL) under N2 was added trifluoroacetic acid (0.35 mL). The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. To a solution of the residue in dry tetrahydrofuran (0.7 mL) was added triethylamine (28 μL, 0.2 mmol) and di-tert-amyl dicarbonate (25 μL, 0.1 mmol). The mixture was stirred at room temperature for 3 hours, diluted with water (1 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound as a white crystal (28 mg, yield 91%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:13])[O:11][CH:12]=2)=[C:4]([F:14])[CH:3]=1.[C:15]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)(=[O:22])=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[NH2:13][C:10]1[O:11][CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[C:23]([S:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:21])=[O:22])=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:3][C:4]=2[F:14])[N:9]=1
Reactant: Nc1nc(-c2ccc(Br)cc2F)co1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2coc(N)n2)c(F)c1

Procedure:
The title compound was prepared using methods described in Example 427 using 4-(4-bromo-2-fluorophenyl)oxazol-2-amine and (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd. for C19H20FN3O3S, 389.12; m/z found, 390.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, J=7.9, 1.4, 1H), 7.98 (m, 1H), 7.66 (d, J=4.2, 1H), 7.57 (m, 1H), 7.54-7.48 (m, 1H), 7.38-7.30 (m, 3H), 4.63 (s, 2H), 3.64 (s, 1H), 1.03 (s, 9H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[F:15][C@H:16]1[C@H:21]([OH:22])[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17]1.CC([O-])(C)C.[K+]>C1COCC1>[F:15][C@H:16]1[C@H:21]([O:22][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](F)C1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)[C@H](F)C1
Temperature: 0 °C
Yield: 72 %

Procedure:
A mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (2.1 g, 1.0 eq, 10.1 mmol) and tert-butyl (3R,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (2.1 g, 1.0 eq, 9.6 mmol) (see, e.g., WO 2012/016217) was taken in annhydrous THF (50 mL) and stirred at 0° C. KOtBu (1.9 g, 1.8 eq, 17.3 mmol) was added to the above solution at 0° C. and the heterogeneous mixture was warmed to room temperature. Then the reaction mixture was refluxed overnight. After completion of the reaction, the mixture was concentrated under reduced pressure. EtOAc (100 mL) was added to the crude mixture and partioned with aqueous saturated NaHCO3 (50 mL) solution. The layers were separated and the organic layer was washed with aqueous saturated NaHCO3 (50 mL) solution and brine (1×50 mL). The organic layers were dried over Na2SO4 and concentrated to leave a crude solid. Purification of the crude mixture by column chromatography on silica gel (ISCO System) using EtOAc/hexane (gradient system from 0:1 to 3:7) as eluent gave the product in 72% yield.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][C:16](O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:19][C@H:20]([C:25]([OH:27])=[O:26])[C:21]([CH3:24])([CH3:23])[CH3:22]>S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>[CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][C:16]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: O=C(O)CCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CC(C)(C)[C@H](NC(=O)CCC1c2ccccc2-c2ccccc21)C(=O)O

Procedure:
A solution of 3-(fluoren-9-yl)propionic acid (2.4 g, 10 mmol) in thionyl chloride was refluxed for two hours. The reaction mixture was cooled down and the solvent was removed in vacuum. A solution of the resulting 3-(fluoren-9-yl)propionic acid chloride was dissolved in dioxane (20 mL) and added into a solution of L-tert-leucine (4 g, 30.5 mmol) in 10% aqueous sodium carbonate (40 mL). The reaction mixture was monitored by quenching an aliquot with methanol than monitor the resulting methyl ester by TLC (10% MeOH in chloroform). After an 1.5 hr water was added and most of the dioxane was removed in vacuum. The aqueous layer was washed with diethyl ether (×3) then was acidified to pH 1 with 10% HCl. The resulting precipitate was purified by a short path chromatography (silica, 5% MeOH in chloroform) to yield 1.5 g (42.1%), mp 79°-83° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=1)[C:12]#[N:13].[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.Cl>O1CCCC1>[C:12]([C:11]1[CH:14]=[C:7]([B:16]([OH:21])[OH:17])[CH:8]=[CH:9][C:10]=1[CH3:15])#[N:13]
Reactant: Cc1ccc(Br)cc1C#N
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)cc1C#N
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
17.5 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 5 g of 5-bromo-2-methylbenzonitrile in 80 ml of dry tetrahydrofuran at −78° C. After stirring at this temperature for 35 minutes, 7.3 ml of triisopropyl borate are added. After one hour, 50 ml of 1N HCl are added to the reaction mixture at −78° C., and the mixture is warmed to room temperature. The phases are separated and the aqueous phase is extracted three more times with 100 ml of diethyl ether each time. The combined organic phases are dried with sodium sulphate, and the solvent is concentrated to 5 ml. The residue is mixed with 150 ml of pentane. The precipitate which has separated out is filtered off with suction and washed twice with pentane. Drying under high vacuum results in 2.85 g of the title compond as a pale yellow solid. Rt=2.98.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[N:14]=[C:15]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[N:30]=[N:31][NH:32][N:33]=5)[CH:24]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:5][CH:4]=1.CI.[C:36]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]3[N:14]=[C:15]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[N:30]=[N:31][N:32]([CH3:36])[N:33]=5)[CH:24]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Nc4cccc(-c5nn[nH]n5)c4)nn23)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnc3c4ccccc4c(Nc4cccc(-c5nnn(C)n5)c4)nn23)cc1
Temperature: 25 °C
Yield: 20.5 %

Procedure:
To a suspension of [3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-[3-(2H-tetrazol-5-yl)-phenyl]-amine (compound T3) (111 mg, 0.25 mmol) in a mixture of DMF/acetone 1:1 (8 mL) are added methyl iodide (79 μg, 1.25 mmol) and K2CO3 (53 mg, 0.37 mmol). The mixture is stirred at room temperature over night. The reaction mixture is concentrated and water is added. The resulting precipitate is filtered and washed with methanol to yield 23 mg of the title compound as white powder.